Dementia

Molecular Pathways and Treatment Updates on Huntington’s Disease with Special Preference to Juvenile Phase: A Comprehensive Review

A degenerative brain ailment called Huntington's disease (HTD) causes irritable behavior, emotional distress, cognition, etc. It is also known as Huntington's chorea. Compared to men, women are more likely to get HTD. However, in India, if 3 to 5% of Europeans are affected, it is difficult to estimate the disease's prevalence. The full pathophysiological status, several molecular pathways, and pharmaceutical and non-pharmacological treatments for Huntington's disease are covered in this article. Google, PubMed, Scopus, Bentham, Elsevier, and other significant web resources were used to gather the scientific data. Moreover, this review article may serve as the foundation for future study, particularly on Huntington's illness.

“A Comprehensive Review of Anaemia Associated with Hypothyroidism”

Background: Thyroid hormones play a crucial role in erythropoiesis, both directly and indirectly, with reduced secretion potentially causing anaemia—a commonly overlooked symptom of hypothyroidism. By compiling existing data, discussing recent advancements, identifying root causes, and proposing potential treatment options, this work acknowledges the complexity of the issue and aims to serve as a foundational reference for those in the early stages of research or clinical practice.

Methods: To comprehend the concept of this disease condition, a number of medical textbooks were consulted. Various search engines, such as PubMed, Google Scholar, Research Gate, Science Direct, Scopus, etc., were cited to explore the recent advancements and obtain data on the topic in question. Later, all the information and data gathered were organised into a review article.

Conclusion: Anemia, often referred to as the “haematological mask” of hypothyroidism, can manifest even before hypothyroidism is clinically diagnosed. Hypothyroidism must be considered as a potential cause when confronted with refractory anemia, as its treatment is pivotal for achieving comprehensive and lasting improvements in haematological parameters.

Physalin B Reduces Tau Phosphorylation and Cell Apoptosis in HEK293 Cells by Activating FoxO1

Background: Physalin B (PB) is one of the main active compounds of Solanaceae plants, with a wide range of biological activities. PB reportedly has the potential to treat Alzheimer’s disease (AD).

Objective: In this study, we investigated the effect of PB on Tau phosphorylation and cell apoptosis using Tau-expressing HEK293 cells (HEK293/Tau) as a cellular model.

Methods: The optimum concentration of PB to treat HEK293/Tau cells was determined using the CCK-8 assay. Additionally, the expression of FoxO1, Tau-5, p-Tau (T231, S262, and S404), ERK, p-ERK, GSK-3β, and p-GSK-3β was detected using western blotting to determine the effect of PB on Tau phosphorylation. The apoptosis rate was detected using flow cytometry, and the expression of Bax and Bcl-2 was detected using western blotting and verified using real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, cells were transfected with FoxO1 siRNA to downregulate FoxO1 expression, and the expression of the above-mentioned proteins was detected to verify the effect of PB on Tau phosphorylation and cell apoptosis.

Results: After 24 h of PB treatment, the phosphorylation levels of Tau at S404, S262, and T231 sites decreased significantly, and the activities of GSK-3β and ERK were inhibited. PB also reduced cell apoptosis by reducing the expression of Bax and increasing the expression of Bcl-2. In addition, PB decreased Tau phosphorylation and cell apoptosis by upregulating FoxO1.

Conclusion: The natural compound PB exhibited a protective effect in the AD cell model by increasing FoxO1 expression and reducing Tau phosphorylation and cell apoptosis.

Targeting Cellular Senescence: A Potential Therapeutic approach for Alzheimer’s Disease

Although Amyloid beta plaque and neurofibrillary tangles are considered the two main hallmarks of Alzheimer’s disease (AD), the mechanism by which they contribute is not clearly understood. Cellular senescence (CS) has been demonstrated to be a key characteristic of AD. Recent research suggests that persistent buildup of senescent cells over time results in protracted activation of inflammatory stress as an organism ages because of the accumulation of irreversible DNA damage and oxidative stress as well as the deterioration of immune system function. Studies on both humans and animals have shown evidence that CS is a crucial factor in AD. The brains of AD patients have been found to have senescent glial cells and neurons, and removal of these senescent cells results in a decrease in Amyloid beta plaque and Neurofibrillary tangles, along with improved cognitive functions. This review summarises recent results and the mechanism by which CS contributes to the development of AD, and how the elimination of senescent cells may be a therapeutic target in the management of AD.

Apelin Receptor Dimerization and Oligomerization

Apelin and its receptor are expressed in many tissues and play an important role in maintaining the homeostasis of the cardiovascular system and body fluids. Also, the association of this system with many diseases, such as diabetes, hypertension, obesity, cancer, diabetic retinopathy, etc., has been determined. This system is considered a therapeutic goal in many mentioned diseases. G protein-coupled receptors (GPCRs) have the ability to form oligomers and dimers with themselves and other receptors. The formation of these oligomers is associated with a change in the signaling pathways of the receptors. Research on the oligo and dimers of these receptors can revolutionize the principles of pharmacology. The apelin receptor (APJ) is also a GPCR and has been shown to have the ability to form dimers and oligomers. This article discusses the dimerization and oligomerization of this receptor with its own receptor and other receptors, as well as the signaling pathways.

Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease

Background: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition.

Aims: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer’s disease.

Methods: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer’s disease through the published article from Pubmed and Scopus.

Description: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by β-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article.

Conclusion: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer’s disease.

All-trans Retinoic Acid Increased Transglutaminase 2 Expressions in BV-2 Cells and Cultured Astrocytes

Background: Activation of microglia and astrocytes has been observed in Alzheimer’s disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.

Objective: We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.

Methods: After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.

Results: In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.

Conclusion: These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.

Differential Kat3 Coactivator Usage Regulates Brain Metabolism and Neuronal Differentiation

Introduction: Our previous work has demonstrated significant effects on the oxidative stress response, mitochondrial function, and oxidative phosphorylation in the livers and intestines of p300 S89A knockin (S89AKI) mice. We now show that this mutation is also associated with brain metabolic defects and neuronal differentiation.

Methods: p300 S89A edited P19 cells, and S89AKI mice demonstrated metabolic and neuronal differentiation defects based on proteomic, cell biological and PET imaging studies.

Results: The metabolic and differentiation defects associated with the p300 S89A knockin mutation could be corrected both in vitro and in vivo utilizing the small molecule CBP/beta-catenin antagonist ICG-001.

Conclusion: Rebalancing the equilibrium between CBP/β-catenin versus p300/β-catenin associated transcription, utilizing the small molecule CBP/beta-catenin antagonist ICG-001, enhances mitochondrial oxidative phosphorylation, metabolic function, and neuronal differentiation and may be able to ameliorate the cognitive decline seen in neurodegenerative disorders, including Alzheimer’s Disease.

Evaluation of Neuroprotective effect of Cassia occidentalis L. against Colchicine Induced Memory Impairment in Wistar Rats

Background: Alzheimer’s disease (AD) is a progressive neurological disorder that develops with aging.

Objective: In this research, we have examined the anti - Alzheimer’s effect of ethanolic extract from roots of Cassia occidentalis L. on colchicine-induced Alzheimer’s in Wistar rats.

Methods: Ethanolic extract was obtained and spectroscopic, chromatography analysis was performed. Acute toxicity studies using Organization of Economic Co-operation and Development (OECD) Guidelines 423 were performed to examine and make sure that there were no signs of toxic effects. The induction of AD was done using colchicine which leads to symptoms like neurotoxicity, neuroinflammation, and neurodegeneration. In this experiment, a thorough analysis of body weight, behavioral parameters, locomotor activity, and biochemical evaluation was performed to estimate the medicinal properties of Cassia occidentalis L in treating Alzheimer’s disease.

Results: Pharmacognostic analysis showed the presence of vascular bundles, starch grains, fibers, calcium oxalate crystals, elongated parenchyma, and collenchyma mucilage as shown in the supplementary files. Locomotor activity, Escape latency time, Conditioned avoidance response, and Transfer latency were improved with treatment. Interleukin- 6 (IL - 6) levels were reduced significantly in the Colchicine + 200 Cassia mg/kg group (739.2 ± 0.37 pg/ml) than in the Colchicine Group (850.6 ± 0.40 pg/ml). Tumor necrosis factor (TNF-α) was decreased in the Colchicine + 200 Cassia mg/kg Group (1030.93 ± 0.51 pg/ml) than in the Colchicine Group (1455.06 ± 1.25 pg/ml). A significant decrease in total protein level was observed in the Colchicine Group (2.52 ± 0.10 mg/ml), (3.33 ± 0.90 mg/ml) as compared to Colchicine + 200 Cassia mg/kg Group (5.27 ± 0.09 mg/ml, (5.01 ± 0.10 mg/ml) respectively, in the Hippocampus and Entorhinal cortex. The levels of antioxidant enzymes such as Catalase (CAT), Serum superoxide dismutase (SOD), Reduced glutathione (GSH) and Malondialdehyde (MDA) were measured. When compared to the Colchicine Group (7.33 ± 0.16 nM/ mg, the MDA level was lower in the Colchicine + 100 Cassia mg/kg Group (3.20 ± 0.01 nM/ mg). The level of CAT in Colchicine + 200 Cassia mg/kg Group (7.01 ± 0.03 μmoles of H₂O₂/mg of protein) was seen to be increased when compared to Colchicine Group (3.32 ± 0.17 μmoles of H₂O₂/mg of protein). The level of SOD in Colchicine + 200 Cassia mg/kg Group (7.43 ± 0.02 U mg -1 of protein) was seen to be increased when compared with Colchicine Group (4.55 ± 0.03 U mg -1 of protein). The level of GSH in Colchicine + 200 Cassia mg/kg Group (10.07 ± 0.19 nM/mg -1 of protein) was increased when compared with the Colchicine Group (5.82 ± 0.11nM/mg -1 of protein). Histopathology of the Hippocampus and Entorhinal cortex showed diminished amyloid plaques, and neurodegeneration in the treatment groups.

Conclusion: The present study showed that ethanolic extract from the roots of Cassia occidentalis L. At 100 and 200 mg/kg doses in Wistar rats improved memory damage, by reducing oxidative stress. Levels of the antioxidant enzymes as CAT, and SOD, GSH were increased and MDA was decreased. The cytokine levels in the serum of Wistar rats of IL-6 level and TNF-α level were reduced significantly. Estimation of total protein level was found to be increased. It restored neuronal degeneration in the Hippocampus, and Entorhinal cortex and reduced oxidative stress. This suggests that the ethanolic extract of Cassia occidentalis L. could be an effective therapeutic treatment for neurodegenerative diseases like AD.

The Neurochemical Anatomy of Runway Acquisition and Extinction

A review is presented as to the neurochemical basis of the straight runway task, usually consisting of an acquisition phase followed by an extinction phase. During the acquisition of the appetitive runway task, running speeds from the start box to the goal box progressively increase over trials and then decrease when the reward is withheld. Runway extinction is susceptible to lesions of the limbic system, including the medial frontal cortex, the hippocampus, the septum, the amygdala, and the dorsomedial thalamus. When specific neurotransmitter systems are examined, extinction was delayed when noradrenaline transmission was impeded, perhaps involving noradrenergic projections to the hippocampus and neocortex. Extinction was likewise delayed after either facilitation or blocking of dopamine transmission, a result implicating an inverted U-shaped function caused by dopamine’s role in behavioral activation or reward processes. Extinction was also delayed by indirect GABA_A receptor agonists injected during acquisition, explained by druginduced disinhibitory tendencies. This simple paradigm may provide information about the effects of a physiological manipulation on both cognition and emotion.

In-silico Design, ADMET Screening, Prime MM-GBSA Binding Free Energy Calculation and MD Simulation of Some Novel Phenothiazines as 5HT₆R Antagonists Targeting Alzheimer’s Disease

Background: Alzheimer's disease is a type of dementia that affects neuronal function, leading to a decline in cognitive functions. Serotonin-6 (5HT₆) receptors are implicated in the etiology of neurological diseases. 5HT₆ receptor antagonists act as anti-dementia agents. PDB ID: 7YS6 represents a membrane protein, and amplification and overexpression of this protein are associated with Alzheimer's disease. Coumarin-fused phenothiazines are significant anti-Alzheimer's agents due to their inhibitory activity on the Serotonin- 6 receptor.

Objectives: Numerous previously unreported Coumarin-substituted Phenothiazines [A2 to A50] were designed using In-silico methods to evaluate their 5HT₆ receptor antagonistic activity. Molecular modeling techniques were employed to study the ligands [A2 to A50] in interaction with the Serotonin-6 receptor (PDB ID: 7YS6) using Schrödinger Suite 2019-4.

Methods: Molecular modeling studies of the designed ligands [A2 to A50] were conducted using the Glide module. In-silico ADMET screening was performed using the QikProp module, and binding free energy calculations were carried out using the Prime MM-GBSA module within the Schrödinger Suite. The binding affinity of the designed ligands [A2 to A50] towards 5HT₆ receptors was determined based on Glide scores. Subsequently, ligand A31 underwent a 100 ns molecular dynamics simulation using the Desmond module of Schrödinger Suite 2020-1, which is based in New York, NY.

Results: The majority of the designed ligands exhibited strong hydrogen bonding interactions and hydrophobic associations with the serotonin-6 receptor, which hinder its activity. These ligands achieved remarkable Glide scores within the range of -4.2859 to -7.7128, in comparison to reference standards such as Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853), and the co-crystallized ligand (-7.02889). In-silico ADMET properties for these ligands fell within the recommended values for drug-likeness. It is worth noting that the MMGBSA binding free energy of the most potent inhibitor was positive, indicating a strong binding interaction. Additionally, the dynamic behavior of the protein (7YS6)-ligand (A31) complex was studied by subjecting ligand A31 to a 100 ns molecular dynamics simulation.

Conclusion: The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential.

Application of Deep Learning in the Diagnosis of Alzheimer’s and Parkinson’s Disease: A Review

Most neurodegenerative diseases such as Alzheimer's and Parkinson's are life-threatening, critical, and incurable affecting mainly the elderly population. Early diagnosis is challenging as disease phenotype is very crucial for predicting, preventing the progression, and effective drug discovery. In the last few years, Deep learning (DL) based neural networks are the state-of-the-art models deployed in industries and academics across different areas like natural language processing, image analysis, speech recognition, audio classification, and many more It has been slowly realized that they have a high potential in medical image analysis and diagnostics and medical management in general. As this field is vast and expanding rapidly, we have put focused on existing DL-based models to detect Alzheimer’s and Parkinson's in particular. This study gives a summary of related medical examinations for these diseases. Frameworks and applications of many deep learning models have been discussed. We have given precise notes on pre-processing techniques used by various studies for MRI image analysis. An overview of the application of DLbased models in different stages of medical image analysis has been conferred. It has been realized from the review that more studies are focused on Alzheimer's compared to Parkinson's disease Additionally, we have tabulated the various public datasets available for these diseases. We have highlighted the potential use of a novel biomarker for the early diagnosis of these disorders. Also, some challenges and issues in implementing deep learning techniques for the detection of these diseases have been addressed. Finally, We concluded with some future research directions regarding deep learning techniques for diagnosis of the above diseases.

An Early Detection and Classification of Alzheimer's Disease Framework Based on ResNet-50

Objective: The objective of this study is to develop a more effective early detection system for Alzheimer's disease (AD) using a Deep Residual Network (ResNet) model by addressing the issue of convolutional layers in conventional Convolutional Neural Networks (CNN) and applying image preprocessing techniques.

Methods: The proposed method involves using Contrast Limited Adaptive Histogram Equalizer (CLAHE) and Boosted Anisotropic Diffusion Filters (BADF) for equalization and noise removal and K-means clustering for segmentation. A ResNet-50 model with shortcut links between three residual layers is proposed to extract features more efficiently. ResNet-50 is preferred over other ResNet types due to its intermediate depth, striking a balance between computational efficiency and improved performance, making it a widely adopted and effective architecture for various computer vision tasks. While other ResNet variations may offer higher depths, they are more prone to overfitting and computational complexity, which can hinder their practical application. The proposed method is evaluated on a dataset of MRI scans of AD patients.

Results: The proposed method achieved high accuracy and minimum losses of 95% and 0.12, respectively. While some models showed better accuracy, they were prone to overfitting. In contrast, the suggested framework, based on the ResNet-50 model, demonstrated superior performance in terms of various performance metrics, providing a robust and reliable approach to Alzheimer's disease categorization.

Conclusion: The proposed ResNet-50 model with shortcut links between three residual layers, combined with image preprocessing techniques, provides an effective early detection system for AD. The study demonstrates the potential of deep learning and image processing techniques in developing accurate and efficient diagnostic tools for AD. The proposed method improves the existing approaches to AD classification and provides a promising framework for future research in this area.

Ultrasonographically Measured Rectus Femoris Cross-sectional Area might Predict Osteosarcopenia

Aim: We have aimed to investigate the role of ultrasonographic muscle parameters (UMP) in predicting osteosarcopenia in bedridden patients in a palliative care center.

Background: The role of ultrasound has not been evaluated in predicting osteosarcopenia.

Objective: Reduced muscle thickness (MT) and cross-sectional area (CSA) have often been observed in individuals with sarcopenia, reflecting muscle loss and atrophy. Meanwhile, the potential role of muscle ultrasound has not been evaluated in predicting osteosarcopenia.

Methods: We have conducted a prospective, observational study between January 2021 and 2022. We have recorded the demographics, comorbidities, and nutritional status by using the mini nutritional assessment-short form. We measured handgrip strength with a hand dynamometer and the muscle mass with dual X-ray absorptiometry. Sarcopenia was defined by the European Working Group on Sarcopenia in Older People 2 criteria. Osteoporosis was diagnosed according to the World Health Organization criteria. We have categorized the body phenotypes into four groups: “non-sarcopenic non-osteoporotic,” “sarcopenic alone,” “osteoporotic alone,” and “sarcopenic osteoporotic.” We have measured the subcutaneous fat thickness (SFT), MT, and CSA of the rectus femoris (RF) and biceps brachii (BB) via ultrasonography. A multivariate regression analysis was performed and area under curve (AUC) values were used to evaluate the accuracy of UMPs.

Results: We included 31 patients (mean age: 74.6±12.1 years, 54.8%: male). The prevalences of sarcopenia, osteoporosis, and sarcopenic osteoporosis were 71%, 48.4%, and 41.9%, respectively. Only the “sarcopenic osteoporotic” phenotype was negatively correlated with all UMPs. In the regression analysis, only the “sarcopenic osteoporotic” phenotype was independently associated with RFCSA (ß=-0.456, p= 0.024). The AUC for all patients was >0.700.

Conclusion: RFCSA measurement might be useful in the screening for osteosarcopenia. This has been the first study investigating the relationship between UMPs and body phenotypes. Multi-center and large-scale studies are, however, needed.

Cost-effectiveness of Dementia Medication

Aim: This review has examined and organized the available research on dementia medication care costs. Although the accessible database in this area is growing and is still quite limited, there are many clear scientific methods.

Objective: The use of Memantine, a non-competitive antagonist with low to moderate affinity for the NMDA (N-methyl-D-aspartate) receptor, has been approved for the treatment of mild to moderately severe Alzheimer's disease (AD). The efficacy of cholinesterase inhibitors (ChEIs) in the treatment of dementia varies depending on the drug type and ease of administration. Numerous techniques have been employed to evaluate the quality of life (QOL) of individuals suffering from dementia. QOL data is a well-established measure of an intervention's effectiveness. Up to now, cost-effectiveness studies have concentrated on both pharmaceutical and non-pharmacological therapy. Each unit of QoL-AD improvement costs USD27.82578 at mean values.

Methods: Searches were conducted to observe studies of the pharmacoeconomic impact of dementia medications with the help of previous articles published in journals and collected from Google Scholar with name search dementia or Alzheimer's cross-referenced with pharmacoeconomic or costs and effectiveness.

Advances in Imaging Techniques of the Blood-brain Barrier and Clinical Application

The blood-brain barrier (BBB) is an important structure that maintains the normal function of the central nervous system (CNS). The functional structure of BBB is closely related to diseases of CNS, including degenerative diseases, brain tumours, traumatic brain injury, stroke, etc. Imaging methods were commonly used to monitor the integrity of BBB, such as DCE-MRI, DSC-MRI, and PET, this contributes to understand the process of related diseases and develop appropriate treatment options. In recent years, many studies had shown that the MRI methods (ASL, IVIM, CEST, etc.) could evaluate blood-brain barrier function, which use endogenous contrast agents and become an increasingly great concern. Another image methods (FUS, uWB-eMPs) can open up the normal BBB, allowing macromolecular drugs across the locally opening BBB, which could be beneficial to the treatment of some brain diseases. In this review, we briefly introduce the theory of BBB imaging modalities and its clinical application.

Secondary Degeneration of White Matter Tract following Basal Ganglia Infarction: A Longitudinal Diffusion Tensor Imaging Study

Introduction: We explored the relationship between secondary degeneration of white matter (WM) tracts and motor outcomes after left basal ganglia infarction and investigated alterations in the diffusion indices of WM tracts in distal areas.

Methods: Clinical neurological evaluations were accomplished using the Fugl–Meyer scale (FMS). Then, the fractional anisotropy (FA) of the bilateral superior corona radiata (SCR), cerebral peduncle (CP), corticospinal tracts (CST), and corpus callosum (CC) were measured in all patients and control subjects.

Results: Regional-based analysis revealed decreased FA values in the ipsilesional SCR, CP, and CST of the patients, compared to the control subjects at 5- time points. The relative FA (rFA) values of the SCR, CP, and CST decreased progressively with time, the lowest values recorded at 90 days before increasing slightly at 180 days after stroke. Compared to the contralateral areas, the FA values of the ipsilesional SCR and CST areas were significantly decreased (P=0.023), while those of the CP decreased at 180 days (P=0.008). Compared with the values at 7 days, the rFA values of the ipsilesional SCR and CP areas were significantly reduced at 14, 30, and 90 days, while those in the CST area were significantly reduced at 14, 90, and 180 days. The CP rFA value at 7 days correlated positively with the FM scores at 180 days (r=0.469, P=0.037).

Conclusion: This study provides an objective, comprehensive, and automated protocol for detecting secondary degeneration of WM, which is important in understanding rehabilitation mechanisms after stroke.

Quantification of Iron Deposition in the Brain of Hypertensive Patients using 3D-enhanced Susceptibility-weighted Angiography (ESWAN)

Background: Cerebral microbleeds (CMBs) are commonly present in patients with hypertension, producing iron-containing metabolites. A small amount of regional iron deposition is hardly discernible on conventional magnetic resonance imaging (MRI). Three-dimensional enhanced susceptibilityweighted angiography (ESWAN) provides tissue images with high spatial resolution and signal-noise ratio, and has been widely used to measure brain iron deposition in neurodegenerative diseases and intracranial hemorrhage.

Objective: The study aimed to demonstrate iron deposition in the brain of hypertensive patients using ESWAN.

Methods: Twenty-seven hypertension patients, with or without CMBs, and 16 matched healthy controls (HCs) were enrolled. From the post-processed ESWAN images, phase and magnitude values of the regions of interest (ROIs) were calculated. Two-sample t-test and one-way variance analysis were applied to compare groups. The relationship between ESWAN parameters and clinical variables was assessed using Pearson’s correlation coefficient.

Results: Compared to HCs, the phase value of the hippocampus, head of caudate nucleus (HCN), and substantia nigra (SN) was decreased in hypertension with the CMBs subgroup, while that of HCN and SN was decreased in hypertension without CMBs subgroup. Similarly, the magnitude value of the hippocampus, HCN, thalamus red nucleus, and SN was significantly lower in the hypertension group than HCs. In addition, the phase and magnitude values showed a correlation with clinical variables, including disease duration and blood pressure.

Conclusion: Deep grey matter nuclei displayed greater iron content in hypertension patients. Iron deposition may precede the appearance of CMBs on MRI, serving as a potential marker of microvascular damage.

A Multimodal Ultrasound Observation Study on the Effect of Vitamin D on Uterine Fibroids in Non-menopausal Women

Introduction: It has been reported in the literature that Vitamin D can inhibit the growth of uterine fibroids, but the evaluation index is only the size of the uterine fibroids. The purpose of this study was to evaluate the effect of vitamin D on the size, hardness, and blood flow of uterine fibroids in premenopausal women by multimodal ultrasound.

Methods: A total of 64 pre-menopausal women with uterine fibroids complicated vitamin D deficiency were enrolled in this study and randomly divided into two groups: the vitamin D group (n=32) which received oral vitamin D (1600 IU/ day) and the control group (n=32) without vitamin D supplementation. After three months of intervention, the mean diameter of uterine fibroids, elastic strain ratio, and blood flow grade were evaluated by multimodal ultrasound, and the clinical symptoms of the two groups were evaluated by questionnaire.

Results: The vitamin D group reported a significant increment in the serum 25-hydroxyvitamin D (P < 0.001). In addition, there were significant reductions in the mean diameter, and elastic strain ratio of uterine fibroids (P =.043 and P =.038, respectively), but no significant difference in the blood flow grade of uterine fibroids was observed (P =.272). Compared with the control group, the vitamin D group achieved significant relief in dysmenorrhea and frequent urination, as well as improvement in heavy menstrual bleeding.

Conclusion: The application of multimodal ultrasound provides a more comprehensive theoretical basis for vitamin on uterine fibroids. Vitamin D can effectively reduce the size of uterine fibroids in pre-menopausal women and relieve their symptoms. It is highly likely to be a promising, safe, effective, and inexpensive drug for uterine fibroids, which has good application value and promotion prospects.

3D Synthetic Brain MRI with Compressed Sensing: Can It be a Promising way Forward for Daily Neuroimaging?

Background: Synthetic MRI can provide multiple contrast-weighted brain images with high resolution from a single scan via a 3D sequence using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS).

Objective: This study aimed to assess the diagnostic image quality of 3D synthetic MRI using compressed sensing (CS) in clinical practice.

Methods: We retrospectively reviewed the imaging data of 47 patients who underwent brain MRI, including 3D synthetic MRI using CS in a single session, between December 2020 and February 2021. Two neuroradiologists independently evaluated the overall image quality, anatomic demarcation, and artifacts for synthetic 3D T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR), phase-sensitive inversion recovery (PSIR), and double inversion recovery images, using a 5-point Likert scale. The interobserver agreement between the two readers was assessed using percent agreement and weighted κ statistics.

Results: The overall image quality of 3D synthetic T1WI and PSIR was good to excellent, with easy or excellent anatomic demarcation and mild or no visible artifact. However, other 3D synthetic MRI-derived images showed insufficient image quality and anatomic demarcation with marked CSF pulsation artifacts. In particular, 3D synthetic FLAIR showed high-signal artifacts on the brain surface.

Conclusion: 3D synthetic MRI, at its current status, cannot completely replace conventional brain MRI in daily clinical practice. However, 3D synthetic MRI can achieve scan-time reduction using CS and parallel imaging and may be useful for motion-prone or pediatric patients requiring 3D images where time-efficiency is important.

A Preliminary Study of Brain Functional Magnetic Resonance Imaging in Text Reading and Comprehension

Background: Few studies have focused on the changes in human brain function activities caused by reading Chinese characters with different intelligibility and whether it can reflect the understanding and cognitive ability of the human brain.

Objective: Task-fMRI based on Chinese character reading tasks with different intelligibility was used to explore activated brain regions and their cognitive changes.

Methods: Volunteers were randomly recruited using advertisements. Forty volunteers were recruited based on strict inclusion and exclusion criteria, and 40 volunteers were recruited. Brain function data of 40 healthy right-handed volunteers in fuzzy/clear Chinese reading tasks were collected using a Siemens Skyra 3.0T magnetic resonance scanner. Data were preprocessed and statistically analyzed using the statistical software SPM12.0 to observe the activation of the cortex and analyze its characteristics and possible changes in cognitive function.

Results: Task-fMRI analysis: (1) The main brain regions activated in fuzzy/clear reading tasks were located in the occipital visual cortex (P < 0.001); (2) a paired sample t-test suggested that there was a significant difference in BOLD signals in the brain regions activated by fuzzy/clear reading tasks (P < 0.001, equiv Z = 4.25). Compared with the fuzzy reading task, the brain regions more strongly activated in the clear reading task were mainly located in the right superior frontal gyrus and the bilateral temporal lobe. Compared with the clear reading task, the brain region that was more strongly activated in the fuzzy reading task was mainly located in the right fusiform gyrus.

Conclusion: Clear Chinese character information mainly activates the dorsal stream of the visual-spatial network. This reflects the information transmission of the brain after understanding the text content and is responsible for guiding and controlling attention. Fuzzy words that cannot provide clear text content activate the fusiform gyrus of the ventral stream of the visual-spatial network, strengthening the function of orthographic processing.

Effects of Glutamine Synthetase on Neovascularization in Glioma: In Vivo MR Vessel Size Imaging and Histology

Background: Glutamine Synthetase (GS) could induce vascular sprouting through the improvement of endothelial cell migration in inflammatory diseases. MR vessel-size imaging has been proposed as a valuable approach for visualizing the underlying angiogenic processes in the brain.

Objective: This study aims to investigate the role of GS in the neovascularization of gliomas through the utilization of MR vessel-size imaging and histopathological techniques.

Methods: In this exploratory animal study, we randomly divided the C6 glioma rat models into a control group and an L-methionine sulfoximine (MSO) treatment group. Daily intraperitoneal injections were administered for three consecutive days, starting from day 10 following the implantation of C6 glioma cells in rats. Subsequently, MR vessel size imaging was conducted using a BRUKER 7 T/200 mm MRI scanner, and the MRI results were validated through histopathological examination.

Results: A significant decrease in microvessel density was observed in both the tumor periphery and center areas in the MSO treatment group compared to that in the control group. The mean vessel diameter (mVD) and vessel size index (VSI) did not exhibit significant changes compared to the control group. Moreover, the staining intensity of platelet endothelial cell adhesion molecule-1 (CD31) and GS in the tumor periphery was significantly decreased in the MSO treatment group. Additionally, the MSO treatment demonstrated a substantial inhibition of tumor growth.

Conclusion: GS inhibitors significantly reduced angiogenesis in the periphery area of C6 glioma, exerting an inhibitory effect on tumor progression. Thus, GS inhibitors could be potential therapeutic agents for treating glioma. Additionally, in vivo MR vessel size imaging detects changes in vascularrelated parameters after tumor treatment, making it a promising method for detecting neovascularization in glioma.

Diagnostic Value of Chest X-Ray in Febrile Patients without Localizing Signs or Symptoms at the Emergency Department

Background: The chest X-ray (CXR) remains a widely used examination in the evaluation of patients with fever, to diagnose or rule out pneumonia. Recently, a study by our group suggested that it has no diagnostic value in patients with fever without respiratory signs and/or symptoms.

Objective: The objective of this study is to validate the results of our previous study.

Design: A retrospective study was conducted in two hospitals in the Netherlands.

Patients: All patients that were referred to the internal medicine emergency department between May 2018 and May 2019 with a suspected infection defined as fever (temperature ≥38°C) or hypothermia (temperature <36°C) or CRP ≥100μg/mL.

Main Measures: We defined our primary outcome as the number of newly diagnosed pneumonia by CXR in cases of suspected infection with no obvious site of infection and nor localizing symptoms or signs.

Key Results: We included 1052 patients, of which 106 did not have respiratory signs or symptoms. In this group, none of the CXRs (95% CI 0-2.36%) showed an infiltrate. Combined with our previous study, 176 CXRs were performed in patients with no respiratory signs or symptoms. None (95% CI 0-1.42%) showed an infiltrate.

Conclusion: Our results confirm that a CXR has no diagnostic value in the workup of fever without localizing signs or symptoms.

Unravelling the Impact: Pulmonary Side Effects of Anti-Seizure Medications

Background: Epilepsy is a chronic brain condition affecting over 50 million people worldwide. Several new anti-seizure medications (ASMs) have been introduced to treat epilepsy in recent decades.

Objective: Nearby the specific therapeutic action, ASMs, like other types of pharmacotherapy, can produce various side effects. In this review, we shall analyze the different pharmaceutical classes of ASMs, their mechanism of action, and their interaction with the respiratory system.

Methods: This manuscript is based on a retrospective review of English publications indexed by Pubmed, UpToDate and datasheets published by the European Medicines Agency and the Food and Drug Administration (FDA), using various terms reminiscent of ASMs and pulmonary function.

Results: ASMs act on organism homeostasis in different ways, acting on lung function directly and indirectly and playing a protective or damaging role. A damaging direct lung involvement ranged from infections, hypersensitivity reactions, and respiratory depression to other structured pulmonary diseases. Meanwhile, a damaging indirect effect, might be constituted by pulmonary artery hypertension. On the other hand, a protective effect might be the expression of developmental processing, decreasing airway remodelling in asthma patients, vascular remodelling in pulmonary hypertension and, nonetheless, anti-inflammatory and immunomodulatory actions.

Conclusion: An adequate awareness of ASMs effects on the respiratory system seems essential for better managing frail individuals or/and those predisposed to respiratory disorders to improve our patients' clinical outcomes.

Incretin Therapy and Insulin Signaling: Therapeutic Targets for Diabetes And Associated Dementia

Dementia is the primary cause of disability and dependence among the elderly population worldwide. The population living with dementia is anticipated to double in the next 17 years. Recent studies show the fact that compared to people without diabetes, people with Type 2 Diabetes (T2D) have about a 60% increased chance of developing dementia. In addition to cholinergic function being downregulated, improper insulin signalling also has a negative impact on synaptic plasticity and neuronal survival. Type 2 diabetes and dementia share various similar pathophysiological components. The ageing of the population and the ensuing rise in dementia prevalence are both results of ongoing medical advancements. It is possible that restoring insulin signaling could be a helpful therapy against dementia, as it is linked to both diminished cognitive function and the development of dementia, including AD. This review article comprehensively focused on scientific literature to analyze the relationship of Dementia with diabetes, recent experimental studies, and insight into incretin-based drug therapy for diabetes-related dementia.

Cognitive Rehabilitation For Early-Stage Dementia: A Review

In the primary phases of Alzheimer's disease (AD) and vascular dementia, memory impairments and cognitive abnormalities are common. Because of the rising prevalence of dementia among the elderly, it is critical to promote healthy habits that can delay the onset of cognitive decline. Cognitive training (CT) and cognitive rehabilitation (CR) are particular treatments aimed to resolve memory and further areas of cognitive working in order to overcome these challenges. These are some of the different kinds of non-pharmacological treatments like reality orientation and skills training programs that can be used to deal with the cognitive and non-cognitive repercussions. The purpose of this review is to assess the efficacy and influence of cognitive training and cognitive rehabilitation in patients who are in their early phases of Alzheimer's disease or vascular dementia. These interventions are geared toward improving the patients' memory, in addition to other aspects of their cognitive functioning.

P-glycoproteins in the Pathology and Treatment of Alzheimer's Disease

Alzheimer's disease (AD), a central cause of dementia, is characterized by the accumulation of amyloid β-peptide (Aβ) peptides in the brain. P-glycoprotein (P-gp), a highly expressed protein in the BBB, plays a fundamental role in transporting Aβ from the brain to the blood and protecting the blood-brain barrier (BBB). The dysfunction or decreased abundance of this transporting protein is associated with the accumulation of Aβ, leading to dementia and cognitive deficits. In this review article, we consolidate the existing literature on the impact of P-gp in the pathophysiology and therapy of AD. Current evidence claims that p-gp is involved in AD pathology and that enhancing the activity of this transporter may be a promising therapeutic approach to hinder AD progression. There is also a growing interest in P-gp as a potential therapeutic target for AD. Hence, ongoing clinical trials and research should investigate P-gp inhibitor efficacy as a therapeutic approach for improving AD drug delivery to the brain and treatment outcomes.

Beneficial Effects of Spirulina on Brain Health: A Systematic Review

Background: This review provides a concise overview of existing scientific research concerning the potential advantages of incorporating spirulina, a blue-green algae, into one's diet to promote brain health. The substantial nutritional composition and associated health benefits of algae have drawn significant interest.

Methods: Numerous studies have illuminated the neuroprotective characteristics of spirulina, contributing to its positive influence on brain functionality. Primarily, spirulina boasts antioxidants, like phycocyanin and beta-carotene, that effectively counter oxidative stress and curb inflammation within the brain. This is particularly significant as these factors play roles in the advancement of neurodegenerative conditions like Parkinson's and Alzheimer's disease. Additionally, spirulina has demonstrated the capacity to enhance cognitive capabilities and enrich memory and learning aptitudes.

Results: Animal-based investigations have revealed that introducing spirulina can bolster spatial learning and memory, as well as guard against cognitive decline linked to aging. Research has indicated its potential in shielding against neurotoxins, encompassing heavy metals and specific environmental pollutants. Its potential to neutralize heavy metals and counteract free radicals contributes to these protective effects, potentially thwarting neuronal harm.

Conclusion: In conclusion, the extant scientific literature proposes that spirulina integration can elicit advantageous outcomes for brain health. Its antioxidative, neuroprotective, cognitiveenhancing, and mood-regulating properties present a promising avenue for bolstering brain health and potentially diminishing the susceptibility to neurodegenerative ailments. Nonetheless, further research, notably well-designed human clinical trials, is imperative to ascertain the optimal dosing, duration, and enduring consequences of spirulina supplementation concerning brain health.

Therapeutic Significance of Cornin in Medicine for Their Biological Importance and Pharmacological Activity: An Overview of Iridoid Glycosides of Verbena Officinalis L.

Background: Plant products have been used for the treatment of numerous kinds of human disorders since the very ancient age. Iridoid glycosides are secondary plant metabolites of medicinal importance that have been well investigated in the scientific field for their role in plants. Numerous iridoid class phytochemicals have cardiovascular, anti-viral, anti-hepatotoxic, anti-inflammatory, anti-cancer, immunomodulatory, anti-spasmodic, hypolipidemic, choleretic, purgative, and hypoglycaemic activity.

Methods: Here in the present work, we have collected scientific information on cornin and presented it with respect to its medicinal importance and pharmacological activities with their analytical aspects. Scientific information on cornin has been collected from numerous scientific databases such as PubMed, Science Direct, Google, and Scopus to know the biological potential of cornin in medicine. Further, pharmacological activity scientific data of cornin has been presented in this work with proper citations.

Results: The scientific data of the present paper described the biological significance of cornin in medicine. The further detailed pharmacological activity of cornin signified its therapeutic effectiveness on cerebral ischemia, angiogenesis, autophagy, myocardial injury, cerebral injury, oxidative injury, lipid peroxidation, proliferation, and cytochrome p450. Analytical data signified the separation, isolation, and identification techniques of cornin in medicine.

Conclusion: The scientific information of the present work will be beneficial for all scientific people to explore the therapeutic effectiveness of cornin in medicine.

Targeting GM2 Ganglioside Accumulation in Dementia: Current Therapeutic Approaches and Future Directions

Dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) is a progressive neurological condition affecting millions worldwide. The amphiphilic molecule GM2 gangliosides are abundant in the human brain and play important roles in neuronal development, intercellular recognition, myelin stabilization, and signal transduction. GM2 ganglioside’s degradation requires hexosaminidase A (HexA), a heterodimer composed of an α subunit encoded by HEXA and a β subunit encoded by HEXB. The hydrolysis of GM2 also requires a non-enzymatic protein, the GM2 activator protein (GM2-AP), encoded by GM2A. Pathogenic mutations of HEXA, HEXB, and GM2A are responsible for autosomal recessive diseases known as GM2 gangliosidosis, caused by the excessive intralysosomal accumulation of GM2 gangliosides. In AD, PD and DLB, GM2 ganglioside accumulation is reported to facilitate Aβ and α-synuclein aggregation into toxic oligomers and plaques through activation of downstream signaling pathways, such as protein kinase C (PKC) and oxidative stress factors. This review explored the potential role of GM2 ganglioside alteration in toxic protein aggregations and its related signaling pathways leading to neurodegenerative diseases. Further review explored potential therapeutic approaches, which include synthetic and phytomolecules targeting GM2 ganglioside accumulation in the brain, holding a promise for providing new and effective management for dementia.

The Role of Resveratrol in Alzheimer's Disease: A Comprehensive Review of Current Research

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and impaired daily functioning. The etiology of AD is complex and multifactorial, involving various pathological mechanisms such as the accumulation of amyloid-beta plaques, neurofibrillary tangles, neuroinflammation, and oxidative stress. As the global prevalence of AD continues to rise, there is a growing interest in identifying potential therapeutic interventions to prevent or slow down the progression of the disease. Resveratrol, a natural polyphenolic compound found in various plant sources such as grapes, berries, and peanuts, has gained considerable attention due to its potential neuroprotective effects. Numerous preclinical studies utilizing in vitro and animal models have investigated the impact of resveratrol on AD pathology and associated cognitive impairments. This review aims to provide a comprehensive summary of the current research on the role of resveratrol in AD. In conclusion, resveratrol holds promise as a potential therapeutic agent for AD due to its ability to target multiple pathological processes involved in the disease. Further research, including well-designed clinical trials with larger sample sizes, is needed to fully elucidate the efficacy, optimal dosage, and long-term effects of resveratrol in AD patients. Nevertheless, resveratrol remains an intriguing compound with neuroprotective properties and may contribute to the development of novel therapeutic approaches for AD in the future.

A Comprehensive Study of Allium Sativum Linn

Allium Sativum, commonly known as garlic, has been employed for ages for both cuisines and restorative purposes. Many sulfur-containing phytochemical constituents are abundant in garlic and they are responsible for its many pharmacological properties. The most extensively studied compound in garlic is allicin, however, other forms of garlic such as aged garlic, raw garlic, and oil maceration of garlic, have their own unique chemical properties. Garlic has been shown to lower blood pressure, reduce cholesterol levels, improve insulin sensitivity, inhibit cell proliferation, enhance peristalsis motion, modulate acetylcholine, and inhibit lipid oxidation. Apart from all its traditional therapeutic activity, it has much more potential for further study such as cancer treatment with lesser side-effects, improving mitochondrial dysfunction in Huntington’s disease, enhancement psoriasis treatment, affinity to treat glomerular disease, and vast scope in polycystic ovary syndrome and in uterine contraction. This review talks about pharmacology activities, future aspects, phytochemicals, and the privileged aspects of Allium Sativum.

Nutritional and Health Benefits of Cereals and Grains

The consumption of cereals and grains, along with whole grain food, is considered a healthy food that has various health benefits. Minerals, proteins, carbohydrates, and vitamins are present in the diet of many people. Phytochemicals play an essential role in combating oxidative stress and are present in high amounts in grains. These phytochemicals are also known as secondary metabolites that are present in plants. The nutritional components of basil (Ocimum basilicum), chia (Salvia hispanica), flax (Linum usitatissimmum), Proso millet (Panicum miliaceum), and oat (Avena sativa) are analyzed. Seeds are considered a good source of omega-3 and omega-6 fatty acids that have a significant impact on human health. The high amount of tocopherol (vitamin E) is due to the high content of polyunsaturated fatty acids (PUFAs). γ-Tocopherol is an antioxidant nutrient that usually blocks the formation of carcinogenic nitrosamines from nitrites present in food in the stomach. This review provides detailed information on the nutritional and health benefits of these cereals and grains, in which all the major components have been discussed. Conclusively, the potential use of these cereals and grains alone and by mixing them with other food products is also discussed which may enhance the nutritional content of the food product.

Opportunities and Regulatory Challenges of Functional Foods and Nutraceuticals During COVID-19 Pandemic

The novel Coronavirus has brought global mortality, disruption, and a significant loss of life. A compromised immune system is a known risk factor for all viral influenza infections. Due to the perceived “immune-boosting” properties of nutraceutical products, sales of dietary supplements have grown globally. In recent years, consumers have increasingly demanded nutraceutical products rather than curative synthetic medicines for preventive therapies for the coronavirus disease outbreak of 2019 (COVID-19). Healthy foods and nutraceuticals have become daily diet plans for consumers. Although there has been an increase in demand, there is no such regulation and harmonized process, which stands as a barrier to the approval of these products. Therefore, many misbranded and spurious products are entering the market, which may harm consumers. This article focuses on the role of functional foods and nutraceutical in the management of COVID-19 also focuses on the different nutraceutical regulations in each country and compare the similarities and differences of the following countries: India, the USA (United States of America), the EU (European Union), and China. The comparative study of nutraceutical regulations in India, the USA, Europe, and China shows that there is a difference regarding the nutraceutical regulations; however, despite the differences, it is observed that it has the same underlying objective, i.e., ensuring the safety of the consumers by maintaining the product quality.

Lifestyle, Environment, and Dietary Measures Impacting Cognitive Impairment: The Evidence Base for Cognitive Subtypes

Cognition includes all phases of valid functions and processes, e.g., sensitivity, judgment, assessment, and decision-making. Thinking is also a cognitive procedure since it involves considering potential opportunities. There are various types of cognition. Hot cognition involves mental procedures where emotion plays a role, while cold cognition includes mental processes that do not include feelings or emotions. Cognitive memories of various types include sensor memory, sensing touch, smell, and sight; short-term memory allows one to recall, e.g., what one had for lunch a few days ago; working memory includes remembering telephone numbers or directions to a destination; and long-term memory comprises of major milestones in life and recalling one’s childhood events. These are further classified as episodic, e.g., the first day in primary school, and semantic memories, such as recalling the capital city of a country and filling out crossword puzzles. Declarative memories include remembering significant past events, such as global information. Cognition is affected by factors, such as nutrition, aging, addiction, environment, mental health, physical activity, smoking, and keeping the brain active. Consumption of plant- based foods plays a prominent role in the prevention of cognitive memory. Playing games and instruments, reading books, and being socially active make life more satisfying, thus assisting in the preservation of mental function and slowing mental decline.

Role of Chronotherapy in the Management of Hypertension: An Overview

The rise in age-adjusted mortality rates from hypertension and hypertensive diseases over the last several years suggests that hypertension is one of the main risk factors for heart disease. As a result, managing hypertension, both via preventive and therapeutic medicine, involves a heavy socioeconomic burden. This review paper's objective is to summarize information on chronotherapy techniques, which can make it possible for an active component to be distributed predictably and at a pace that may also minimize the patient’s illness symptoms. To incorporate published research and review papers, a comprehensive review of the literature from many sources during the past 25 years was conducted. This paper summarizes the principle and method of the chronotherapy technique. The review also throws light on different approaches that could be used to meet the need for medication for the hypertensive patient according to the circadian cycle. From the study, it was concluded that different formulation approaches are there that can work according to the principle of chronotherapy with improvement in drug bioavailability and patient compliance. To encourage future researchers to include chronotherapy in the creation of additional formulations, this review study intends to shed light on various benefits and methods of chronotherapy.

Evaluation of Clozapine-induced Toxicities in Psychic Patients in Mental Health Care Hospitals in the Southern Region of the Saudi Arabia Kingdom

Background: Clozapine is a psychiatric medication that may cause various side effects, some of them may be serious and fatal adverse effects, such as severe neutropenia, agranulocytosis, lymphocytopenia, myocarditis, and orthostatic hypotension, that have been associated to an increased risk of death.

Objectives: This study aimed to evaluate the serious and potentially fatal adverse effects of clozapine toxicity in psychic patients at mental health care hospitals in the Southern region of the Kingdom of Saudi Arabia.

Methods: By using a survey, data were retrospectively collected from 193 adult psychic patient reports who have been administrated clozapine with regular follow-ups, in mental health hospitals in the Southern region of Saudi Arabia between 2019 and 2021. Then, these data are recorded and analyzed Statistically using SPSS software, with suitable tests, and predetermined statistical significance (p-value) of less than 0.001.

Results: The occurrence of agranulocytosis, neutropenia, hypotension, and seizures showed a highly significant correlation with higher doses of clozapine administration (i.e. p < 0.001). Similarly, agranulocytosis and neutropenia were significantly associated with the occurrence of both hypotension and seizures (i.e. p < 0.001).

Conclusion: The collected data in this study showed an increased incidence of agranulocytosis and neutropenia associated with clozapine-treated psychic patients in the Southern region of the Kingdom of Saudi Arabia which warrants further clinical studies to find this correlation.

Prevalence and Related Factors of Dizziness Among Older Adults: A Cross-Sectional Study in Ardakan City, Iran

Background: Dizziness and balance disorders are directly related to aging in humans- Dizziness is one of the most important factors causing the burden of disability after the age of 65. Bearing in mind the increase in the elderly population in Iran and the world and the prevalence of dizziness in old age, early diagnosis of dizziness and determination of the factors affecting its severity facilitate its treatment and are effective in preventing its adverse consequences.

Objective: To determine the prevalence of dizziness and its related factors among older adults in Ardakan city, Yazd province, Iran, in 2022.

Methods: This cross-sectional study was conducted in four comprehensive health centers of Ardakan city with the participation of 260 elderly people aged ≥60 years, who were randomly included in the study. Data were collected using a series of questionnaires which were completed by interviewing the participants. The variables of this study included demographic information, information related to the dizziness status, diseases, medications, use of mobility aids, physical activity level, fear of falling, quality of life and depression.

Results: The prevalence of dizziness among older adults of Ardakan city was 48.5%. In terms of the severity of dizziness, 38.8% had substantial dizziness, and 9.6% had mild dizziness. Dizziness was significantly related to physical activity (p<0.05), fear of falling (p <0.01), depression (p <0.05), history of falling (p <0.01), use of mobility aids (p <0.01), age (p<0.01), education level (p<0.01), gender (p <0.05) and diseases such as high blood pressure (p<0.05), hypothyroidism (p <0.01) and ear diseases(p <0.01). Also, elderly people with dizziness used significantly more medications such as sedatives (p<0.01), antihypertensive drugs (p <0.05) and cytotoxic drugs (p <0.01).

Conclusion: About half of the older adults experience dizziness, and this problem is associated with depression, fear of falling, history of falling, low physical activity, age, female gender, ear diseases, high blood pressure, and hypothyroidism. In addition, the use of medications such as anti- hypertensives, sedatives and cytotoxic drugs is related to dizziness. Families with elderly people, doctors and healthcare workers need to be educated and pay more attention to the above.

Recombinant Antibody Fragments for Neurological Disorders: An Update

Recombinant antibody fragments are promising alternatives to full-length immunoglobulins, creating big opportunities for the pharmaceutical industry. Nowadays, antibody fragments such as antigen-binding fragments (Fab), single-chain fragment variable (scFv), single-domain antibodies (sdAbs), and bispecific antibodies (bsAbs) are being evaluated as diagnostics or therapeutics in preclinical models and in clinical trials. Immunotherapy approaches, including passive transfer of protective antibodies, have shown therapeutic efficacy in several animal models of Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), Huntington’s disease (HD), transmissible spongiform encephalopathies (TSEs) and multiple sclerosis (MS). There are various antibodies approved by the Food and Drug Administration (FDA) for treating multiple sclerosis and two amyloid beta-specific humanized antibodies, Aducanumab and Lecanemab, for AD. Our previous review summarized data on recombinant antibodies evaluated in pre-clinical models for immunotherapy of neurodegenerative diseases. Here, we explore recent studies in this fascinating research field, give an update on new preventive and therapeutic applications of recombinant antibody fragments for neurological disorders and discuss the potential of antibody fragments for developing novel approaches for crossing the blood-brain barrier (BBB) and targeting cells and molecules of interest in the brain.

Characterization of Intrinsically Disordered Proteins in Healthy and Diseased States by Nuclear Magnetic Resonance

Introduction: Intrinsically Disordered Proteins (IDPs) are active in different cellular procedures like ordered assembly of chromatin and ribosomes, interaction with membrane, protein, and ligand binding, molecular recognition, binding, and transportation via nuclear pores, microfilaments and microtubules process and disassembly, protein functions, RNA chaperone, and nucleic acid binding, modulation of the central dogma, cell cycle, and other cellular activities, post-translational qualification and substitute splicing, and flexible entropic linker and management of signaling pathways.

Methods: The intrinsic disorder is a precise structural characteristic that permits IDPs/IDPRs to be involved in both one-to-many and many-to-one signaling. IDPs/IDPRs also exert some dynamical and structural ordering, being much less constrained in their activities than folded proteins. Nuclear magnetic resonance (NMR) spectroscopy is a major technique for the characterization of IDPs, and it can be used for dynamic and structural studies of IDPs.

Results and Conclusion: This review was carried out to discuss intrinsically disordered proteins and their different goals, as well as the importance and effectiveness of NMR in characterizing intrinsically disordered proteins in healthy and diseased states.

Spinacia Oleracea: Exploring the Therapeutic Potential in Persian Medicine and Modern Pharmacology

Background: Spinach is a widely cultivated dark leafy vegetable highly regarded for its medicinal properties in traditional Persian medicine. It is rich in vitamins, minerals, flavonoids, carotenoids, and other bioactive compounds, and this review aims to explore the historical applications of spinach in Persian medicine and juxtapose them with current scientific evidence. Despite its historical significance, there remains a need to comprehensively evaluate and integrate traditional knowledge with modern research on the therapeutic benefits of spinach.

Methods: To achieve this, a comprehensive search was conducted in Persian medicine references and scientific databases to gather information on the traditional uses, chemical composition, and pharmacological effects of spinach. Studies that met the inclusion criteria were meticulously categorized, and relevant data were analyzed to draw insightful comparisons.

Results: Persian medicine describes spinach as a nutrient-rich, laxative, and fast-digesting agent with therapeutic effects on inflammation, lung diseases, back pain, sore throats, jaundice, urinary disorders, joint pain, eye inflammation, insomnia, dementia, and more. Modern studies have substantially corroborated these traditional uses, revealing that spinach possesses antioxidant, anti-inflammatory, anti-cancer, blood sugar-lowering, lipid-lowering, anti-obesity, neurological, ocular, and musculoskeletal effects.

Conclusion: Spinach exhibits a wide range of beneficial effects on various health conditions. Its widespread availability, low cost, and exceptional nutritional richness position it as a promising candidate for further investigation. Future studies should explore the clinical effectiveness of spinach in various diseases, while taking into consideration the principles emphasized in Persian medicine to guide research and inform therapeutic strategies.

Auvelity: A New Era in Medicine - Unraveling the Multifaceted Benefits of Dextromethorphan/Bupropion Combination

Background: Depression is a prevalent global illness, impacting 280 million people worldwide, and Major Depressive Disorder (MDD) is ranked as the third leading cause of disease burden globally. People previously diagnosed with depression are more likely to develop Alzheimer's disease (AD). The recent approval of Auvelity by the FDA has made a remarkable breakthrough in drug development, offering a multi-dimensional approach for managing multiple diseases.

Objective: The main objective of this study is to investigate the role of Auvelity, a new drug, in treating MDD and its potential to manage agitation in individuals with Alzheimer's disease (AD).

Methodology: Data on Auvelity was collected from various sources, including accessdata.fda.gov, PubMed, and Scopus, and compiled for analysis.

Discussion: Auvelity is the first oral medication to demonstrate the rapid onset of action, with statistically significant antidepressant efficacy observed as early as one week compared to a placebo. It contains a combination of dextromethorphan (45 mg) and bupropion (105 mg). The drug's mechanism of action involves a combination of NMDA receptor blockade and agonism of the sigma-1 receptor, resulting in the antagonization of the glutamatergic neurotransmitter pathway. Due to the similarity in the mechanism of action with AD medications like Memantine, there is a hypothesis that Auvelity could effectively reduce symptoms of AD.

Conclusion: The approval of Auvelity marks a significant advancement in depression treatment with its unique NMDA antagonist mechanism, rapid onset of action, and low-risk profile.

Metabolic Disorder Therapeutics and their Effects on Memory

Diabetes is one of the major metabolic disorders of this era. It not only impacts a person's lifestyle but also has a long-term impact on the brain. It has a detrimental effect on a person's health when combined with hypertension and hyperlipidaemia. Several studies have suggested that the incidence of dementia is higher in people with metabolic syndrome. Investigations are underway to determine whether antidiabetic, hypolipidemic, hypercholesteraemic, anti-hypertensive, and other combination medicines can minimize the incidence of cognitive impairment. Some studies have suggested that anti-diabetic drugs like metformin, liraglutide, and dapagliflozin might enhance memory in long-term users. At the same time, other studies indicate that long-term insulin use may cause memory decline. Similarly, drugs like ACEIs, CCBs, fibrates, statins, and various nutraceuticals have been shown to improve cognition via multiple mechanisms. Literature suggests that drugs that can treat metabolic syndrome can also partially reduce the accumulation of beta-amyloid, whereas some studies contradict these findings. We review the past thirty years' of research work and summarize the effects of most commonly used drugs and nutraceuticals for treating metabolic syndrome on memory. Here, we review the effects of antidiabetic, hypolipidemic, anti-hypertensive, and hypercholesteremic, and their combination in learning and memory.

Exerkines: A Crosstalk between Lactate Production, Exercise and Mental Health

Muscle skeletal striated cells secrete a wide range of proteins called myokines or “exerkines”, which in turn perform autocrine, paracrine, or endocrine functions. For being able to act in the communication between skeletal muscle, adipose tissue, and mainly the brain, exerkines play a prominent role and potential influence on health promotion. Furthermore, we detected in the literature that one of these potential therapeutic substances derived from muscle contraction is a molecule derived from glycolytic metabolism that in the past was largely marginalized, the lactate. Currently, studies are dedicated to examining the target structures for exerkines that may contribute to the maintenance and restoration of mental health. Thus, lactate appears to be recognized as a critical mediator of exercise-related changes and their health benefits, particularly in their role in communication and coordination between organs. It is inferred that the BDNF expression mechanism can be induced by lactate, which in turn derives from the activation of SIRT pathways 1 and 2 and activates the PGC1-α cascade. The behavior of lactate concentration is intensity-dependent, directly related to the type of fast-twitch fibers (type IIb) and the recruitment of these fibers would potentiate the responses in the brain. In this sense, high-intensity exercise would establish itself as an important strategy to be considered. Despite this understanding, there is still much to be done. However, lactate appears to be a highly promising exerkine for future research initiatives and a potential biomarker to reduce illness and promote mental health.

Role of Imaging Genetics in Alzheimer’s Disease: A Systematic Review and Current Update

Background: Alzheimer’s disease is a neurodegenerative disorder characterized by severe cognitive, behavioral, and psychological symptoms, such as dementia, cognitive decline, apathy, and depression. There are no accurate methods to diagnose the disease or proper therapeutic interventions to treat AD. Therefore, there is a need for novel diagnostic methods and markers to identify AD efficiently before its onset. Recently, there has been a rise in the use of imaging techniques like Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) as diagnostic approaches in detecting the structural and functional changes in the brain, which help in the early and accurate diagnosis of AD. In addition, these changes in the brain have been reported to be affected by variations in genes involved in different pathways involved in the pathophysiology of AD.

Methodology: A literature review was carried out to identify studies that reported the association of genetic variants with structural and functional changes in the brain in AD patients. Databases like PubMed, Google Scholar, and Web of Science were accessed to retrieve relevant studies. Keywords like ‘fMRI’, ‘Alzheimer’s’, ‘SNP’, and ‘imaging’ were used, and the studies were screened using different inclusion and exclusion criteria.

Results: 15 studies that found an association of genetic variations with structural and functional changes in the brain were retrieved from the literature. Based on this, 33 genes were identified to play a role in the development of disease. These genes were mainly involved in neurogenesis, cell proliferation, neural differentiation, inflammation and apoptosis. Few genes like FAS, TOM40, APOE, TRIB3 and SIRT1 were found to have a high association with AD. In addition, other genes that could be potential candidates were also identified.

Conclusion: Imaging genetics is a powerful tool in diagnosing and predicting AD and has the potential to identify genetic biomarkers and endophenotypes associated with the development of the disorder.

Repurposing of Antidiarrheal Loperamide for Treating Melanoma by Inducing Cell Apoptosis and Cell Metastasis Suppression In vitro and In vivo

Background: Melanoma is the most common skin tumor worldwide and still lacks effective therapeutic agents in clinical practice. Repurposing of existing drugs for clinical tumor treatment is an attractive and effective strategy. Loperamide is a commonly used anti-diarrheal drug with excellent safety profiles. However, the affection and mechanism of loperamide in melanoma remain unknown. Herein, the potential anti-melanoma effects and mechanism of loperamide were investigated in vitro and in vivo.

Methods: In the present study, we demonstrated that loperamide possessed a strong inhibition in cell viability and proliferation in melanoma using MTT, colony formation and EUD incorporation assays. Meanwhile, xenograft tumor models were established to investigate the anti-melanoma activity of loperamide in vivo. Moreover, the effects of loperamide on apoptosis in melanoma cells and potential mechanisms were explored by Annexin V-FITC apoptosis detection, cell cycle, mitochondrial membrane potential assay, reactive oxygen species level detection, and apoptosis-correlation proteins analysis. Furthermore, loperamide-suppressed melanoma metastasis was studied by migration and invasion assays. What’s more, immunohistochemical and immunofluorescence staining assays were applied to demonstrate the mechanism of loperamide against melanoma in vivo. Finally, we performed the analysis of routine blood and blood biochemical, as well as hematoxylin- eosin (H&E) staining, in order to investigate the safety properties of loperamide.

Results: Loperamide could observably inhibit melanoma cell proliferation in vitro and in vivo. Meanwhile, loperamide induced melanoma cell apoptosis by accumulation of the sub-G1 cells population, enhancement of reactive oxygen species level, depletion of mitochondrial membrane potential, and apoptosis-related protein activation in vitro. Of note, apoptosis-inducing effects were also observed in vivo. Subsequently, loperamide markedly restrained melanoma cell migration and invasion in vitro and in vivo. Ultimately, loperamide was witnessed to have an amicable safety profile.

Conclusion: These findings suggested that repurposing of loperamide might have great potential as a novel and safe alternative strategy to cure melanoma via inhibiting proliferation, inducing apoptosis and cell cycle arrest, and suppressing migration and invasion.

Synthesis of Symmetrical and Unsymmetrical Tetrahydroxybiphenyls and their Evaluation as Amyloid-β Aggregation Inhibitors

Our group recently reported that the polyhydroxy aromatic compound 3,3′,4,4′- biphenyltetrol (2a) is a successful inhibitor of amyloid-β peptide (Aβ) aggregation, decreasing Aβ aggregation by 50 % when present in equimolar concentrations. In the present study, several additional biphenyltetrols were prepared and examined for their in vitro activity against aggregation of Aβ to investigate the effect of the relative positions of hydrogen-bond donors on the aggregation process. Congo red spectral shift assays demonstrated that, of the eight (8) additional biphenyltetrol compounds prepared, three (3) successfully inhibited the association of Aβ monomers, two symmetrical isomers, 2,2′,5,5′-biphenyltetrol (2c), and 2,2′,3,3′-biphenyltetrol (2d), along with one unsymmetrical isomer, 2,3′,4′,5-biphenyltetrol (2g). These results, along with the previously reported results of 2a, strongly suggest that hydroxyl group position affects the ability of the inhibitor to bind to Aβ assemblies, thus impacting inhibitory efficacy.

Recent Advances in the Treatment Strategies of Friedreich’s Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms

Background: Friedreich's Ataxia (FRDA) is a rare hereditary neurodegenerative disorder characterized by progressive ataxia, cardiomyopathy, and diabetes. The disease is caused by a deficiency of frataxin, a mitochondrial protein involved in iron-sulfur cluster synthesis and iron metabolism.

Objective: This review aims to summarize recent advances in the development of treatment strategies for FRDA, with a focus on potential drug candidates and their mechanisms of action.

Methods: A comprehensive literature search was conducted using various authentic scientific databases to identify studies published in the last decade that investigated potential treatment strategies for FRDA. The search terms used included “Friedreich's ataxia”, “treatment”, “drug candidates”, and “mechanisms of action”.

Results: To date, only one drug got approval from US-FDA in the year 2023; however, significant developments were achieved in FRDA-related research focusing on diverse therapeutic interventions that could potentially alleviate the symptoms of this disease. Several promising drug candidates have been identified for the treatment of FRDA, which target various aspects of frataxin deficiency and aim to restore frataxin levels, reduce oxidative stress, and improve mitochondrial function. Clinical trials have shown varying degrees of success, with some drugs demonstrating significant improvements in neurological function and quality of life in FRDA patients.

Conclusion: While there has been significant progress in the development of treatment strategies for FRDA, further research is needed to optimize these approaches and identify the most effective and safe treatment options for patients. The integration of multiple therapeutic strategies may be necessary to achieve the best outcomes in FRDA management.

Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease

The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.

Role of BDNF Signaling in the Neuroprotective and Memory-enhancing Effects of Flavonoids in Alzheimer’s Disease

Background: Foods rich in flavonoids are associated with a reduced risk of various chronic diseases, including Alzheimer's disease (AD). In fact, growing evidence suggests that consuming flavonoid- rich foods can beneficially affect normal cognitive function. Animal models have shown that many flavonoids prevent the development of AD-like pathology and improve cognitive deficits.

Objective: Identifying the molecular causes underlying the memory-enhancing effect of flavonoid-rich foods makes it possible to provide the best diet to prevent cognitive decline associated with aging and Alzheimer's disease. Based on the most recent scientific literature, this review article critically examines the therapeutic role of dietary flavonoids in ameliorating and preventing the progression of AD and enhancement of memory with a focus on the role of the BDNF signaling pathway.

Methods: The databases of PubMed, Web of Science, Google Scholar, and Scopus were searched up to March 2023 and limited to English language. Search strategies were using the following keywords in titles and abstracts: (Flavonoid-rich foods OR Flavonoids OR Polyphenols); AND (Brain-Derived Neurotrophic Factor OR BDNF OR CREB OR) AND (Alzheimer's disease OR memory OR cognition OR).

Results: Flavonoid-rich foods including green tea, berries, curcumin and pomegranate exert their beneficial effects on memory decline associated with aging and Alzheimer's disease mostly through the direct interaction with BDNF signaling pathway.

Conclusion: The neuroprotective effects of flavonoid-rich foods through the CREB-BDNF mechanism have the potential to prevent or limit memory decline due to aging and Alzheimer's disease, so their consumption throughout life may prevent age-related cognitive impairment.

Artificial Intelligence in The Management of Neurodegenerative Disorders

Neurodegenerative disorders are characterized by a gradual but irreversible loss of neurological function. The ability to detect and treat these conditions successfully is crucial for ensuring the best possible quality of life for people who suffer from them. The development of effective new methods for managing and treating neurodegenerative illnesses has been made possible by recent developments in computer technology. In this overview, we take a look at the prospects for applying computational approaches, such as drug design, AI, ML, and DL, to the treatment of neurodegenerative diseases. To review the current state of the field, this article discusses the potential of computational methods for early disease detection, quantifying disease progression, and understanding the underlying biological mechanisms of neurodegenerative diseases, as well as the challenges associated with these approaches and potential future directions. Moreover, it delves into the creation of computational models for the individualization of care for neurodegenerative diseases. The article concludes with suggestions for future studies and clinical applications, highlighting the advantages and disadvantages of using computational techniques in the treatment of neurodegenerative diseases.

Mendelian Randomization Highlights Gut Microbiota of Short-chain Fatty Acids’ Producer as Protective Factor of Cerebrovascular Disease

Background: Recent research advancements have indicated a potential association between gut microbiota and cerebrovascular diseases, although the precise causative pathways and the directionality of this association remain to be fully elucidated.

Objective: This study utilized a bidirectional two-sample Mendelian Randomization (MR) methodology to explore the causal impact of gut microbiota compositions on the risk of cerebrovascular disease.

Methods: Genome-wide Association Study (GWAS) data pertaining to gut microbiota were obtained from the MiBioGen consortium. For Ischemic Stroke (IS), Transient Ischemic Attack (TIA), Vascular Dementia (VD), and Subarachnoid Hemorrhage (SAH), GWAS summary data were sourced from the FinnGen consortium, the IEU Open GWAS project, and the GWAS catalog, respectively.

Results: Our MR analyses identified that specific bacterial strains, notably those involved in the production of Short-chain Fatty Acids (SCFAs), including Barnesiella, Ruminococcus torques group, and Coprobacter, serve as protective factors against IS, TIA, and SAH. Linkage Disequilibrium Score Regression (LDSC) analysis corroborated a significant genetic correlation between these gut microbiota strains and various forms of cerebrovascular disease. In contrast, reverse MR analysis failed to establish a bidirectional causal relationship between genetically inferred gut microbiota profiles and these cerebrovascular conditions.

Conclusion: This investigation has pinpointed particular strains of gut microbiota that play protective or detrimental roles in cerebrovascular disease pathogenesis. These findings offer valuable insights that could be pivotal for the clinical management, prevention, and treatment of cerebrovascular diseases.

Hypoparathyroidism: Musculoskeletal Manifestations Related to Parathormone Deficiency

Background: Hypoparathyroidism is a rare metabolic disorder that can be responsible for musculoskeletal manifestations.

Aim: We present a systematic review of musculoskeletal manifestations of adult-onset nonsurgical nongenetic hypoparathyroidism.

Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline using the MEDLINE database, including manuscripts describing musculoskeletal manifestations of adult-onset nonsurgical nongenetic hypoparathyroidism.

Results: Musculoskeletal manifestations included myopathy, shoulder disorder, immune-negative non-erosive peripheral arthritis, axial involvement simulating spondylarthritis, and diffuse ligamentous ossifications. An association between hypoparathyroidism and spondyloarthritis or autoimmune diseases is possible. T-cell activation, seen in patients with hypoparathyroidism, may explain the co-occurrence of hypoparathyroidism with other autoimmune diseases.

The treatment of these manifestations is based on calcium and active vitamin D supplementation. Parathyroid hormone may have an anabolic effect on muscle atrophy and muscle weakness. Parathyroid hormone can also promote bone formation and bone resorption by stimulating osteoclast differentiation by increasing RANKL (receptor activator for nuclear factor kappa-B ligand) expression. Therefore, hypoparathyroidism can be responsible for an increase in bone mineral density. However, the risk of fractures does not appear to be reduced due to changes in bone microarchitecture and the high risk of falls. Treatment with parathyroid hormone has been shown to improve bone microarchitecture.

Conclusion: Our review showed that musculoskeletal manifestations are frequent in patients with hypoparathyroidism, including muscular, axial, peripheral articular, and entheseal manifestations.

Reaction Time in Fibromyalgia Patients

Background: Fibromyalgia has unknown aetiology and is associated with reduced information processing speed and therefore prolonged reaction time. However, the processes underlying this are unknown.

Objectives: First, to compare the reaction time in a cohort of fibromyalgia patients and a matched group of normal controls. Second, to assess whether detailed symptoms of pain and autonomic function, as well as measures of tinnitus, fatigue, daytime sleepiness and Mycoplasma pneumoniae infection are predictors of reaction time in fibromyalgia.

Methods: The between-groups mean serial five-choice reaction time difference was assessed in a cohort of fibromyalgia patients and in a matched group of normal controls in an analytical casecontrolled study. With the mean serial five-choice reaction time as the dependent variable for the fibromyalgia group, a mixed stepwise multiple linear regression was performed with inputs relating to pain, dysautonomia, tinnitus, fatigue, daytime sleepiness and Mycoplasma pneumoniae infection.

Results: The mean (standard error) serial five-choice reaction time for the fibromyalgia group was 448.4 (23.0) ms, compared with 386.3 (8.3) ms for the control group (p = 0.007). The final multiple linear regression model (p < 0.001; adjusted R² = 0.772) contained 13 predictors: eight sensory pain and three affective pain parameters, and Mycoplasma pneumoniae IgG and IgA assay results.

Conclusion: Certain sensory and affective pain parameters, as well as Mycoplasma pneumoniae infection, appear to be predictors of reaction time in fibromyalgia. Further research into the pathophysiological mechanisms by which they affect information processing is warranted and may shed light on the aetiology of fibromyalgia.

A Comprehensive Review of the Pharmacological Effects of Genus Ferula on Central Nervous System Disorders

Background: Plants of the genus Ferula have long been used to treat neurological diseases such as Alzheimer's disease (AD), pain, depression, and seizures. The main compounds include coumarins, monoterpenes, sulfide compounds, and polyphenol compounds, which can improve the functioning of the nervous system.

Objective: This article has been compiled with the aim of collecting evidence and articles related to the Ferula effects on central nervous system disease.

Methods: This review article was prepared by searching the terms Ferula and analgesic, anticonvulsant, antidepressant, anti-multiple sclerosis, anti-dementia, and neuroprotective effects.The relevant information was collected through searching electronic databases such as ISI Web of Knowledge, PubMed, and Google Scholar.

Results: Genus Ferula has a protective effect on nerve cells by reducing cytokines such as IL-6, IL- 1b, and TNF-α. Therefore, the effects of Ferula plants and their effective ingredients can be used to prevent or improve diseases that destroy the nervous system. The members of this genus play a role in strengthening and improving the antioxidant system, reducing the level of oxidative stress, and inhibiting or reducing inflammatory factors in the nervous system.

Conclusion: Although the effects of several species of Ferula on the nervous system have been investigated, most studies have not clearly identified the molecular mechanisms as well as the specific functional regions of the brain. The present study was compiled in order to investigate different aspects of the effects of Ferula plants on the central nervous system.

Marine-derived Compounds: A Powerful Platform for the Treatment of Alzheimer’s Disease

Alzheimer's disease (AD) is a debilitating form of dementia that primarily affects cholinergic neurons in the brain, significantly reducing an individual's capacity for learning and creative skills and ultimately resulting in an inability to carry out even basic daily tasks. As the elderly population is exponentially increasing, the disease has become a significant concern for society. Therefore, neuroprotective substances have garnered considerable interest in addressing this universal issue. Studies have shown that oxidative damage to neurons contributes to the pathophysiological processes underlying AD progression. In AD, tau phosphorylation and glutamate excitotoxicity may play essential roles, but no permanent cure for AD is available. The existing therapies only manage the early symptoms of AD and often come with numerous side effects and toxicities. To address these challenges, researchers have turned to nature and explored various sources such as plants, animals, and marine organisms. Many historic holy books from different cultures emphasize that adding marine compounds to the regular diet enhances brain function and mitigates its decline. Consequently, researchers have devoted significant time to identifying potentially active neuroprotective substances from marine sources. Marine-derived compounds are gaining recognition due to their abundant supply of diverse chemical compounds with biological and pharmacological potential and unique mechanisms of action. Several studies have reported that plants exhibit multitarget potential in treating AD. In light of this, the current study focuses on marine-derived components with excellent potential for treating this neurodegenerative disease.

Neuroprotective Properties of Antiepileptics: What are the Implications for Psychiatric Disorders?

Since the discovery of the first antiepileptic compound, increasing attention has been paid to antiepileptic drugs (AEDs), and recently, with the understanding of the molecular mechanism underlying cells death, a new interest has revolved around a potential neuroprotective effect of AEDs. While many neurobiological studies in this field have focused on the protection of neurons, growing data are reporting how exposure to AEDs can also affect glial cells and the plastic response underlying recovery; however, demonstrating the neuroprotective abilities of AEDs remains a changeling task. The present work aims to summarize and review the literature available on the neuroprotective properties of the most commonly used AEDs. Results highlighted how further studies should investigate the link between AEDs and neuroprotective properties; while many studies are available on valproate, results for other AEDs are very limited and the majority of the research has been carried out on animal models. Moreover, a better understanding of the biological basis underlying neuro-regenerative defects may pave the way for the investigation of further therapeutic targets and eventually lead to an improvement in the actual treatment strategies.

Synthesis and Biological Evaluation of 2-Amino-1-phenyl-benzimidazole Derivatives as BACE1 Inhibitors

Background: Alzheimer’s disease (AD), a chronic neurodegenerative disorder predominantly occurs among the elderly, is the leading cause of dementia. The accumulation of β-amyloid (Aβ) is considered the main pathogenies of AD, and β-site APP-cleaving enzyme 1 (BACE1) plays an important role in the formulation of Aβ.

Objective: In order to find a new scaffold as BACE1 inhibitors, a series of novel 2-amino-1-phenylbenzimidazole derivatives were designed and synthesized in this work.

Methods: Using our previous L-5 as a lead compound, we applied a scaffold hopping method and merged 2-amino-1-methyl-4-phenyl-1H-imidazol-5 (4H)-one into benzimidazole, so a novel class of BACE1 inhibitors T1~T20 with the structure of 2-amino-1-phenyl-benzimidazole were designed and synthesized.

Results: The biological activity evaluation indicated that the target compounds showed inhibitory activities against BACE1, with T14 being the most potent (IC₅₀ = 0.45 μM), it also exhibited good logP value and tPSA. The docking studies indicated that compound T14 could form important hydrogen bonds with Asp289 and Asp93.

Conclusion: Compound T14 could be used as a potential BACE1 inhibitor for further modification to treat AD.

Food-derived Peptides as Promising Neuroprotective Agents: Mechanism and Therapeutic Potential

Many food-derived peptides have the potential to improve brain health and slow down neurodegeneration. Peptides are produced by the enzymatic hydrolysis of proteins from different food sources. These peptides have been shown to be involved in antioxidant and anti-inflammatory activity, neuro-transmission modulation, and gene expression regulation. Although few peptides directly affect chromatin remodeling and histone alterations, others indirectly affect the neuroprotection process by interfering with epigenetic changes. Fish-derived peptides have shown neuroprotective properties that reduce oxidative stress and improve motor dysfunction in Parkinson's disease models. Peptides from milk and eggs have been found to have anti-inflammatory properties that reduce inflammation and improve cognitive function in Alzheimer's disease models. These peptides are potential therapeutics for neurodegenerative diseases, but more study is required to assess their efficacy and the underlying neuroprotective benefits. Consequently, this review concentrated on each mechanism of action used by food-derived peptides that have neuroprotective advantages and applications in treating neurodegenerative diseases. This article highlights various pathways, such as inflammatory pathways, major oxidant pathways, apoptotic pathways, neurotransmitter modulation, and gene regulation through which food-derived peptides interact at the cellular level.

Activation Effect of 2-β-hydroxy Manoyl Oxide Isolated from Sideritis perfoliata on Carbonic Anhydrase Isoenzymes I and II

Background: Sideritis species were used for the treatment of mental disorders such as Alzheimer’s and dementia traditionally in Turkey. Several in vivo studies report that the mid-polar extract of Sideritis species can develop the brain functions of mice. 2-β-hydroxy manoyl oxide, isolated from ethyl acetate extract of Sideritis perfoliata, was assayed in vitro and in silico on human erythrocytes CA I and CA II. The compound was found to be an activator on two isoenzymes. It has been reported that activators of carbonic anhydrases may be used as a novel approach to treating disorders such as Alzheimer’s and age-related diseases. This study aimed to investigate the activity effect of 2-β-hydroxy manoyl oxide in vitro and in silico on human erythrocytes CA I and CA II (hCA I and hCA II) and to elucidate its pharmacokinetic and physicochemical characteristics.

Methods: The test compound was isolated from ethyl acetate extract of Sideritis perfoliata using chromatographic techniques and identified with spectroscopic evidence. Carbonic anhydrase activities were assayed using CO2 substrates. Docking studies were carried out with Molegro Virtual Docker. The compound underwent ADME-Tox prediction by using AdmetSAR and SwissADME software.

Results: 2-β-hydroxy manoyl oxide was found to increase the hCA-l and hCAII activity with AC50 values 9 and 19 μM, respectively. These results were further confirmed in silico molecular modeling. It showed favorable pharmacokinetic and physicochemical characteristics as a new drug candidate.

Conclusion: These findings demonstrated that 2-β-hydroxy manoyl oxide activated the hCA-l and hCA II. These results provide a novel and alternative activator for the carbonic anhydrase and confirm the traditional usage of the Sideritis perfoliata.

Post-Translational Modifications in Tau and Their Roles in Alzheimer's Pathology

Microtubule-Associated Protein Tau (also known as tau) has been shown to accumulate into paired helical filaments and neurofibrillary tangles, which are known hallmarks of Alzheimer’s disease (AD) pathology. Decades of research have shown that tau protein undergoes extensive post-translational modifications (PTMs), which can alter the protein's structure, function, and dynamics and impact the various properties such as solubility, aggregation, localization, and homeostasis. There is a vast amount of information describing the impact and role of different PTMs in AD pathology and neuroprotection. However, the complex interplay between these PTMs remains elusive. Therefore, in this review, we aim to comprehend the key post-translational modifications occurring in tau and summarize potential connections to clarify their impact on the physiology and pathophysiology of tau. Further, we describe how different computational modeling methods have helped in understanding the impact of PTMs on the structure and functions of the tau protein. Finally, we highlight the tau PTM-related therapeutics strategies that are explored for the development of AD therapy.

Current Progress on Central Cholinergic Receptors as Therapeutic Targets for Alzheimer's Disease

Acetylcholine (ACh) is ubiquitously present in the nervous system and has been involved in the regulation of various brain functions. By modulating synaptic transmission and promoting synaptic plasticity, particularly in the hippocampus and cortex, ACh plays a pivotal role in the regulation of learning and memory. These procognitive actions of ACh are mediated by the neuronal muscarinic and nicotinic cholinergic receptors. The impairment of cholinergic transmission leads to cognitive decline associated with aging and dementia. Therefore, the cholinergic system has been of prime focus when concerned with Alzheimer’s disease (AD), the most common cause of dementia. In AD, the extensive destruction of cholinergic neurons occurs by amyloid-β plaques and tau protein-rich neurofibrillary tangles. Amyloid-β also blocks cholinergic receptors and obstructs neuronal signaling. This makes the central cholinergic system an important target for the development of drugs for AD. In fact, centrally acting cholinesterase inhibitors like donepezil and rivastigmine are approved for the treatment of AD, although the outcome is not satisfactory. Therefore, identification of specific subtypes of cholinergic receptors involved in the pathogenesis of AD is essential to develop future drugs. Also, the identification of endogenous rescue mechanisms to the cholinergic system can pave the way for new drug development. In this article, we discussed the neuroanatomy of the central cholinergic system. Further, various subtypes of muscarinic and nicotinic receptors involved in the cognition and pathophysiology of AD are described in detail. The article also reviewed primary neurotransmitters that regulate cognitive processes by modulating basal forebrain cholinergic projection neurons.

Prominent Perspective on Existing Biological Hallmarks of Alzheimer’s Disease

Biomarkers are the most significant diagnosis tools tending towards unique approaches and solutions for the prevention and cure of Alzheimer’s Disease (AD). The current report provides a clear perception of the concept of various biomarkers and their prominent features through analysis to provide a possible solution for the inhibition of events in AD. Scientists around the world truly believe that crucial hallmarks can serve as critical tools in the early diagnosis, cure, and prevention, as well as the future of medicine. The awareness and understanding of such biomarkers would provide solutions to the puzzled mechanism of this neuronal disorder. Some of the argued biomarkers in the present article are still in an experimental phase as they need to undergo specific clinical trials before they can be considered for treatment.

The Postoperative Effects of Anesthesia Exposure on Cognitive Decline in Older Adults: A Narrative Review

Background: As modern medicine continues to make strides in effective surgical treatments, we must also consider the critical impact of anesthesia on neuropsychological outcomes. Recent evidence suggests that anesthesia exposure may be a risk factor for postoperative cognitive decline and the eventual development of dementia.

Objectives: To explore the vulnerability of the aging brain in the context of anesthesia exposure in surgery, studies will be reviewed, and pertinent findings will be highlighted and explored to better understand risks and possible factors that need to be considered when contemplating surgery.

Methods: A narrative review was conducted using a combination of MEDLINE and APA PsycINFO databases to shed light on themes across studies assessing general trends regarding the influence of anesthesia on postoperative cognitive decline.

Results: A search of relevant literature identified 388 articles. Excluding results outside the parameters of this study, the review includes quality assessments for 24 articles.

Conclusion: While findings are inconclusive, suggestions for further investigation into the relationship between anesthesia exposure and increased risk for postoperative cognitive decline are discussed, in addition to factors that may allow for greater informed disclosure of potential risks of anesthesia in older adults.

Cross Talks between CNS and CVS Diseases: An Alliance to Annihilate

Cardiovascular and neurological diseases cause substantial morbidity and mortality globally. Moreover, cardiovascular diseases are the leading cause of death globally. About 17.9 million people are affected by cardiovascular diseases and 6.8 million people die every year due to neurological diseases. The common neurologic manifestations of cardiovascular illness include stroke syndrome which is responsible for unconsciousness and several other morbidities significantly diminished the quality of life of patients. Therefore, it is prudent need to explore the mechanistic and molecular connection between cardiovascular disorders and neurological disorders. The present review emphasizes the association between cardiovascular and neurological diseases specifically Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease.

Lavender Plant: Farming and Health Benefits

Natural remedies from a range of sources, including plants, animals, microorganisms, and marine life, have made a significant contribution to the treatment of many ailments. Lavender is a Mediterranean shrub from the Lamiaceae family. Lavender flowers (Lavandula flores) include active ingredients (3%), anthocyanins, sugars, phytosterols, minerals, and tannins and are majorly used for herbal applications. Lavender essential oil's descriptive and analytical composition varies depending on genotype, growing region, climatic circumstances, propagation, and morphological characteristics. There are around 300 chemical components in essential oil. Linalool, terpinen-4-ol, linalyl acetate, ocimene, acetate lavandulol, and cineole are the most prominent constituents. Lavender oil has antibacterial and antioxidant properties. The lavender extract helps to prevent dementia and may slow cancer cell growth, while lavender oil is used to treat skin problems. This review will cover the recent medical, economic and regional advancements in levander propagation and how the Council of Scientific & Industrial Research Indian Institute of Integrative (CSIR IIIM) aroma mission is actively acting as a bridge between farmers and their economic improvement by attracting them to the field of medicinal plant cultivation.

Hydrophilic Interaction Liquid Chromatography for the Analysis of Pharmaceutical Formulations

For a long time, Reversed-Phase Liquid Chromatography (RPLC) was the most dominant technique for the analysis of pharmaceutical compounds, but with poor efficiency in the separation of small polar molecules. From the efforts to solve the problem of insufficient retention of these molecules, during the last decades, a mode of liquid chromatography named Hydrophilic Interaction Liquid Chromatography (HILIC) has experienced vast expansion. It is based on the use of a highly hydrophilic stationary phase along with an aqueous mobile phase with high organic modifier content. In this review, the characteristics of stationary and mobile phases used in HILIC are described, and corresponding separation mechanisms are discussed. An overview of recently published papers dealing with the application of HILIC in analyzing pharmaceuticals in biological and non-biological samples is provided. Besides, the application of HILIC systems in the determination of the physicochemical properties of compounds is described.

Does “Moringa Miracle” Happen to You Ever?

This is a short discussion about an opinion on the limitless benefits of a miraculous tree, scientifically called ‘Moringa oleifera’. This article aimed to collect all the latest informational research about the tree whose every part is full of nutrients. This paper highlights all the possible ingredients present in moringa, its uses for every part of the human body, and its usefulness against certain important diseases. Intake of moringa, its benefits, and the prevention of some major diseases after using it, have been precisely discussed in this piece of research.

An Investigation into the Effects of Chemical, Pharmaceutical, and Herbal Compounds on Neuroglobin: A Literature Review

Neuroglobin (Ngb) is an oxygen-binding globin protein that is mainly expressed in the neurons of the central and peripheral nervous system. However, moderate levels of Ngb have also been detected in non-neural tissues. Ngb and Ngb modulating factors have been increasingly studied over the last decade due to their neuroprotective role in neurological disorders and hypoxia. Studies have shown that a number of chemicals, pharmaceuticals, and herbal compounds can modulate the expression of Ngb at different dose levels, indicating a protective role against neurodegenerative diseases. Iron chelators, hormones, antidiabetic drugs, anticoagulants, antidepressants, plant derivatives and short-chain fatty acids are among these compounds. Therefore, this study aimed to review the literature focused on the possible effects and mechanisms of chemical, pharmaceutical, and herbal compounds on Ngbs.

Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation

Tau dysfunction has a close association with many neurodegenerative diseases, which are collectively referred to as tauopathies. Neurofibrillary tangles (NFTs) formed by misfolding and aggregation of tau are the main pathological process of tauopathy. Therefore, uncovering the misfolding and aggregation mechanism of tau protein will help to reveal the pathogenic mechanism of tauopathies. Molecular dynamics (MD) simulation is well suited for studying the dynamic process of protein structure changes. It provides detailed information on protein structure changes over time at the atomic resolution. At the same time, MD simulation can also simulate various conditions conveniently. Based on these advantages, MD simulations are widely used to study conformational transition problems such as protein misfolding and aggregation. Here, we summarized the structural features of tau, the factors affecting its misfolding and aggregation, and the applications of MD simulations in the study of tau misfolding and aggregation.

Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases

Neurodegenerative disorders are distinguished by the progressive loss of anatomically or physiologically relevant neural systems. Atypical mitochondrial morphology and metabolic malfunction are found in many neurodegenerative disorders. Alteration in mitochondrial function can occur as a result of aberrant mitochondrial DNA, altered nuclear enzymes that interact with mitochondria actively or passively, or due to unexplained reasons. Mitochondria are intimately linked to the Endoplasmic reticulum (ER), and ER-mitochondrial communication governs several of the physiological functions and procedures that are disrupted in neurodegenerative disorders. Numerous researchers have associated these disorders with ER-mitochondrial interaction disturbance. In addition, aberrant mitochondrial DNA mutation and increased ROS production resulting in ionic imbalance and leading to functional and structural alterations in the brain as well as cellular damage may have an essential role in disease progression via mitochondrial malfunction. In this review, we explored the evidence highlighting the role of mitochondrial alterations in neurodegenerative pathways in most serious ailments, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD).

Potential Therapeutic Approach using Aromatic l-amino Acid Decarboxylase and Glial-derived Neurotrophic Factor Therapy Targeting Putamen in Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative illness characterized by specific loss of dopaminergic neurons, resulting in impaired motor movement. Its prevalence is twice as compared to the previous 25 years and affects more than 10 million individuals. Lack of treatment still uses levodopa and other options as disease management measures. Treatment shifts to gene therapy (GT), which utilizes direct delivery of specific genes at the targeted area. Therefore, the use of aromatic L-amino acid decarboxylase (AADC) and glial-derived neurotrophic factor (GDNF) therapy achieves an effective control to treat PD. Patients diagnosed with PD may experience improved therapeutic outcomes by reducing the frequency of drug administration while utilizing provasin and AADC as dopaminergic protective therapy. Enhancing the enzymatic activity of tyrosine hydroxylase (TH), glucocorticoid hormone (GCH), and AADC in the striatum would be useful for external L-DOPA to restore the dopamine (DA) level. Increased expression of glutamic acid decarboxylase (GAD) in the subthalamic nucleus (STN) may also be beneficial in PD. Targeting GDNF therapy specifically to the putaminal region is clinically sound and beneficial in protecting the dopaminergic neurons. Furthermore, preclinical and clinical studies supported the role of GDNF in exhibiting its neuroprotective effect in neurological disorders. Another Ret receptor, which belongs to the tyrosine kinase family, is expressed in dopaminergic neurons and sounds to play a vital role in inhibiting the advancement of PD. GDNF binding on those receptors results in the formation of a receptor-ligand complex. On the other hand, venous delivery of recombinant GDNF by liposome-based and encapsulated cellular approaches enables the secure and effective distribution of neurotrophic factors into the putamen and parenchyma. The current review emphasized the rate of GT target GDNF and AADC therapy, along with the corresponding empirical evidence.

Gait Parameters can Reflect Cognitive Performance in Older Adults with Cerebral Small Vessel Disease: A Cross-sectional Research

Background: Cerebral small vessel disease (CSVD) is a common chronic progressive disease. It remains unclear whether high gait variability is a marker of cognitive cortical dysfunction.

Methods: This study included 285 subjects (aged from 60 to 85 years, 60.3% female) including 37 controls, 179 presented as Fazekas II, and 69 presented as Fazekas III. The severity of white matter hyperintensities was assessed by the Fazekas Rating Scale. Gait parameters were assessed using a vision-based artificial intelligent gait analyzer. Cognitive function was tested by MMSE, MoCA, DST, and VFT.

Results: Three gait parameters including gait speed, gait length, and swing time were associated with cognitive performance in patients with CSVD. Gait speed was associated with cognitive performance, including MMSE (β 0.200; 95%CI 1.706-6.018; p <.001), MoCA (β 0.183; 95%CI 2.047-7.046; p <.001), DST (order) (β 0.204; 95%CI 0.563-2.093; p =.001) and VFT (β 0.162; 95%CI 0.753-4.865; p =.008). Gait length was associated with cognitive performance, including MMSE (β 0.193; 95%CI 3.475-12.845; p =.001), MoCA (β 0.213; 95%CI 6.098-16.942; p <.001), DST (order) (β 0.224; 95%CI 1.056-4.839; P <.001) and VFT (β 0.149; 95%CI 1.088- 10.114; p =.015). Swing time was associated with cognitive performance, including MMSE (β - 0.242; 95%CI -2.639 to -0.974; p<.001), MoCA (β -0.211; 95%CI -2.989 to -1.034; p <.001) and DST (reverse order) (β -0.140; 95%CI -0.568 to -0.049; p =.020).

Conclusion: This study revealed that the relationship between gait parameters and cognitive performance in patients with CSVD and the deteriorated gait parameters can reflect cognitive impairment and even dementia in older people with CSVD.

Bibliometric Analysis of the Research Status and Global Trends in Behavioral and Psychological Symptoms of Dementia in Alzheimer’s Disease from 2002 to 2022

Background: Several reviews on behavioral and psychological symptoms (BPSDs) in patients with Alzheimer’s disease (AD) have summarized the current state of this field, but global trends are unclear.

Objective: This study utilized CiteSpace to provide a global overview of the current state of research on AD and its BPSDs and to predict future research trends in the field.

Methods: Data were retrieved from the Web of Science Core Collection. Bibliometric and cooccurrence analyses were performed using CiteSpace software. In total, 787 valid publications were included in the analysis.

Results: Publications on AD and BPSD have shown an increasing trend since 2002. The United States and the University of Toronto were the countries and institutions with the highest total number of publications, respectively. Japan and China were the second and third most influential in the field. Clive Ballard was the top author in terms of the number of publications. Journal of Alzheimer's Disease had the highest number of publications on this topic. Co-occurrence analysis showed that AD, behavioral symptoms, cognitive impairment, and early markers are hot topics in this area. Non-drug management of BPSDs, pharmacological treatment, and physiotherapy will be a hot topic in this field in the future.

Conclusion: Our study visualized the relevant articles over the past 21 years to detect global hotspots and trends. Our findings may help researchers to identify research hotspots in this field and will help in the selection of appropriate research topics, while possibly leading to cross-regional cooperation.

Natural Medicinal Compounds Used in Neurodegenerative Diseases

The medicinal plants discussed at this moment and their active isolated components seem promising for the treatment of neurodegenerative diseases viz. Disease (HD) in Huntington, Alzheimer's disease (AD), and Parkinson's disease (PD). These compounds can lay the groundwork for a new pharmacological approach to treatment, as patients tolerate herbal compounds more easily because they are relatively more protective than synthetic drugs. Meanwhile, there are anti-inflammatory, antioxidant, altered tau phosphorylation, anti-amyloidogenic, decreased aggregation of neurofibrillary tangles, and anticholinesterase processes in natural compound structures, including flavonoids, polyphenols, triterpenes, tannins, alkaloids and so on. We have summarized the pathogenesis and mechanism of different natural/bioactive components for treating HD, AD, and PD. An herbal source with well-established antioxidant and neuroprotective activity showed favourable impacts in both in vivo and in vitro studies against the symptoms of neurodegenerative diseases. The future outlook of herbal medicine can allow us to research their synergistic interactions, the action of multiple targets, and the elucidation of complex mechanisms of neuroprotective properties. However, in future scientific research on bioactive compounds, the efficacy of their active ingredients should be investigated to discover their neuroprotective therapeutic potential. Also, the mechanisms of action of herbal extracts and active ingredients remain to be clarified appropriately.

Signalling Pathways Involved in Microglial Activation in Alzheimer’s Disease and Potential Neuroprotective Role of Phytoconstituents

Alzheimer’s disease (AD) is a commonly reported neurodegenerative disorder associated with dementia and cognitive impairment. The pathophysiology of AD comprises Aβ, hyperphosphorylated tau protein formation, abrupt cholinergic cascade, oxidative stress, neuronal apoptosis, and neuroinflammation. Recent findings have established the profound role of immunological dysfunction and microglial activation in the pathogenesis of AD. Microglial activation is a multifactorial cascade encompassing various signalling molecules and pathways such as Nrf2/NLRP3/NF-kB/p38 MAPKs/ GSK-3β. Additionally, deposited Aβ or tau protein triggers microglial activation and accelerates its pathogenesis. Currently, the FDA-approved therapeutic regimens are based on the modulation of the cholinergic system, and recently, one more drug, aducanumab, has been approved by the FDA. On the one hand, these drugs only offer symptomatic relief and not a cure for AD. Additionally, no targetedbased microglial medicines are available for treating and managing AD. On the other hand, various natural products have been explored for the possible anti-Alzheimer effect via targeting microglial activation or different targets of microglial activation. Therefore, the present review focuses on exploring the mechanism and associated signalling related to microglial activation and a detailed description of various natural products that have previously been reported with anti-Alzheimer’s effect via mitigation of microglial activation. Additionally, we have discussed the various patents and clinical trials related to managing and treating AD.

Why Pharmacovigilance of Non-steroidal Anti-inflammatory Drugs is Important in India?

Background: Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are among the drugs that are most regularly administered to manage inflammation and pain. Over-the-Counter (OTC) NSAIDs are widely accessible, particularly in developing countries like India. This casual approach to using NSAIDs may operate as a magnet for NSAID-related adverse drug reactions (ADRs) among patients.

Objectives: As patients in India are less informed about the appropriate use of NSAIDs and consumption patttern, adverse drug reactions, and the importance of reporting ADRs, the current study's objective is to promote patient safety by using pharmacovigilance as a tool to educate patients.

Methods: A targeted literature methodology was utilized to gather the data pertaining to NSAIDs, their ADRs and their pharmacovigilance. Different scientific databases, such as Science Direct, PubMed, Wiley Online Library, Springer, and Google Scholar, along with authentic textbooks, were explored as reference literature.

Results: In general, NSAIDs consumption pattern depends upon the different age groups. Around 1.6 billion tablets of NSAIDs are consumed in India for ailments, such as headaches, arthritis, menstrual cramps, osteoarthritis, back pain, rheumatoid arthritis, gout, osteoporosis, tendinitis, cancer pain and chronic pain. Common ADRs of NSAIDs include nausea, vomiting, headache, gastritis, abdominal pain, and diarrhoea. Also, they can cause renal damage and cardiovascular problems if not consumed in a dose-dependent manner. However, Diclofenac and Ibuprofen have both been linked to depression and dementia. There have been reports of aplastic anaemia, agranulocytosis linked to phenylbutazone, Stevens-Johnson, and Lyell's syndrome linked to isoxicam and piroxicam, as well as the vulnerability of new-borns to Reye's syndrome after aspirin use. Lack of awareness, time constraints and unpredictability, poor training in ADRs identification, etc., are some of the reasons for the under-reporting of ADR of NSAIDs in India.

Conclusion: In order to rationally prescribe NSAIDs, it is essential to be aware of probable ADR’s and establish prescription guidelines. Prescribers' behaviour can be changed toward excellent prescribing practices by conducting routine prescription assessments dealing with NSAIDs and providing feedback. In the near future, it will be critical to strengthen ADR data management and expand the reach of pharmacovigilance programs, ADR monitoring centers, and healthcare professionals' especially pharmacists’ training in rural locations.

An Update on Parkinson’s Disease and its Neurodegenerative Counterparts

Introduction: Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases.

Background: Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism.

Method: Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers.

Results: Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations.

Conclusion: We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.

Disruptions of Gut Microbiota are Associated with Cognitive Deficit of Preclinical Alzheimer's Disease: A Cross-Sectional Study

Background: Alzheimer's Disease (AD) is the most prevalent type of dementia. The early change of gut microbiota is a potential biomarker for preclinical AD patients.

Objective: The study aimed to explore changes in gut microbiota characteristics in preclinical AD patients, including those with Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI), and detect the correlation between gut microbiota characteristics and cognitive performances.

Methods: This study included 117 participants [33 MCI, 54 SCD, and 30 Healthy Controls (HC)]. We collected fresh fecal samples and blood samples from all participants and evaluated their cognitive performance. We analyzed the diversity and structure of gut microbiota in all participants through qPCR, screened characteristic microbial species through machine learning models, and explored the correlations between these species and cognitive performances and serum indicators.

Results: Compared to the healthy controls, the structure of gut microbiota in MCI and SCD patients was significantly different. The three characteristic microorganisms, including Bacteroides ovatus, Bifidobacterium adolescentis, and Roseburia inulinivorans, were screened based on the best classification model (HC and MCI) having intergroup differences. Bifidobacterium adolescentis is associated with better performance in multiple cognitive scores and several serum indicators. Roseburia inulinivorans showed negative correlations with the scores of the Functional Activities Questionnaire (FAQ).

Conclusion: The gut microbiota in patients with preclinical AD has significantly changed in terms of composition and richness. Correlations have been discovered between changes in characteristic species and cognitive performances. Gut microbiota alterations have shown promise in affecting AD pathology and cognitive deficit.

Biology of Tenascin C and its Role in Physiology and Pathology

Tenascin-C (TNC) is a multimodular extracellular matrix (ECM) protein hexameric with several molecular forms (180-250 kDa) produced by alternative splicing at the pre-mRNA level and protein modifications. The molecular phylogeny indicates that the amino acid sequence of TNC is a well-conserved protein among vertebrates. TNC has binding partners, including fibronectin, collagen, fibrillin-2, periostin, proteoglycans, and pathogens. Various transcription factors and intracellular regulators tightly regulate TNC expression. TNC plays an essential role in cell proliferation and migration. Unlike embryonic tissues, TNC protein is distributed over a few tissues in adults. However, higher TNC expression is observed in inflammation, wound healing, cancer, and other pathological conditions. It is widely expressed in a variety of human malignancies and is recognized as a pivotal factor in cancer progression and metastasis. Moreover, TNC increases both pro-and anti-inflammatory signaling pathways. It has been identified as an essential factor in tissue injuries such as damaged skeletal muscle, heart disease, and kidney fibrosis. This multimodular hexameric glycoprotein modulates both innate and adaptive immune responses regulating the expression of numerous cytokines. Moreover, TNC is an important regulatory molecule that affects the onset and progression of neuronal disorders through many signaling pathways. We provide a comprehensive overview of the structural and expression properties of TNC and its potential functions in physiological and pathological conditions.

Beyond Conventional Therapies: Molecular Dynamics of Alzheimer's Treatment through CLOCK/BMAL1 Interactions

Background: Alzheimer's Disease (AD) represents a neurodegenerative disorder characterized by cognitive and behavioral impairments significantly hindering social and occupational functioning. Melatonin, a hormone pivotal in regulating the body's intrinsic circadian rhythm, also acts as a catalyst in the breakdown of beta-amyloid deposits, offering a promising therapeutic approach for AD. The upregulation of Brain and Muscle ARNT-Like 1 (Bmal1) gene expression, stimulated by melatonin, emerges as a potential contributor to AD intervention. Current pharmacological interventions, such as FDA-approved cholinesterase inhibitors and the recently authorized monoclonal antibody, Lecanemab, are utilized in AD management. However, the connection between these medications and Bmal1 remains insufficiently explored.

Objective: This study aims to investigate the molecular effects of FDA-endorsed drugs on the CLOCK: Bmal1 dimer. Furthermore, considering the interactions between melatonin and Bmal1, this research explores the potential synergistic efficacy of combining these pharmaceutical agents with melatonin for AD treatment.

Methods: Using molecular docking and MM/PBSA methodologies, this research determines the binding affinities of drugs within the Bmal1 binding site, constructing interaction profiles.

Results: The findings reveal that, among FDA-approved drugs, galanthamine and donepezil demonstrate notably similar binding energy values to melatonin, interacting within the Bmal1 binding site through analogous amino acid residues and functional groups.

Conclusion: A novel therapeutic approach emerges, suggesting the combination of melatonin with Lecanemab as a monoclonal antibody therapy. Importantly, prior research has not explored the effects of FDA-approved drugs on Bmal1 expression or their potential for synergistic effects.

Estimating Dementia Onset: AT(N) Profiles and Predictive Modeling in Mild Cognitive Impairment Patients

Background: Mild Cognitive Impairment (MCI) usually precedes the symptomatic phase of dementia and constitutes a window of opportunities for preventive therapies.

Objectives: The objective of this study was to predict the time an MCI patient has left to reach dementia and obtain the most likely natural history in the progression of MCI towards dementia.

Methods: This study was conducted on 633 MCI patients and 145 subjects with dementia through 4726 visits over 15 years from Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. A combination of data from AT(N) profiles at baseline and longitudinal predictive modeling was applied. A data-driven approach was proposed for categorical diagnosis prediction and timeline estimation of cognitive decline progression, which combined supervised and unsupervised learning techniques.

Results: A reduced vector of only neuropsychological measures was selected for training the models. At baseline, this approach had high performance in detecting subjects at high risk of converting from MCI to dementia in the coming years. Furthermore, a Disease Progression Model (DPM) was built and also verified using three metrics. As a result of the DPM focused on the studied population, it was inferred that amyloid pathology (A+) appears about 7 years before dementia, and tau pathology (T+) and neurodegeneration (N+) occur almost simultaneously, between 3 and 4 years before dementia. In addition, MCI-A+ subjects were shown to progress more rapidly to dementia compared to MCI-A- subjects.

Conclusion: Based on proposed natural histories and cross-sectional and longitudinal analysis of AD markers, the results indicated that only a single cerebrospinal fluid sample is necessary during the prodromal phase of AD. Prediction from MCI into dementia and its timeline can be achieved exclusively through neuropsychological measures.

Multimodal Gamma Stimulation Improves Activity but not Memory in Aged Tgf344-AD Rats

Background: Multimodal sensory gamma stimulation is a treatment approach for Alzheimer’s disease that has been shown to improve pathology and memory in transgenic mouse models of Alzheimer's. Because rats are closer to humans in evolution, we tested the hypothesis that the transgenic rat line bearing human APP and PS1, line TgF344-AD, would be a good supplemental candidate to test the efficacy of this treatment. Current therapy approaches under investigation seek to utilize the immune response to minimize or degrade the accumulation of β-amyloid plaque load in mouse models designed to overexpress Aβ. However, many of these models lack some of the hallmarks of Alzheimer's disease, such as hyperphosphorylated tau and neuronal cell loss. The TgF344-AD transgenic rat model is a good candidate to bridge the gap between mouse models and clinical efficacy in humans.

Objective: The objective of this study was to use multimodal gamma stimulation at light and auditory modalities simultaneously to test whether this enhances memory performance as measured by the object location task and the spontaneous alternation task.

Methods: In our study, we designed and built a low-cost, easy-to-construct multimodal light and sound gamma stimulator. Our gamma stimulation device was built using an Arduino microcontroller, which drives lights and a speaker at the gamma frequency. We have included in this paper our device’s parts, hardware design, and software architecture for easy reproducibility. We then performed an experiment to test the effect of multimodal gamma stimulation on the cognitive performance of fourteen-month-old TgF344-AD rats. Rats were randomly assigned to either an experimental group that received gamma stimulation or a control group that did not. Performance in a Novel Object Location (NOL) task and spontaneous alternation task was evaluated in both groups before and after the treatment.

Results: Multimodal gamma stimulation did not improve memory compared to unstimulated TgF344-AD rats. However, the gamma-stimulated rats did spend significantly more time exploring objects in the novel location task than the unstimulated rats. In the spontaneous alternation task, gamma-stimulated rats exhibited significantly greater exploratory activity than unstimulated controls.

Conclusion: Multimodal gamma stimulation did not enhance memory performance in the object location task or the spontaneous alternation task. However, in both tasks, the treatment group had improved measures of exploratory activity relative to the untreated group. We conclude that several limitations could have contributed to this mixed effect, including aging complications, different animal models, or light cycle effects.

Alzheimer's Disease and Suicide: An Integrative Literature Review

Introduction: Suicide has been described in patients with Alzheimer's disease. Some promising medications for treating Alzheimer's disease have had their studies suspended because they increase the risk of suicide. Understanding the correlations between suicide and Alzheimer's disease is essential in an aging world.

Methods: A search was carried out on electronic websites (PubMed and Scielo) using the MeSH Terms “suicide” and “Alzheimer” (1986-2023). Of a total of 115 articles, 26 were included in this review.

Results: Depression and the allele ε4 of Apolipoprotein (APOE4) were demonstrated to be the main risk factors for suicide in patients with Alzheimer's disease.

Conclusion: Adequately delineating which elderly people are vulnerable to suicide is important so that new treatments for Alzheimer's disease can be successful. This review showed a need for new studies to investigate the interface between Alzheimer's disease and suicide.

Proton Pump Inhibitors and Cognitive Health: Review on Unraveling the Dementia Connection and Co-morbid Risks

Dementia, an international health issue distinguished by the impairment of daily functioning due to cognitive decline, currently affects more than 55 million people worldwide, with the majority residing in low-income and middle-income countries. Globally, dementia entails significant economic burdens in 2019, amounting to a cost of 1.3 trillion US dollars. Informal caregivers devote considerable hours to providing care for those affected. Dementia imposes a greater caregiving and disability-adjusted life-year burden on women. A recent study has established a correlation between prolonged Proton Pump Inhibitor (PPI) usage and dementia, in addition to other neurodegenerative conditions. PPIs are frequently prescribed to treat peptic ulcers and GERD (gastroesophageal reflux disease) by decreasing stomach acid secretion. They alleviate acid-related symptoms through the inhibition of acid-secreting H⁺-K⁺ ATPase. In a number of observational studies, cognitive decline and dementia in the elderly have been linked to the use of PPIs. The precise mechanism underlying this relationship is unknown. These drugs might also alter the pH of brain cells, resulting in the accumulation of amyloid-beta (Aβ) peptides and the development of Alzheimer's disease (AD). Despite the compelling evidence supporting the association of PPIs with dementia, the results of studies remain inconsistent. The absence of a correlation between PPI use and cognitive decline in some studies emphasizes the need for additional research. Chronic PPI use can conceal underlying conditions, including cancer, celiac disease, vitamin B12 deficiency, and renal injury, highlighting dementia risk and the need for further investigations on cognitive health.

Handwriting Markers for the Onset of Alzheimer’s Disease

Introduction: Alzheimer's disease has an impact on handwriting (AD). Numerous researchers reported that fact. Therefore, examining handwriting characteristics could be a useful way to screen for AD. The aim of the article is to present the reliability and effectiveness of the AD-HS tool.

Methods: Most of the existing studies examine either linguistic manifestations of writing or certain motor functions. However, handwriting is a complex of cognitive and motor activities. Since the influence of AD on handwriting is individual, it is important to analyze the complete set of handwriting features. The AD-HS instrument is based on this principle. Validation of the AD-HS instrument for revealing cognitive impairment in AD-diagnosed persons in comparison to the control group. The study is based on the evaluation of free handwritten texts. AD-HS includes 40 handwriting and 2 linguistic features of handwritten texts. It is based on the standard protocol for handwriting analysis. The cumulative evaluation of all features builds a quantitative AD-Indicator (ADI) as a marker of possible AD conditions. The analyzed experiment includes 53 AD-diagnosed persons and a control group of 192 handwriting specimens from the existing database.

Results: AD-HS shows a distinct difference in evaluated ADI for the participants (the mean value equals 0.49) and the control group (the mean value equals 0.28).

Conclusion: The handwriting marker of AD could be an effective supplement instrument for earlier screening. It is also useful when traditional biomarkers and neurological tests could not be applied. AD-HS can accompany therapy as an indication of its effect on a person.

The Association of Allergy-Related and Non-Allergy-Related Olfactory Impairment with Cognitive Function in Older Adults: Two Cross- Sectional Studies

Background: Evidence on the association of Olfactory Impairment (OI) with age-related cognitive decline is inconclusive, and the potential influence of allergy remains unclear.

Objective: We aimed to evaluate the cross-sectional associations of allergy-related and non-allergy- related OI to cognitive function.

Methods: We included 2,499 participants from the Health and Retirement Study (HRS)-Harmonized Cognitive Assessment Protocol (HCAP) sub-study and 1,086 participants from the English Longitudinal Study of Ageing (ELSA)-HCAP. The Olfactory Function Field Exam (OFFE) using Sniffin’ Stick odor pens was used to objectively assess olfactory function and an olfactory score <6/11 indicated OI. Mini-Mental Status Examination (MMSE) was used to assess global cognitive function and define cognitive impairment (<24/30). A neuropsychologic battery was used to assess five cognitive domains.

Results: Compared to non-OI participants, individuals with OI had lower MMSE z-score [β_HRS = -0.33, 95% Confidence Interval (CI): -0.41 to -0.24; β_ELSA = -0.31, -0.43 to -0.18] and higher prevalence of cognitive impairment (Prevalence Ratio (PR)HRS = 1.46, 1.06 to 2.01; PR_ELSA = 1.63, 1.26 to 2.11). The associations were stronger for non-allergy-related OI (β_HRS = -0.36; β_ELSA = -0.34) than for allergy-related OI (β_HRS = -0.26; β_ELSA = 0.13). Similar associations were observed with domain- specific cognitive function measures.

Conclusion: OI, particularly non-allergy-related OI, was related to poorer cognitive function in older adults. Although the current cross-sectional study is subject to several limitations, such as reverse causality and residual confounding, the findings will provide insights into the OI-cognition association and enlighten future attention to non-allergy-related OI for the prevention of potential cognitive impairment.

Association Between Cannabis Use and Subjective Cognitive Decline: Findings from the Behavioral Risk Factor Surveillance System (BRFSS)

Background: Cannabis consumption has rapidly increased in the United States due to more states legalizing non-medical and medical use. There is limited research, however, investigating whether cannabis may be associated with cognitive function, particularly across multiple dimensions of cannabis use.

Objective: The objective of this study was to examine whether cannabis consumption reason, frequency, and method are associated with subjective cognitive decline (SCD).

Methods: Data were obtained from 4,744 U.S. adults aged 45 and older in the 2021 Behavioral Risk Factor Surveillance System (BRFSS). SCD was a self-reported increase in confusion or memory loss in the past year. Odds of SCD by cannabis use reason, frequency, and methods (e.g., smoke, eat, vaporize) were examined using multiple logistic regression after imputing missing data, applying sampling weights, and adjusting for sociodemographic, health, and substance use covariates.

Results: Compared to non-users, non-medical cannabis use was significantly associated with 96% decreased odds of SCD (aOR=0.04, 95% CI=0.01-0.44, p<.01). Medical (aOR=0.46, 95% CI=0.06-3.61, p=.46) and dual medical and non-medical use (aOR=0.30, 95% CI=0.03-2.92, p=.30) were also associated with decreased odds of SCD, although not significant. Cannabis consumption frequency and method were not significantly associated with SCD.

Conclusion: The reason for cannabis use, but not frequency and method, is associated with SCD. Further research is needed to investigate the mechanisms that may contribute to the observed associations between non-medical cannabis use and decreased odds of SCD.

Therapeutic Potential and Prospects of L-arginine in Various Diseases and its Clinical Intervention

The goal of this review is to explored the therapeutic application of L-Arginine (L-ARG) against various pathological illnesses, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), cardiovascular disorder, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS), sickle cell anemia, tumour, epilepsy, erectile dysfunction therapy (ED), gestational hypertension (GH), and menopause issues. L-ARG is an important semi-essential alpha-amino acid that serves as a natural precursor for the synthesis of nitric oxide (NO). It is generally synthesized from proteinogenic amino acid proline through glutamine and glutamate. The degradation of L-ARG is a complex process due to the expression of multiple enzymes in the form of a substrate. The metabolism of L-ARG takes place in various multiple pathways, such as nitric oxide synthase, Arginine glycine amidinotransferase, and Arginine decarboxylase which results in the production of a diverse range of biochemical compounds, such as nitric oxide, polyamines, proline, glutamate, creanine, agmatine homoarginine, and urea. NO is a highly diffusible free radicle with a regulatory function in the heart and acts as an important vasodilator in intact endothelium. NO serves as an important neurotransmitter in the brain and a mediator of host defense in the immune system. L-ARG is also needed for ammonia detoxification, which is a very toxic chemical to the central nervous system. This review article focuses on the relevance of L-ARG in the prevention and treatment of a variety of illnesses.

Neuronal Vulnerability to Degeneration in Parkinson’s Disease and Therapeutic Approaches

Parkinson's disease is the second most common neurodegenerative disease affecting millions of people worldwide. Despite the crucial threat it poses, currently, no specific therapy exists that can completely reverse or halt the progression of the disease. Parkinson's disease pathology is driven by neurodegeneration caused by the intraneuronal accumulation of alpha-synuclein (α-syn) aggregates in Lewy bodies in the substantia nigra region of the brain. Parkinson’s disease is a multiorgan disease affecting the central nervous system (CNS) as well as the autonomic nervous system. A bidirectional route of spreading α-syn from the gut to CNS through the vagus nerve and vice versa has also been reported. Despite our understanding of the molecular and pathophysiological aspects of Parkinson’s disease, many questions remain unanswered regarding the selective vulnerability of neuronal populations, the neuromodulatory role of the locus coeruleus, and alpha-synuclein aggregation. This review article aims to describe the probable factors that contribute to selective neuronal vulnerability in Parkinson’s disease, such as genetic predisposition, bioenergetics, and the physiology of neurons, as well as the interplay of environmental and exogenous modulators. This review also highlights various therapeutic strategies with cell transplants, through viral gene delivery, by targeting α-synuclein and aquaporin protein or epidermal growth factor receptors for the treatment of Parkinson’s disease. The application of regenerative medicine and patient-specific personalized approaches have also been explored as promising strategies in the treatment of Parkinson’s disease.

Emerging Nanotechnology for the Treatment of Alzheimer’s Disease

Nanotechnology is a great choice for medical research, and the green synthesis approach is a novel and better way to synthesize nanoparticles. Biological sources are cost-effective, environmentally friendly, and allow large-scale production of nanoparticles. Naturally obtained 3 β-hydroxy-urs- 12-en-28-oic acids reported for neuroprotective and dendritic structure are reported as solubility enhancers. Plants are free from toxic substances and act as natural capping agents. In this review, the pharmacological properties of ursolic acid (UA) and the structural properties of the dendritic structure are discussed. UA acid appears to have negligible toxicity and immunogenicity, as well as favorable biodistribution, according to the current study, and the dendritic structure improves drug solubility, prevents drug degradation, increases circulation time, and potentially targets by using different pathways with different routes of administration. Nanotechnology is a field in which materials are synthesized at the nanoscale. Nanotechnology could be the next frontier of humankind's technological advancement. Richard Feynman first used the term ‘Nanotechnology’ in his lecture, “There is Plenty of Room at the Bottom”, on 29th December, 1959, and since then, interest has increased in the research on nanoparticles. Nanotechnology is capable of helping humanity by solving major challenges, particularly in neurological disorders like Alzheimer's disease (AD), the most prevalent type, which may account for 60-70% of cases. Other significant forms of dementia include vascular dementia, dementia with Lewy bodies (abnormal protein aggregates that form inside nerve cells), and a number of illnesses that exacerbate frontotemporal dementia. Dementia is an acquired loss of cognition in several cognitive domains that are severe enough to interfere with social or professional functioning. However, dementia frequently co-occurs with other neuropathologies, typically AD with cerebrovascular dysfunction. Clinical presentations show that neurodegenerative diseases are often incurable because patients permanently lose some neurons. A growing body of research suggests that they also advance our knowledge of the processes that are probably crucial for maintaining the health and functionality of the brain. Serious neurological impairment and neuronal death are the main features of neurodegenerative illnesses, which are also extremely crippling ailments. The most prevalent neurodegenerative disorders cause cognitive impairment and dementia, and as average life expectancy rises globally, their effects become more noticeable.

Risk Stratification in People with Diabetes for Fasting During Ramadan: Consensus from Arabic Association for the Study of Diabetes and Metabolism

Background: Current international guidelines recommend a pre-Ramadan risk assessment for people with diabetes (PwDM) who plan on fasting during the Holy month. However, a comprehensive risk assessment-based recommendation for the management of PwDM intending to fast is still controversial. Therefore, the Arabic Association for the Study of Diabetes and Metabolism (AASD) developed this consensus to provide further insights into risk stratification in PwDM intending to fast during Ramadan.

Methods: The present consensus was based on the three-step modified Delphi method. The modified Delphi method is based on a series of voting rounds and in-between meetings of the expert panel to reach agreements on the statements that did not reach the consensus level during voting. The panel group comprised professors and consultants in endocrinology (both adult and pediatric). Other members included experts in the fields of cardiovascular medicine, nephrology, ophthalmology, and vascular surgery, affiliated with academic institutions in Egypt.

Result: In PwDM who intend to fast during Ramadan, risk stratification is crucial to optimize patient outcomes and prevent serious complications. The present consensus provides risk assessment of those living with diabetes according to several factors, including the type of diabetes, presence, and severity of complications, number of fasting hours, and other socioeconomic factors. According to their risk factors, patients were classified into four categories (very high, high, moderate, and low risk).

Conclusion: Future research is warranted due to the controversial literature regarding the impact of fasting on certain comorbidities.

Revolutionizing Drug Discovery: The Role of Artificial Intelligence and Machine Learning

Montelukast Ameliorates 2K1C-Hypertension Induced Endothelial Dysfunction and Associated Vascular Dementia

Background: Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT₁) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis.

Objective: This research aims to examine the consequence of montelukast (specific CysLT₁ antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals.

Methods: 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain’s oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined.

Results: Montelukast in doses of 5.0 and 10.0 mg kg^-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension- provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction.

Conclusion: The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT₁ receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.

Glutamate Receptors and C-ABL Inhibitors: A New Therapeutic Approach for Parkinson's Disease

Parkinson's disease (PD) is the second-most prevalent central nervous system (CNS) neurodegenerative condition. Over the past few decades, suppression of BCR-Abelson tyrosine kinase (c-Abl), which serves as a marker of -synuclein aggregation and oxidative stress, has shown promise as a potential therapy target in PD. c-Abl inhibition has the potential to provide neuroprotection against PD, as shown by experimental results and the first-in-human trial, which supports the strategy in bigger clinical trials. Furthermore, glutamate receptors have also been proposed as potential therapeutic targets for the treatment of PD since they facilitate and regulate synaptic neurotransmission throughout the basal ganglia motor system. It has been noticed that pharmacological manipulation of the receptors can change normal as well as abnormal neurotransmission in the Parkinsonian brain. The review study contributes to a comprehensive understanding of the approach toward the role of c-Abl and glutamate receptors in Parkinson's disease by highlighting the significance and urgent necessity to investigate new pharmacotherapeutic targets. The article covers an extensive insight into the concept of targeting, pathophysiology, and c-Abl interaction with α-synuclein, parkin, and cyclin-dependent kinase 5 (Cdk5). Furthermore, the concepts of Nmethyl- D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA) receptor, and glutamate receptors are discussed briefly. Conclusion: This review article focuses on in-depth literature findings supported by an evidence-based discussion on pre-clinical trials and clinical trials related to c-Abl and glutamate receptors that act as potential therapeutic targets for PD.

Sulfonamide Derivatives: Recent Compounds with Potent Anti-alzheimer’s Disease Activity

Facile synthetic procedures and broad spectrum of biological activities are special attributes of sulfonamides. Sulfonamide derivatives have demonstrated potential as a class of compounds for the treatment of Alzheimer's disease (AD). Recent sulfonamide derivatives have been reported as prospective anti-AD agents, with a focus on analogues that significantly inhibit the function of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes and exhibit remarkable antioxidant and anti-inflammatory properties, all of which are critical for the treatment of AD. Sulfonamide- mediated activation of nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of the endogenous antioxidant response, has also been suggested as a potential therapeutic approach in AD. Additionally, it has been discovered that a number of sulfonamide derivatives show selectivity for the β- and γ-secretase enzymes and a significant reduction of amyloid B (Aβ) aggregation, which have been implicated in AD. The comparative molecular docking of benzenesulfonamide and donepezil, an AD reference drug showed comparable anti-AD activities. These suggest that sulfonamide derivatives may represent a new class of drugs for the treatment of AD. Thus, the current review will focus on recent studies on the chemical synthesis and evaluation of the anti-AD properties, molecular docking, pharmacological profile, and structure-activity relationship (SAR) of sulfonamide derivatives, as well as their potential anti-AD mechanisms of action. This paper offers a thorough assessment of the state of the art in this field of study and emphasizes the potential of sulfonamide derivatives synthesized during the 2012-2023 period as a new class of compounds for the treatment of AD.

Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases

Mitochondria are essential organelles for the survival of a cell because they produce energy. The cells that need more mitochondria are neurons because they perform a variety of tasks that are necessary to support brain homeostasis. The build-up of abnormal proteins in neurons, as well as their interactions with mitochondrial proteins, or MAM proteins, cause serious health issues. As a result, mitochondrial functions, such as mitophagy, are impaired, resulting in the disorders described in this review. They are also due to mtDNA mutations, which alter the heritability of diseases. The topic of disease prevention, as well as the diagnosis, requires further explanation and exploration. Finally, there are treatments that are quite promising, but more detailed research is needed.

Cholinergic Transporters Serve as Potential Targets in Alzheimer’s Disease

Alzheimer's disease (AD) is a specific brain disease that gradually worsens due to dementia over a long period. AD accounts for almost 60% to 80% of cases of dementia. Any damage to neurons affects their ability to communicate, leading to alteration in thinking, behaviour and feelings. Besides mental, motor abilities of an individual may also be affected due to AD. Therefore, it is cardinal to understand the key mechanisms by which either AD progression can be ceased or, after the onset of the disease it could be reverted. Both of these steps need the identification of a particular receptor or a molecular marker through which a drug can enter the neurons. Cholinergic transporters are such potential targets of AD, which regulate the movement of acetylcholine and thus regulate the nerve impulse conduction in the brain. The current article entails information regarding a variety of cholinergic transporters, which will provide a research gap to the global scientific community.

Erucic Acid: A Possible Therapeutic Agent for Neurodegenerative Diseases

Neurodegenerative disorders are among the most common life-threatening disorders among the elderly worldwide and are marked by neuronal death in the brain and spinal cord. Several studies have demonstrated the beneficial role of dietary fatty acids in different brain disorders. This is due to their neurotrophic, antioxidant, and anti-inflammatory properties. Furthermore, extensive evidence shows that an unbalanced intake of certain dietary fatty acids increases the risk of neuropsychiatric diseases. Several research has been done on erucic acid, an ingestible omega-9 fatty acid that is found in Lorenzo's oil. Erucic acid was previously thought to be a natural toxin because of its negative effects on heart muscle function and hepatic steatosis, but it has been discovered that erucic acid is regularly consumed in Asian countries through the consumption of cruciferous vegetables like mustard and rapeseed oil with no evidence of cardiac harm. Erucic acid can also be transformed into nervonic acid, a crucial element of myelin. Therefore, erucic acid may have remyelinating effects, which may be crucial for treating different demyelinating conditions. Also, erucic acid exerts antioxidant and anti-inflammatory effects, suggesting its possible therapeutic role in different neurodegenerative disorders. Considering the fruitful effects of this compound, this article reviews the probable role of erucic acid as a pharmacological agent for treating and managing different neurodegenerative disorders.

Neuropsychiatric Symptoms are Related to Blood-biomarkers in Major Neurocognitive Disorders

Background: Neuropsychiatric symptoms (NPS) are highly prevalent among individuals with major neurocognitive disorders (MNCD). Objective: Here, we characterized blood biomarkers (metabolic, inflammatory, neurotrophic profiles and total antioxidant), body composition, physical fitness and quality of life (QoL) in individuals with MNCD according to NPS.

Methods: The sample comprised 34 older adults (71.4% women; 74.06±6.03 yrs, with MNCD diagnosis) categorized according to 50th percentile [Low (≤12) or High (≥13)] for NPS (Neuropsychiatric Inventory Questionnaire). Sociodemographic, clinical data, body composition, anthropometric, cognitive assessment (ADAS-Cog), physical fitness (Senior Fitness Test), QoL (QoL-Alzheimer’s Disease scale) were evaluated, and blood samples were collected for biochemical analysis.

Results: Low compared to high NPS group showed higher levels of IL-6, IGF-1and neurotrophic zscore (composite of IGF-1, VEGF-1, BDNF). Additionally, low compared to high NPS group have higher QoL, aerobic fitness and upper body and lower body strength.

Conclusion: The severity of NPS seems to be related to modified neurotrophic and inflammatory outcomes, lower physical fitness, and poor QoL. Strategies to counteract NPS development may preserve the physical and mental health of individuals with MNCD.