Central Nervous System Vascular Malformations

Intracranial Structural Malformations in Children in Tibet: CT and MRI Findings in a Single Tertiary Center

Objectives: The objective of this study was to summarize the findings of children’s intracranial congenital or developmental malformations found during imaging procedures in the Tibetan plateau.

Methods: We retrospectively reviewed the imaging data of the suspected patients who presented with the central nervous system (CNS) malformations and were enrolled either through the clinic or after ultrasound examinations between June 2019 and June 2023 in our institution. All imaging data were interpreted by two experienced radiologists through consensus reading.

Results: In this study, we recruited 36 patients, including two neonates, 17 infants and 17 children. Seven cases underwent an MRI examination, while the others had a CT scan. Polygyria and pachygyria malformation were the most common type of congenital neurological malformations (7 cases, 31.8%), followed by cystic changes of the cerebral parenchyma (3 cases, 13.6%). Cerebral atrophy was the most common type of secondary CNS abnormality (8 cases, 57.1%), followed by communicative hydrocephalus (3 cases, 21.4%). Five patients in the congenital group and 4 patients in the secondary group had complex malformations. In the current study group, there were 8 deaths, 12 cases with neurological sequelae, 1 case with normal development, and 15 cases lost to follow-up. There were no significant differences between the primary and secondary CNS groups in terms of the outcome for both the infants and children groups.

Conclusions: CNS malformations in the Tibetan Plateau are associated with high mortality and morbidity rates. Better utilization of imaging modalities could help design tailored treatments as early as possible.

Imaging Features and Misdiagnosis of Giant Cerebral Cavernous Malformations

Background: While cerebral cavernous malformations (CCMs) have been extensively described, few reports have described the imaging appearance of giant CCMs (GCCMs).

Objective: To describe the imaging characteristics of GCCMs and study the reasons for preoperative misdiagnosis.

Methods: We retrospectively analyzed the data of 12 patients (5 men, 7 women; mean age, 35.23 ± 12.64 years) with histopathologically confirmed GCCMs. Two radiologists analyzed the CT (n = 12) and MRI (n = 10) features: location, number, size, shape, boundary, signal intensity, and enhancement.

Results: The sellar region, cerebral hemisphere, skull bone, and ventricle were involved in 5, 4, 2, and 1 patients, respectively. Three tumors were irregularly shaped, while nine were oval. Eleven lesions showed slightly high- and/or high-density on CT; 1 lesion appeared as a low-density cyst. Calcifications were found in 11 lesions. Four tumors showed uniform hypointensity on T1-weighted imaging (T1WI) and hyperintense signals on T2-weighted imaging (T2WI). Six tumors showed mixed low-, equal-, and high-intensity signals on T1WI and T2WI. Noticeable contrast enhancement and gradual strengthening were noted on T1WI. Ten lesions showed hemorrhage and hemosiderin deposition. The GCCMs were wrongly diagnosed as cartilage-derived tumors/ meningioma (3 patients); tumor and hematoma (2 patients each); and pituitary tumor/ meningioma, chondroma, chordoma, ependymoma, and macroadenoma (1 patient each).

Conclusions: GCCMs present as an oval mass with slightly high- and/or high-density calcifications on CT and show hemorrhage and hemosiderin accumulation on MRI. Therefore, slightly high- and/or high-density calcification and hemosiderin accumulation are critical clinical characteristics of GCCMs.

Coexistence of Large Meningioma and Arteriovenous Malformation: A Case Report and Literature Review

Introduction The simultaneous presence of a giant intracranial meningioma and an arteriovenous malformation(AVM)in the same cerebral hemisphere is extremely rare. The treatment should be individualized depending on the case.

Case Presentation A 49-year-old man presented with hemiparesis. Preoperative neuroimaging revealed a giant lesion and an AVM on the left hemisphere of the brain. Craniotomy and tumour resection were performed. The AVM was not treated and needed to be followed up. The histological diagnosis was meningioma (World Health Organization grade I). The patient was in good neurological condition postoperatively.

Conclusion This case adds to the growing literature suggesting that the association between the two lesions is complex. Besides, treatment depends on the risk of neurologic function damage and hemorrhagic stroke of meningiomas and AVMs.

Malignant and Benign Head and Neck Tumors of the Pediatric Age: A Narrative Review

Malignant tumors of the head and neck are rare in children, but it is important to know these lesions and identify them early in order to have a good outcome for these patients. Benign lesions of the head and neck are much more frequent and have an excellent prognosis. For this reason, it is necessary to recognize the warning signs and symptoms and understand when to refer the patient to a reference center for the treatment of these pathologies. The clinical presentation of both benign and malignant lesions in children may be similar as usually, both categories have compressive effects. This confirms the fact that the clinical diagnosis is not sufficient and always requires instrumental investigations and biopsies. In this narrative review, we analyzed both malignant lesions such as lymphoma, rhabdomyosarcoma, thyroid tumors, salivary gland tumors, neuroblastoma, and nasopharyngeal carcinoma, and benign ones such as cystic dermoid teratoma, hemangioma, juvenile angiofibroma and fibrosis dysplasia. Indeed, we set out to discuss the most common lesions of this site by evaluating their characteristics to highlight the differentiation of malignant tumors from benign lesions and their correct clinical-therapeutic management. A literature search was carried out in the PubMed and Google Scholar databases to identify all narrative reviews addressing malignant and benign head and neck tumors of the pediatric age. In conclusion, the care of children affected by head and neck benign lesions and malignancy must be combined and multidisciplinary. It is essential to recognize the diseases early in order to differentiate and intervene as soon as possible for the correct clinical-therapeutic management.

Infratentorial Cerebral Cavernous Malformation May be a Risk Factor for Symptomatic Bleeding and Precocity of Symptoms: A Multicenter, Propensity Score Matched, Case-Control Study

Background: Cerebral Cavernous Malformation (CCM) is one of the most common types of vascular malformation of the central nervous system. Intracerebral hemorrhage, seizures, and lesional growth are the main clinical manifestations. Natural history studies have tried to identify many risk factors; however, the clinical course remains highly unpredictable.

Objective: Here, we have analyzed a multicenter CCM cohort looking for the differential clinical data regarding the patients harboring supra and/or infratentorial cavernous malformations in order to better understand risk factors involved in the anatomical location of the unique neurosurgical disease.

Methods: We have presented a multicenter, Propensity Score Matched (PSM), case-control study including 149 consecutive CCM cases clinically evaluated from May 2017 to December 2022 from three different neurosurgical centers. Epidemiological data were defined at each clinical assessment. Logistic regression was used to identify the independent contribution of each possible risk factor to the bleeding risk. To balance baseline covariates between patients with and without symptoms, and specifically between those with and without symptomatic bleeding, we used a PSM strategy. The Kaplan-Meier curve was drawn to evaluate if patients with infratentorial lesions had a greater chance of bleeding earlier in their life.

Results: The presence of infratentorial lesions was a risk factor in the multivariate analysis comparing the bleeding risk with pure asymptomatic individuals (OR: 3.23, 95% CI 1.43 – 7.26, P = 0.005). Also, having an infratentorial CCM was a risk factor after PSM (OR: 4.56, 95% CI 1.47 - 14.10, P = 0.008). The presence of an infratentorial lesion was related to precocity of symptoms when the time to first bleed was compared to all other clinical presentations in the overall cohort (P = 0.0328) and in the PSM group (P = 0.03).

Conclusion: Here, we have provided some evidence that infratentorial cerebral cavernous malformation may have a more aggressive clinical course, being a risk factor for symptomatic haemorrhage and precocity of bleeding.

An Updated Review on the Significance of DNA and Protein Methyltransferases and De-methylases in Human Diseases: From Molecular Mechanism to Novel Therapeutic Approaches

Epigenetic mechanisms are crucial in regulating gene expression. These mechanisms include DNA methylation and histone modifications, like methylation, acetylation, and phosphorylation. DNA methylation is associated with gene expression suppression; however, histone methylation can stimulate or repress gene expression depending on the methylation pattern of lysine or arginine residues on histones. These modifications are key factors in mediating the environmental effect on gene expression regulation. Therefore, their aberrant activity is associated with the development of various diseases. The current study aimed to review the significance of DNA and histone methyltransferases and demethylases in developing various conditions, like cardiovascular diseases, myopathies, diabetes, obesity, osteoporosis, cancer, aging, and central nervous system conditions. A better understanding of the epigenetic roles in developing diseases can pave the way for developing novel therapeutic approaches for affected patients.

Perinatal Management of Pregnancies with Fetal Congenital Anomalies: A Guide to Obstetricians and Pediatricians

Background: Congenital anomalies are responsible for approximately 20% of all neonatal deaths worldwide. Improvements in antenatal screening and diagnosis have significantly improved the prenatal detection of birth defects; however, these improvements have not translated into the improved neonatal prognosis of babies born with congenital anomalies.

Objectives: An attempt has been made to summarise the prenatal interventions, if available, the optimal route, mode and time of delivery and discuss the minimum delivery room preparations that should be made if expecting to deliver a fetus with a congenital anomaly.

Methods: The recent literature related to the perinatal management of the fetus with prenatally detected common congenital anomalies was searched in English peer-reviewed journals from the PubMed database to work out an evidence-based approach for their management.

Results: Fetuses with prenatally detected congenital anomalies should be delivered at a tertiary care centre with facilities for neonatal surgery and paediatric intensive care if needed. There is no indication for preterm delivery in the majority of cases. Only a few congenital malformations, like highrisk sacrococcygeal teratoma, congenital lung masses with significant fetal compromise, fetal cerebral lesions or neural tube defects with Head circumference >40 cm or the biparietal diameter is ≥12 cm, gastroschisis with extracorporeal liver, or giant omphaloceles in the fetus warrant caesarean section as the primary mode of delivery.

Conclusion: The prognosis of a fetus with congenital anomalies can be significantly improved if planning for delivery, including the place and time of delivery, is done optimally. A multidisciplinary team should be available for the fetus to optimize conditions right from when it is born.

Anti-obesity Properties of Phytochemicals: Highlighting their Molecular Mechanisms against Obesity

Obesity is a complex, chronic and inflammatory disease that affects more than one-third of the world’s population, leading to a higher incidence of diabetes, dyslipidemia, metabolic syndrome, cardiovascular diseases, and some types of cancer. Several phytochemicals are used as flavoring and aromatic compounds, also exerting many benefits for public health. This study aims to summarize and scrutinize the beneficial effects of the most important phytochemicals against obesity. Systematic research of the current international literature was carried out in the most accurate scientific databases, e.g., Pubmed, Scopus, Web of Science and Google Scholar, using a set of critical and representative keywords, such as phytochemicals, obesity, metabolism, metabolic syndrome, etc. Several studies unraveled the potential positive effects of phytochemicals such as berberine, carvacrol, curcumin, quercetin, resveratrol, thymol, etc., against obesity and metabolic disorders. Mechanisms of action include inhibition of adipocyte differentiation, browning of the white adipose tissue, inhibition of enzymes such as lipase and amylase, suppression of inflammation, improvement of the gut microbiota, and downregulation of obesity-inducing genes. In conclusion, multiple bioactive compounds-phytochemicals exert many beneficial effects against obesity. Future molecular and clinical studies must be performed to unravel the multiple molecular mechanisms and anti-obesity activities of these naturally occurring bioactive compounds.

Treating Sensorineural Hearing Loss: Recent Advances in Inner Ear Drug Delivery

This review aims to provide historical, present, and future drug deliveries for treating inner ear disorders. Systemic delivery, such as antibiotics and steroids for the inner ear, was the basis on which current drug delivery systems and devices have been researched and developed. Researchers and clinicians had to develop and deliver drugs locally due to adverse effects caused by drugs systemically. Intratympanic method of antibiotics and steroid delivery has been common; however, newer techniques such as microcatheter implantation, hydrogels, nanoparticles, and intracochlear implants are being investigated successfully. Recently advances in microfluidic and microsystems technology have applied medications directly into the inner ear. This technology will also be adopted to deliver gene therapy, RNA interference technology, and stem cell therapy by clinicians in the future.

Biomarkers in Hypertension and Hypertension-related Disorders

Systemic arterial hypertension (SAH) is a major risk factor for several secondary diseases, especially cardiovascular and renal conditions. SAH has a high prevalence worldwide, and its precise and early recognition is important to prevent the development of secondary outcomes. In this field, the study of biomarkers represents an important approach to diagnosing and predicting the disease and its associated conditions. The use of biomarkers in hypertension and hypertension-related disorders, such as ischemic stroke, intracerebral hemorrhage, transient ischemic attack, acute myocardial infarction, angina pectoris and chronic kidney disease, are discussed in this review. Establishing a potential pool of biomarkers may contribute to a non-invasive and improved approach for their diagnosis, prognosis, risk assessment, therapy management and pharmacological responses to a therapeutic intervention to improve patients' quality of life and prevent unfavorable outcomes.

Involvement of Metabolites and Non-coding RNAs in Diseases

Non-coding RNAs have a role in gene regulation and cellular metabolism control. Metabolism produces metabolites which are small molecules formed during the metabolic process. So far, a direct relationship between metabolites and genes is not fully established; however, pseudogenes and their progenitor genes regulate health and disease states. Other non-coding RNAs also contribute to this regulation at different cellular processes. Accumulation and depletion of metabolites accompany the dynamic equilibrium of health and disease state. In this study, metabolites, their roles in the cell, and the link between metabolites and non-coding RNAs are discussed.

Physiological Properties, Functions, and Trends in the Matrix Metalloproteinase Inhibitors in Inflammation-Mediated Human Diseases

Background: Matrix metalloproteinases (MMPs), also known as metalloproteinases, are enzymes that degrade proteins and require the presence of active metal atoms. There are more than 20 types of MMPs, and they promote cell migration through the proteolytic degradation of the extracellular basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM). In other words, they decompose most of the components related to the ECM, in their roles as key enzymes in cellular and pathophysiological events in the body.

Introduction: Zn²⁺-containing endo-type peptidases directly degrade and remodel the ECM region in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins in the ECM and the basement membranous region, which are the supporting structures of cells.

Methods: This review describes the developments in the research examining the general and selective inhibitors for MMP associated with various human diseases over the past 20 years in terms of structure remodeling, substrate-recognizing specificities, and pharmacological applicability.

Results: Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa, while MMP-9 is termed gelatinase-B with a 92 kDa. Both of these play a key role in this action. Therefore, both enzymatic expression levels coincide during the onset and progression of diseases. Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP- 9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance that inhibits MMPs would be very important for preventing and treating various MMP-dependent diseases.

Conclusion: Considerable research has examined MMP inhibitors, but most of these have been synthetic compounds. Research using natural products as MMP inhibitors has only recently become a subject of interest. This review intends to discuss recent research trends regarding the physiological properties, functions, and therapeutic agents related to MMPs.

Unravelling Micro and Nano Vesicular System in Intranasal Drug Delivery for Epilepsy

Background: Epilepsy is one of the major neurological disorders, affecting about 50 million people globally. Oral, intravenous and rectal delivery systems are available for the management of epileptic seizures. However, intranasal delivery serves as beneficial for delivering antiepileptic drugs owing to the advantages it offers.

Objective: Various approaches have been developed over the years aiming to attain either a safer or faster brain delivery; a nasal delivery system proposes significant outcomes. The noninvasiveness and high vascularity contribute to the high permeability of the nasal mucosa, allowing rapid drug absorption. This review highlights some promising novel approaches to efficiently deliver anti-epileptic drugs by employing the nasal route.

Methods: The method includes a collection of data from different search engines like PubMed, ScienceDirect and SciFinder for obtaining appropriate and relevant literature regarding epilepsy, intranasal delivery of anti-epileptic agents, and novel therapeutics.

Results: The present review underlines the majority of work related to intranasal delivery in the treatment of epilepsy, aiming to draw the attention of the researchers towards the easiest and most efficient ways of formulation for the delivery of anti-epileptics during seizures.

Conclusion: This review intends to provide an understanding of the delivery aspects of antiepileptic drugs, the benefits of intranasal delivery and the novel approaches employed for the treatment of epilepsy.

Perinatal Exposure to Bisphenol A and Developmental Programming of the Cardiovascular Changes in the Offspring

Bisphenol A (BPA) is an industrial ubiquitous compound, frequently used to produce synthetic polymers and epoxy resins. BPA is a well-recognized endocrine disruptor and xenoestrogen compound. Evidence from epidemiological and experimental studies suggests that perinatal BPA exposure (gestation and/or lactation) increases the risk of developing various diseases, including the cardiovascular system. Developmental programming refers to environmental insults during the critical window of development that affect the structure and physiology of body systems, causing permanent changes in later stages. BPA influences the developmental programming of non-communicable diseases in the offspring. In the present review, we discuss the developmental programming of cardiovascular diseases related to perinatal exposure to BPA, supported by epidemiological and experimental evidence from published literature. The majority of the reported studies found a positive association between perinatal BPA exposure and adverse cardiovascular repercussions in the fetal, neonatal, and adulthood stages. The possible underlying mechanisms include epigenetic modifications of genes involved in cardiac muscle development, autonomic tone, collagenous and non-collagenous extracellular matrix, cardiac remodeling and calcium homeostasis, and mitochondrial energy metabolism. Epigenetics can modify the outcome of any disease. Hence, in the present review, we also discuss the role of epigenetics in preventing cardiovascular diseases following perinatal exposure to BPA. We also highlight how future treatment and drug delivery related to cardiovascular involvement could be based on epigenetic markers.

High-output Cardiac Failure: A Forgotten Phenotype in Clinical Practice

Introduction: The knowledge on High-Output Cardiac Failure (HOCF) has greatly improved in the last two decades. One of the advances was the identification of a new phenotype of HOCF, characterized by the absence of ventricular dilation, already associated with liver disease, Arteriovenous Fistulas (AVF), lung disease, myelodysplastic syndromes, and obesity. However, it has been noted that any aetiology can present with one of the two phenotypes, depending on the evolution.

Objective: The study aims to describe, through an integrative review, the physiopathology and aetiologies of HOCF and to discuss phenotypes associated with this condition.

Methods: Revisions, guidelines, case-controls, cohort studies and clinical studies were searched in MEDLINE and LILACS, using the connectives in the “cardiac output, high” database (MeSH Terms) OR “high cardiac output” (All Fields).

Discussion: Two distinct phenotypes are currently described in the HOCF, regardless of the aetiology: 1) one with enlarged cardiac chambers; and 2) with normal heart chambers. The mechanisms related to HOCF are vasodilation, arteriovenous shunts that cause increased microvascular density, Reduced Systemic Vascular Resistance (RSVR), and high metabolism. These mechanisms lead to activation of the renin-angiotensin-aldosterone system, sodium and water retention, activation of neprilysin, of the sodium-glucose-2 transporter, which promote interstitial fibrosis, ventricular remodeling and a consequent increase in cardiac output >8L/min.

Conclusion: Many aetiologies of HOCF have been described, and some of them are potentially curable. Prompt recognition of this condition and proper treatment may lead to better outcomes.

Prospects of Non-Coding Elements in Genomic DNA Based Gene Therapy

Gene therapy has made significant development since the commencement of the first clinical trials a few decades ago and has remained a dynamic area of research regardless of obstacles such as immune response and insertional mutagenesis. Progression in various technologies like next-generation sequencing (NGS) and nanotechnology has established the importance of non-- coding segments of a genome, thereby taking gene therapy to the next level. In this review, we have summarized the importance of non-coding elements, highlighting the advantages of using full- length genomic DNA loci (gDNA) compared to complementary DNA (cDNA) or minigene, currently used in gene therapy. The focus of this review is to provide an overview of the advances and the future of potential use of gDNA loci in gene therapy, expanding the therapeutic repertoire in molecular medicine.

Valproic Acid and Propionic Acid Modulated Mechanical Pathways Associated with Autism Spectrum Disorder at Prenatal and Neonatal Exposure

Autism spectrum disorder (ASD) is a composite disorder of brain development with uncertain etiology and pathophysiology. Genetic factors are important in ASD causation, although environmental factors are also involved in ASD pathophysiology. Environmental factors might affect the genetic processes of brain development through the modulation of molecular pathways that might be involved with ASD. Valproic acid and propionic acid are the major environmental factors that serve as medicine and food preservative. VPA is used as an anti-epileptic medicine, but it has adverse effects on pregnant women and alters the developmental patterns of the embryo. It is a multi- targeting agent and affects 5-HT, GABA, etc. PPA is a secondary metabolite of gut microbiota that is commonly used as a food preservative. PPA plays a significant role in ASD causation by altering the several developmental molecular pathways like PTEN/Akt, mTOR/Gskβ, Cytokines activated pathways, etc., at the prenatal and neonatal stage. Moreover, ASD complexity might be increased by other important factors like vitamin A deficiency. Vitamin A is important for cortical brain development and neuronal cell differentiation. Additionally, several important genes such as RELN, Lhx2, CREB, IL-6, NMDA, BDNF, etc., are also altered in ASD and involved in brain development, central nervous system, and enteric nervous system. These genes affect neuronal differentiation, hyperactivity, oxidative stress, oxytocin, and GABA imbalance lead to improper behavior in autistic individuals. These genes are also studied in VPA and PPA ASD-like animal models. In this review, we explored the mechanical pathways that might be altered with VPA and PPA exposures at the embryonic developmental stage or neonatal developmental stage.

Advances in the Design and Development of PROTAC-mediated HDAC Degradation

Due to developments in modern chemistry, previously uundruggable substrates are now targetable thanks to selective degradation using the ubiquitin-proteasomal degradation system. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically to degrade target proteins. They are of significant interest to industry and academia as they are highly specific and can target previously undruggable target proteins from transcription factors to enzymes. More than 15 degraders are expected to be evaluated in clinical trials by the end of 2021. Herein, we describe recent advances in the design and development of PROTAC-mediated degradation of histone deacetylases (HDACs). PROTAC-mediated degradation of HDACs can offer some significant advantages over direct inhibition, such as the use of substoichiometric doses and the potential to disrupt enzyme-independent HDAC function. We discuss the potential implication of the degradation of HDACs in comparison with HDAC knockout studies. Along with the selection of HDAC inhibitors and E3 ligase ligands for the design of PROTACs. The potential utility of HDAC PROTACs in various disease pathologies from cancer to inflammation to neurodegeneration is driving the interest in this field.

Drug-Induced Peripheral Neuropathy: Diagnosis and Management

Peripheral neuropathy comes in all shapes and forms and is a disorder which is found in the peripheral nervous system. It can have an acute or chronic onset depending on the multitude of pathophysiologic mechanisms involving different parts of nerve fibers. A systematic approach is highly beneficial when it comes to cost-effective diagnosis. More than 30 causes of peripheral neuropathy exist ranging from systemic and auto-immune diseases, vitamin deficiencies, viral infections, diabetes, etc. One of the major causes of peripheral neuropathy is drug-induced disease, which can be split into peripheral neuropathy caused by chemotherapy or by other medications. This review deals with the latest causes of drug-induced peripheral neuropathy, the population involved, the findings on physical examination and various workups needed and how to manage each case.

Engineered Probiotic and Prebiotic Nutraceutical Supplementations in Combating Non-communicable Disorders: A Review

Nutritional supplementations are a form of nutrition sources that may help in improving the health complexities of a person throughout his or her life span. Being also categorized as food supplementations, nutraceuticals are products that are extracted from edible sources with medical benefits as well as primary nutritional values. Nutraceuticals can be considered as functional foods. There are evidences that nutraceutical supplementations can alter the commensal gut microbiota and help to prevent or fight against chronic non-communicable degenerative diseases in adults, including neurological disorders (Autism Spectrum Disorder [ASD], Parkinson’s disease [PD], Multiple sclerosis [MS]) and metabolic disorders (Type-II diabetes, obesity and non-alcoholic fatty liver disease). They can even lessen the complexities of preterm babies like extra-uterine growth restriction, necrotizing enterocolitis, infant eczema and allergy (during pregnancy) as well as bronchopulmonary dysplasia. Molecular perception of inflammatory and apoptotic modulators regulating the pathogenesis of these health risks, their control and management by probiotics and prebiotics could further emphasize the scientific overview of their utility. In this study, the pivotal role of nutraceutical supplementations in regulating or modulating molecular pathways in the above non-communicable diseases is briefly described. This work also gives an overall introduction of the sophisticated genome-editing techniques and advanced delivery systems in therapeutic activities applicable under these health risks.

CT-negative Subarachnoid Hemorrhage Caused by Telangiectasia: A Case Report

Introduction: At present, the mechanism of telangiectasia is unknown, but some evidence suggests that it may be related to genetic abnormalities. Telangiectasia may lead to bleeding of multiple sites. CT-negative subarachnoid hemorrhage is rare, which is mostly related to hemorrhage with a little amount of bleeding. CT-negative subarachnoid hemorrhage due to telangiectasia has not been reported.

Case Report: In this case report, the patient experienced severe headache with nausea, vomiting, and blurred vision for 12 days, and had a history of hypertension. Physical examination revealed a clear state of mind, normal speech, normal limb muscle strength, 2 transverse fingers of neck stiffness, and negative bilateral Babinski signs. Brain CT, MRI, MRA, and MRV showed no obvious abnormalities. SWI suggested the possibility of capillary dilation. The cerebrospinal fluid was pale yellow in appearance after lumbar puncture.

Diagnosis: The patient was diagnosed with subarachnoid hemorrhage (SAH) and capillary dilatation.

Interventions: Therapeutic management of blood pressure and brain edema was started.

Conclusion: Lumbar puncture should be performed when subarachnoid hemorrhage is clinically suspected and CT is negative. While searching for the cause of subarachnoid hemorrhage, the presence of telangiectasia should be ascertained.

Relationship Between Oxidative Stress, Tau Level and Antioxidant Mechanisms of the KEAP-1/NRF-2/HO-1 in Children with Hydrocephalus

Background: Hydrocephalus is a complex neurologic disorder that has a widespread impact on the central nervous system and a multifactor disease which affects the CSF dynamics and causes severe neurological impairments in children. The pathophysiology of hydrocephalus is not fully understood. However, increasing evidence suggests that oxidative stress may be an important factor in the pathogenesis of hydrocephalus.

Objective: The purpose of this study is to investigate the relationship of the KEAP-1/NRF-2/HO-1 pathway, one of the main regulators of the antioxidant system in the hydrocephalus pathology, on oxidative stress and tau protein level.

Methods: The study included 32 patients with hydrocephalus and 32 healthy controls. KEAP-1, NRF-2, HO-1, TAU, and MPO levels are measured using ELISA method TAS, TOS, and Total THIOL colorimetric method.

Results: KEAP-1, TAS, and Total THIOL levels were found significantly lowerer in the hydrocephalus group than in the control group. Nevertheless, it was identified that in the hydrocephalus group that the NRF-2, HO-1, TAU, MPO, TOS, and OSI levels were significantly elevated.

Conclusion: In conclusion, although the KEAP-1/NRF-2/HO-1 pathway is activated in patients with hydrocephalus, it is identified that the antioxidant defense system is insufficient and ultimately leads to elevated oxidative stress. The elevation in the tau level may be an indicator of oxidative stress induced neurodegenerative damage.

Trefoil Factor Family (TFF) Peptides and their Different Roles in the Mucosal Innate Immune Defense and More: An Update

Mucous epithelia are protected by complex mucus barrier layers, which are part of the innate immune defense. Trefoil factor family peptides TFF1, TFF2, and TFF3 have lectin activities and are predominantly co-secreted together with mucins from these epithelia. TFF1 and TFF2 are mainly expressed in the gastric mucosa, whereas TFF3 is widely secreted from most mucous epithelia and their glands. TFF1 and TFF3 consist of a single TFF domain and an additional free 7th cysteine residue, whereas TFF2 contains two TFF domains. Systematic analyses of the molecular forms of TFFs gave new insights into their diverse molecular functions. TFF1 mainly exists as a monomer with an unusual free thiol group and only minor amounts form a disulfide-linked homodimer as well as heterodimers with gastrokine-2 and IgG-Fc-binding protein (FCGBP). TFF3 mainly forms a heterodimer with FCGBP in vivo, but also binds Deleted in Malignant Brain Tumors/gp340 (DMBT1^gp340) in vitro. In contrast, TFF2 binds as a lectin to a conserved O-linked carbohydrate moiety of the mucin MUC6. Both FCGBP and DMBT1^gp340 are secreted by most mucous epithelia and their glands and are involved in mucosal innate immunity. Thus, a new picture emerged pointing to functions of TFF3-FCGBP (and TFF1-FCGBP) for mucosal innate immune defense, e.g. supporting the clearing of the microorganisms. Such a function could be well be supported by DMBT1^gp340. In contrast, the TFF2/MUC6 lectin complex probably physically stabilizes the inner adherent gastric mucus layer. Furthermore, there are indications that TFF3- FCGBP might also play a role in the blood vessels.

A Review on Hematopoietic Stem Cell Treatment for Epilepsy

Epilepsy responds to pharmacotherapy in its initial stages. The response of some forms of epilepsy, like the refractory epilepsy, is extremely low. Surgical management of epilepsy is associated with complications, which necessitates the search for novel and modern strategies for the treatment of epilepsy. Neuroprotection and neuronal regeneration are the major targets that must be accomplished by the new strategies. Hematopoietic Stem Cell (HSCs) therapy for epilepsy has shown promising results in pre-clinical studies with marginal clinical effects. This review explores the characteristics, mechanism of action, and clinical significance of HSCs therapy for the treatment of epilepsy.

Intracerebral Hemorrhage and Diabetes Mellitus: Blood-Brain Barrier Disruption, Pathophysiology and Cognitive Impairments

There is a surge in diabetes incidence, with an estimated 463 million individuals been diagnosed worldwide. Diabetes Mellitus (DM) is a major stroke-related comorbid condition that increases the susceptibility of disabling post-stroke outcomes. Although less common, intracerebral hemorrhage (ICH) is the most dramatic subtype of stroke associated with higher mortality, particularly in the DM population. Previous studies have focused mainly on the impact of DM on ischemic stroke. Few studies have focused on the impact of DM on ICH and discussed the blood- -brain barrier disruption, brain edema, and hematoma formation. However, more recently, investigating the role of oxidative damage and Reactive Oxygen Species (ROS) production in preclinical studies involving DM-ICH animal models has gained attention. But, little is known about the correlation between neuroinflammatory processes, glial cells activation, and peripheral immune cell invasion with DM-ICH injury. DM and ICH patients experience impaired abilities in multiple cognitive domains by relatively comparable mechanisms, which could get exacerbated in the setting of comorbidities. In this review, we discuss both the pathology of DM as a comorbid condition for ICH and the potential molecular therapeutic targets for the clinical management of the ICH and its recovery.

The Molecular Targets of Cannabinoids in the Treatment of Cancer and Inflammation

Objective: In this review, we discuss the emerging evidence for the effectiveness of cannabinoids in the treatment of cancer and inflammation. The remarkable effects of this study will help in supporting the traditional evidence for their successful application in the treatment of pain and cancer-related side effects.

Methods: We searched Pub Med (132 articles) and Google scholar (9 articles) databases and gathered the clinical (4 articles), and preclinical (28 articles) studies, reports on cell culture models (30 articles), and other original and review articles (78 articles) related to inflammation, cancer, and cannabinoids.

Results: Cannabinoids are described in three different forms, comprising endo- phyto- and synthetic compounds that exert biological effects. The molecular and cellular pathways of endogenous cannabinoids in the maintenance of homeostasis are well documented. In addition to classical cannabinoid receptors type 1 and 2, Vanilloid receptors and G protein-coupled receptor 55 were identified as common receptors. Subsequently, the effectiveness of phyto- and synthetic cannabinoids mediated by cannabinoid receptors has been demonstrated in the treatment of inflammatory diseases, including neurodegenerative diseases as well as gastrointestinal and respiratory inflammations. Another accepted property of cannabinoids is their anti-cancer effects. Cannabinoids were found to be effective in the treatment of lung, colorectal, prostate, breast, pancreas, and hepatic cancers. The anti-cancer effects of cannabinoids were characterized by their anti-proliferative property, inhibition of cancer cell migration, suppression of vascularization, and induction of apoptosis.

Conclusion: The current review provides an overview of the role of the endocannabinoid system in the mediation of physiological functions and the type and expression of cannabinoids receptors under physiological and pathological conditions. In addition, the molecular pathways involved in the effects of cannabinoids and the effectiveness of cannabinoids in the treatment of inflammations and cancers are highlighted.

Renin-Angiotensin System in Central Nervous System Diseases and its Interaction with COVID-19

Background: The Renin-Angiotensin System (RAS) comprises a complex molecular cascade with two counter-regulatory axes, the classical and the alternative. Angiotensin II and Angiotensin-(1-7), the main peptides of the RAS, exert opposite effects in multiple organs and systems, including the cardiovascular, renal, pulmonary, and immune systems. Strong evidence supports the hypothesis of a local RAS in the Central Nervous System (CNS) and its modulatory roles in neuroendocrinology and neurotransmission.

Objective: In this narrative review, we provide a comprehensive approach to experimental and clinical data regarding RAS molecule expression and their possible roles in the physiology and physiopathology of CNS diseases.

Methods: This non-systematic review summarizes evidence on RAS implications in CNS diseases and their possible relationships with COVID-19.

Results: We divided the possible RAS mechanisms in distinct conditions during the lifespan, approaching from congenital infections to neurodegenerative alterations, passing through mood disorders and cerebrovascular diseases. We also gathered current evidence about the possible effects of RAS in Covid-19, particularly in cases with neurological manifestations.

Conclusion: Although there are limitations and controversies, the analysis of RAS mechanisms in the CNS certainly represents an interesting field of research. However, further investigation is necessary to support the noteworthy interactions and provide a better comprehension of the cross-talk between RAS and the CNS. Investigations in this research field may shed light on the novel therapeutic targets.

A Pharmacological Review of Five Widely Used Traditional Medicinal Plants for Sedative-Hypnotic Effects in Bangladesh

Medicinal plants are traditionally familiar to treat various physical abnormalities, diseases and illnesses throughout the world A very large number of plant wealth has been offered by the nature for all living organisms, which preserves medicinal excellence. Traditionally in the rural areas, folk medicinal practitioners perform a more ordinary manner of medicine, where medicinal plants constitute the foremost and most often only components of formulations. Geographical and cultural factors of Bangladesh create an abundant source for herbal remedies. Nowadays, several medicinal herbs having their hypnotic and sedative effects are thoroughly used in the treatment of various psychiatric related disorders that include anxiety and insomnia. Sedatives are those types of drugs which diminish the action, inducing a calming and relaxing outcome. Sedatives, in general, produce sleep at higher doses. In recent years, the prevalence of psychiatric disorders which include anxiety and insomnia is rising and therefore different researches are exploring to reveal better medicine to treat these disorders. In this present review, we have performed a comprehensive literature search to find out the five most frequently used medicinal plants with sedative effects for the treatment of various disorders like anxiety and insomnia and their pharmacological activities in scientific researches. The featured plants of this review articles are, Kaempferia galanga, Cleome Rutidosperma, Kalanchoe pinnata, Calotropis gigantea, Scoparia dulcis L. In herbal and traditional medicines, numerous plants are used without their scientific validation and we intend to carry out a literature review in order to find out the effective scientific value of the featured plants. This study will help to affirm the uses of these plants as traditional medicine and the researchers to detect efficient therapeutic drugs according to their pharmacological studies.

Personalized Medicine Using Cutting Edge Technologies for Genetic Epilepsies

Epilepsy is the most common chronic neurologic disorder in the world, affecting 1-2% of the population. Besides, 30% of epilepsy patients are drug-resistant. Genomic mutations seem to play a key role in its etiology and knowledge of strong effect mutations in protein structures might improve prediction and the development of efficacious drugs to treat epilepsy. Several genetic association studies have been undertaken to examine the effect of a range of candidate genes for resistance. Although, few studies have explored the effect of the mutations into protein structure and biophysics in the epilepsy field. Much work remains to be done, but the plans made for exciting developments will hold therapeutic potential for patients with drug-resistance. In summary, we provide a critical review of the perspectives for the development of individualized medicine for epilepsy based on genetic polymorphisms/mutations in light of core elements such as transcriptomics, structural biology, disease model, pharmacogenomics and pharmacokinetics in a manner to improve the success of trial designs of antiepileptic drugs.

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD

Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.

A Healthy Gut for a Healthy Brain: Preclinical, Clinical and Regulatory Aspects

A large body of research has shown the presence of a complex pathway of communications between the gut and the brain. It is now recognized that, through this pathway, the microbiota can influence brain homeostasis and plasticity under normal and pathological conditions.

This review aims at providing an overview of preclinical and clinical pieces of evidence supporting the possible role of gut-brain axis modulation in physiological aging, in a neurodevelopmental disorder, the autism spectrum disorders and in a substance abuse disorder, the alcohol addiction.

Since the normalization of gut flora can prevent changes in the behavior, we postulate that the gutbrain axis might represent a possible target for pharmacological and dietary strategies aimed at improving not only intestinal but also mental health. The present review also reports some regulatory considerations regarding the use of probiotics, illustrating the most debated issues about the possibility of considering probiotics not only as a food supplement but also as a “full” medicinal product.

Purines and Pyrimidines: Metabolism, Function and Potential as Therapeutic Options in Neurodegenerative Diseases

Various neurodegenerative disorders have various molecular origins but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

Approach in Management of Aplasia Cutis Congenita in a Newborn with Adam Oliver Syndrome

Introduction: Aplasia Cutis Congenita (ACC) is a rare congenital disorder characterized by the absence of skin and adjacent tissue that usually affect the scalp. A large scalp defect in ACC with adjacent tissue anomalies is associated with high morbidity and mortality. The management of these lesions can be challenging. The treatment can be either conservative, surgical, or combined.

Case: A full-term newborn girl delivered with a huge scalp defect. The dura mater was exposed but intact and there was no Cerebrospinal Fluid (CSF) leakage. She also had bilateral talipes equinovarus and terminal reduction of multiple toes in the left foot. Genetic testing was positive for Adam Oliver Syndrome. Conservative medical management was initiated at birth and continued until discharge at 4 weeks of age. The patient had a regular follow-up with plastic surgery and neurosurgery teams. At 11 months old, the defect became smaller, hairless with good granulation tissue, but still soft and compressible.

Conclusion: Large scalp midline ACC is a rare, but potentially devastating disease when involved adjacent tissue. The choice of treatment is not straightforward and it is mainly based upon the size, depth, and the risk of pre and post-treatment complications. Conservative management still is an option with very complex ACC.

An Insight into Molecular Mechanisms and Novel Therapeutic Approaches in Epileptogenesis

Epilepsy is the second most common neurological disease with abnormal neural activity involving the activation of various intracellular signalling transduction mechanisms. The molecular and system biology mechanisms responsible for epileptogenesis are not well defined or understood. Neuroinflammation, neurodegeneration and Epigenetic modification elicit epileptogenesis. The excessive neuronal activities in the brain are associated with neurochemical changes underlying the deleterious consequences of excitotoxicity. The prolonged repetitive excessive neuronal activities extended to brain tissue injury by the activation of microglia regulating abnormal neuroglia remodelling and monocyte infiltration in response to brain lesions inducing axonal sprouting contributing to neurodegeneration. The alteration of various downstream transduction pathways resulted in intracellular stress responses associating endoplasmic reticulum, mitochondrial and lysosomal dysfunction, activation of nucleases, proteases mediated neuronal death. The recently novel pharmacological agents modulate various receptors like mTOR, COX-2, TRK, JAK-STAT, epigenetic modulators and neurosteroids are used for attenuation of epileptogenesis. Whereas the various molecular changes like the mutation of the cell surface, nuclear receptor and ion channels focusing on repetitive episodic seizures have been explored by preclinical and clinical studies. Despite effective pharmacotherapy for epilepsy, the inadequate understanding of precise mechanisms, drug resistance and therapeutic failure are the current fundamental problems in epilepsy. Therefore, the novel pharmacological approaches evaluated for efficacy on experimental models of epilepsy need to be identified and validated. In addition, we need to understand the downstream signalling pathways of new targets for the treatment of epilepsy. This review emphasizes on the current state of novel molecular targets as therapeutic approaches and future directions for the management of epileptogenesis. Novel pharmacological approaches and clinical exploration are essential to make new frontiers in curing epilepsy.

The Stroke-Induced Blood-Brain Barrier Disruption: Current Progress of Inspection Technique, Mechanism, and Therapeutic Target

Stroke is one of the leading causes of mortality and morbidity worldwide. The bloodbrain barrier (BBB) is a characteristic structure of microvessel within the brain. Under normal physiological conditions, the BBB plays a role in the prevention of harmful substances entering into the brain parenchyma within the central nervous system. However, stroke stimuli induce the breakdown of BBB leading to the influx of cytotoxic substances, vasogenic brain edema, and hemorrhagic transformation. Therefore, BBB disruption is a major complication, which needs to be addressed in order to improve clinical outcomes in stroke. In this review, we first discuss the structure and function of the BBB. Next, we discuss the progress of the techniques utilized to study BBB breakdown in in-vitro and in-vivo studies, along with biomarkers and imaging techniques in clinical settings. Lastly, we highlight the mechanisms of stroke-induced neuroinflammation and apoptotic process of endothelial cells causing BBB breakdown, and the potential therapeutic targets to protect BBB integrity after stroke. Secondary products arising from stroke-induced tissue damage provide transformation of myeloid cells such as microglia and macrophages to pro-inflammatory phenotype followed by further BBB disruption via neuroinflammation and apoptosis of endothelial cells. In contrast, these myeloid cells are also polarized to anti-inflammatory phenotype, repairing compromised BBB. Therefore, therapeutic strategies to induce anti-inflammatory phenotypes of the myeloid cells may protect BBB in order to improve clinical outcomes of stroke patients.

FTY720 (Fingolimod) Ameliorates Brain Injury through Multiple Mechanisms and is a Strong Candidate for Stroke Treatment

FTY720 (Fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist that exerts strong anti-inflammatory effects and was approved as the first oral drug for the treatment of multiple sclerosis by the US Food and Drug Administration (FDA) in 2010. FTY720 is mainly associated with unique functional “antagonist” and “agonist” mechanisms. The functional antagonistic mechanism is mediated by the transient down-regulation and degradation of S1P receptors on lymphocytes, which prevents lymphocytes from entering the blood stream from the lymph node. This subsequently results in the development of lymphopenia and reduces lymphocytic inflammation. Functional agonistic mechanisms are executed through S1P receptors expressed on the surface of various cells including neurons, astrocytes, microglia, and blood vessel endothelial cells. These functions might play important roles in regulating anti-apoptotic systems, modulating brain immune and phagocytic activities, preserving the Blood-Brain-Barrier (BBB), and the proliferation of neural precursor cells. Recently, FTY720 have shown receptor-independent effects, including intracellular target bindings and epigenetic modulations. Many researchers have recognized the positive effects of FTY720 and launched basic and clinical experiments to test the use of this agent against stroke. Although the mechanism of FTY720 has not been fully elucidated, its efficacy against cerebral stroke is becoming clear, not only in animal models, but also in ischemic stroke patients through clinical trials. In this article, we review the data obtained from laboratory findings and preliminary clinical trials using FTY720 for stroke treatment.

The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells

The neurovascular unit is a physiological unit present in the brain, which is constituted by elements of the nervous system (neurons and astrocytes) and the vascular system (endothelial and mural cells). This unit is responsible for the homeostasis and regulation of cerebral blood flow. There are two major types of mural cells in the brain, pericytes and smooth muscle cells. At the arterial level, smooth muscle cells are the main components that wrap around the outside of cerebral blood vessels and the major contributors to basal tone maintenance, blood pressure and blood flow distribution. They present several mechanisms by which they regulate both vasodilation and vasoconstriction of cerebral blood vessels and their regulation becomes even more important in situations of injury or pathology. In this review, we discuss the main regulatory mechanisms of brain smooth muscle cells and their contributions to the correct brain homeostasis.

Nimodipine Reappraised: An Old Drug With a Future

Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine’s role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.

Neurodegenerative Process Linking the Eye and the Brain

Recent literature agrees that neurodegenerative processes involve both the retina and the central nervous system, which are two strictly related anatomical structures. However, the causal mechanisms of this dual involvement are still uncertain. To date, anterograde transsynaptic neurodegeneration, triggered by retinal ganglion cells’ death, and retrograde transsynaptic neurodegeneration, induced by neurodegenerative processes of the central nervous system, has been considered the major possible causal mechanisms. The development of novel neuroimaging techniques has recently supported both the study of the central stations of the visual pathway as well as the study of the retina which is possibly an open window to the central nervous system.

Protein Glycation: An Old Villain is Shedding Secrets

The glycation of proteins is non-physiological post-translational incorporation of carbohydrates onto the free amines or guanidines of proteins and some lipids. Although the existence of glycated proteins has been known for forty years, a full understanding of their pathogenic nature has been slow in accruing. In recent years, however, glycation has gained widespread acceptance as a contributing factor in numerous metabolic, autoimmune, and neurological disorders, tying together several confounding aspects of disease etiology. From diabetes, arthritis, and lupus, to multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases, an emerging glycation/inflammation paradigm now offers significant new insight into a physiologically important toxicological phenomenon. It exposes novel drug targets and treatment options, and may even lay foundations for long-awaited breakthroughs.

This ‘current frontier’ article briefly profiles current knowledge regarding the underlying causes of glycation, the structural biology implications of such modifications, and their pathological consequences. Although several emerging therapeutic strategies for addressing glycation pathologies are introduced, the primary purpose of this mini-review is to raise awareness of the challenges and opportunities inherent in this emerging new medicinal target area.

Neuroprotective Methodologies of Co-Enzyme Q10 Mediated Brain Hemorrhagic Treatment: Clinical and Pre-Clinical Findings

Cerebral brain hemorrhage is associated with the highest mortality and morbidity despite only constituting approximately 10-15% of all strokes classified into intracerebral and intraventricular hemorrhage where most of the patients suffer from impairment in memory, weakness or paralysis in arms or legs, headache, fatigue, gait abnormality and cognitive dysfunctions. Understanding molecular pathology and finding the worsening cause of hemorrhage will lead to explore the therapeutic interventions that could prevent and cure the disease. Mitochondrial ETC-complexes dysfunction has been found to increase neuroinflammatory cytokines, oxidative free radicals, excitotoxicity, neurotransmitter and energy imbalance that are the key neuropathological hallmarks of cerebral hemorrhage. Coenzyme Q10 (CoQ10), as a part of the mitochondrial respiratory chain can effectively restore these neuronal dysfunctions by preventing the opening of mitochondrial membrane transition pore, thereby counteracting cell death events as well as exerts an anti-inflammatory effect by influencing the expression of NF-kB1 dependent genes thus preventing the neuroinflammation and energy restoration. Due to behavior and biochemical heterogeneity in post cerebral brain hemorrhagic pattern different preclinical autologous blood injection models are required to precisely investigate the forthcoming therapeutic strategies. Despite emerging pre-clinical research and resultant large clinical trials for promising symptomatic treatments, there are very less pharmacological interventions demonstrated to improve post operative condition of patients where intensive care is required. Therefore, in current review, we explore the disease pattern, clinical and pre-clinical interventions under investigation and neuroprotective methodologies of CoQ10 precursors to ameliorate post brain hemorrhagic conditions.

Fungal Bioactive Compounds in Pharmaceutical Research and Development

Background: Exploration of antibiotics from microorganisms became widespread in the academia and the industry with the serendipitous discovery of Penicillin from Penicillium notatum by Sir Alexander Fleming. This embarked the golden era of antibiotics which lasted for over 60 years. However, the traditional phenotypic screening was replaced with more rational and smarter methods of exploration of bioactive compounds from fungi and microorganisms. Fungi have been responsible for providing a variety of bioactive compounds with diverse activities which have been developed into blockbuster drugs such as Cyclosporine, Caspofungin, Lovastatin and Fingolimod etc. It has been reported that ca. 40% of the 1453 New Chemical Entities (NCE’s) approved by USFDA are natural products, natural product inspired or mimics many of which have their origins from fungi. Hence fungal compounds are playing a very important role in drug discovery and development in the pharmaceutical industry.

Methods: We undertook structured searches of bibliographic databases of peer-reviewed research literature which pertained to natural products, medicinal chemistry of natural products and drug discovery from fungi. With the strategic improvement in screening and identification methods, fungi are still a potential resource for novel chemistries. Thus the searches also comprised of bioactive agents from fungi isolated or derived from special ecological groups and lineages. To find different molecules derived or isolated from fungi under clinical studies, clinical trial data from the NIH as well as from pharmaceutical companies were also explored. This comprised of data wherein the pharmaceutical industries have acquired or licensed a fungal bioactive compound for clinical study or a trial.

Results: Natural product chemistry and medicinal chemistry continue to play an important role in converting a bioactive compound into therapeutic moieties or pharmacophores for new drug development.

Conclusion: Thus one can say fungal bioactive compounds are alive and well for development into new drugs as novel ecological groups of fungi as well as novel chemistries are being uncovered. This review further emphasizes the collaboration of fungal biologists with chemists, pharmacologists and biochemists towards the development of newer drugs for taking them into the drug development pipeline.

NGF and BDNF Alterations by Prenatal Alcohol Exposure

Background: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention.

Objective: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure.

Methods: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways.

Results: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns.

Conclusion: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce a potential prevention of the harmful effects of the paternal and/or maternal alcohol exposure.

Choline-PET/CT in the Differential Diagnosis Between Cystic Glioblastoma and Intraparenchymal Hemorrhage

Objective: Glioblastoma multiforme (GBM) represents the most common and malignant glioma, accounting for 45%-50% of all gliomas. The median survival time for patients with glioblastoma is only 12-15 months after surgical, chemioterapic and radiotherapic treatment; a correct diagnosis is naturally fundamental to establish a rapid and correct therapy. Non-invasive imaging plays a pivotal role in each phase of the diagnostic workup of patients with suspected for diagnosis. The aim of this case report was to describe the potential clinical impact of 18F-fluorocholine (FCH) PET/CT in the assessment of a cystic GBM mimicking a spontaneous hemorrhage.

Methods: a 57 years-old male with intraparenchymal hemorrhage at CT imaging initially in reduction ad serial imaging and suspected right fronto-temporo-parietal lesion at MRI underwent dynamic and static (60' after tracer injection) FCH PET/CT of the brain.

Results: FCH PET/CT showed rapid tracer uptake after few second from injection at dynamic acquisition and consequent incremental mild uptake at static imaging after 60 minutes at the level of oval formation in the right cerebral hemisphere characterized by annular and peripheral high metabolic activity. The central region of the lesion was characterized by the absence 18F-FCH uptake most likely due to blood component. The patient underwent surgery for tumor removal; the histopathological examination confirmed the suspect of GBM. Chemo-radiotherapic adjuvant protocol according to Stupp protocol was therefore administrated; to date the patient is alive without any progression disease at 5 months from treatment.

Conclusion: In this case report FCH PET/CT represented the final diagnostic technique to confirm the suspicious of a cystic GBM. Our case demonstrated the potential role of 18F-FCH PET/CT for discrimination of higher proliferation area over intraparenchymal hemorrhage, supporting the potential use of this imaging biomarker in surgical or radiosurgical approach. Obviously, further prospective studies are needed to confirm this role and to exactly define possible routinely applications.

Statins and the Brain: More than Lipid Lowering Agents?

Background: Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-βhydroxy 3β-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions.

Objective: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information.

Methods: Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke.

Results: 315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect.

Conclusion: Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.

Effect of Neuroinflammation on ABC Transporters: Possible Contribution to Refractory Epilepsy

Background & Objective: Epilepsy is a common and serious chronic neurological disorder that is mainly treated with antiepileptic drugs. Although current antiepileptic drugs used in clinical practice have advanced to the third generation, approximately one-third of patients are refractory to these treatments. More efficacious treatments for refractory epilepsy are therefore needed. A better understanding of the mechanism underlying refractory epilepsy is likely to facilitate the development of a more effective therapy. The abnormal expression and/or dysfunction of efflux transporters, particularly ABC transporters, might contribute to certain cases of refractory epilepsy. Inflammation in the brain has recently been shown to regulate the expression and/or function of ABC transporters in the cerebral vascular endothelial cells and glia of the blood-brain barrier by activating intracellular signalling pathways.

Conclusion: Therefore, in this review, we will briefly summarize recent research advances regarding the possible role of neuroinflammation in regulating ABC transporter expression in epilepsy.

Caveolin-1 in Stroke Neuropathology and Neuroprotection: A Novel Molecular Therapeutic Target for Ischemic-Related Injury

Cardiovascular disease and associated cerebral stroke are a global epidemic attributed to genetic and epigenetic factors, such as diet, life style and an increasingly sedentary existence due to technological advances in both the developing and developed world. There are approximately 5.9 million stroke-related deaths worldwide annually. Current epidemiological data indicate that nearly 16.9 million people worldwide suffer a new or recurrent stroke yearly. In 2014 alone, 2.4% of adults in the United States (US) were estimated to experience stroke, which is the leading cause of adult disability and the fifth leading cause of death in the US There are 2 main types of stroke: Hemorrhagic (HS) and ischemic stroke (IS), with IS occurring more frequently. HS is caused by intra-cerebral hemorrhage mainly due to high blood pressure, while IS is caused by either embolic or thrombotic stroke. Both result in motor impairments, numbness or abnormal sensations, cognitive deficits, and mood disorders (e.g. depression). This review focuses on the 1) pathophysiology of stroke (neuronal cell loss, defective blood brain barrier, microglia activation, and inflammation), 2) the role of the membrane protein caveolin- 1 (Cav-1) in normal brain physiology and stroke-induced changes, and, 3) we briefly discussed the potential therapeutic role of Cav-1 in recovery following stroke.

Treatment of Epileptic Encephalopathies

Background: Epileptic encephalopathies represent the most severe epilepsies, with onset in infancy and childhood and seizures continuing in adulthood in most cases. New genetic causes are being identified at a rapid rate. Treatment is challenging and the overall outcome remains poor. Available targeted treatments, based on the precision medicine approach, are currently few.

Objective: To provide an overview of the treatment of epileptic encephalopathies with known genetic determinants, including established treatment, anecdotal reports of specific treatment, and potential tailored precision medicine strategies.

Method: Genes known to be associated to epileptic encephalopathy were selected. Genes where the association was uncertain or with no reports of details on treatment, were not included. Although some of the genes included are associated with multiple epilepsy phenotypes or other organ involvement, we have mainly focused on the epileptic encephalopathies and their antiepileptic treatments.

Results: Most epileptic encephalopathies show genotypic and phenotypic heterogeneity. The treatment of seizures is difficult in most cases. The available evidence may provide some guidance for treatment: for example, ACTH seems to be effective in controlling infantile spams in a number of genetic epileptic encephalopathies. There are potentially effective tailored precision medicine strategies available for some of the encephalopathies, and therapies with currently unexplained effectiveness in others.

Conclusions: Understanding the effect of the mutation is crucial for targeted treatment. There is a broad range of disease mechanisms underlying epileptic encephalopathies, and this makes the application of targeted treatments challenging. However, there is evidence that tailored treatment could significantly improve epilepsy treatment and prognosis.

Identification of Novel 5,6-Dimethoxyindan-1-one Derivatives as Antiviral Agents

Background: Discovery of novel antiviral agents is essential because viral infection continues to threaten human life globally. Various heterocyclic small molecules have been developed as antiviral agents. The 5,6-dimethoxyindan-1-on nucleus is of considerable interest as this ring is the key constituent in a range of bioactive compounds, both naturally occurring and synthetic, and often of considerable complexity.

Objective: The main purpose of this research was to discover and develop small molecule heterocycles as broad-spectrum of antiviral agents.

Method: A focused small set of 5,6-dimethoxyindan-1-one analogs (6-8) along with a thiopene derivative (9) was screened for selected viruses (Vaccinia virus - VACA, Human papillomavirus - HPV, Zika virus – ZIKV, Dengue virus - DENV, Measles virus - MV, Poliovirus 3 - PV, Rift Valley fever virus - RVFV, Tacaribe virus - TCRV, Venezuelan equine encephalitis virus - VEEV, Herpes simplex virus 1 -HSV-1 and Human cytomegalovirus - HCMV) using the National Institute of Allergy and Infectious Diseases (NIAID)’s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program.

Results: These molecules demonstrated moderate to excellent antiviral activity towards variety of viruses. The 5,6-dimethoxyindan-1-one analog (7) demonstrated high efficacy towards vaccinia virus (EC50: <0.05 µM) and was nearly 232 times more potent than the standard drug Cidofovir (EC50: 11.59 µM) in primary assay whereas it demonstrated moderate activity (EC50: >30.00 µM) in secondary plaque reduction assay. The thiophene analog (9) has shown very good viral inhibition towards several viruses such as Human papillomavirus, Measles virus, Rift Valley fever virus, Tacaribe virus and Herpes simplex virus 1.

Conclusion: Our research identified a novel 5,6-dimethoxyindan-1-one analog (compound 7), as a potent antiviral agent for vaccinia virus, and heterocyclic chalcone analog (compound 9) as a broad spectrum antiviral agent.

Sex Impact on Biomarkers, Pharmacokinetics and Pharmacodynamics

Sex is one of several factors influencing pharmacological responses, but research on its effects on pharmacokinetics and pharmacodynamics, although emerging remarkably, remains poor and contains many methodological issues. In this review, the current state of knowledge about sex differences in pharmacokinetics and some hints to pharmacogenomics were evaluated. Moreover, considering that many pharmacological responses are monitored through biomarkers, the influence of sex on some biomarkers has been reported. Finally, we report sex differences in pharmacodynamics, particularly analysing opioids and their use during pregnancy, labor and breastfeeding. In conclusion, a more precise sex- and genderbased approach appears necessary to achieve more evidence-based therapy in men and women.

The Role of Oxazolidine Derivatives in the Treatment of Infectious and Chronic Diseases

Background: Despite being known for their antibacterial activity, the oxazolidines are molecules with wide pharmacological action and may act as anticonvulsants, anti-inflammatory and antineoplasic agents. However, such activities have been poorly explored and only two oxazolidinic derivatives hit the market until now. Therefore, this review covers the main biological activities of oxazolidines, indicating which of the classes and substituents have the best biological results as well as the synthesis methodology used to obtain them.

Methods: The search for bibliographic data was made using a question focused on the oxazolidine structure and their respective activities, besides using inclusion/exclusion criteria clearly defined. The selected papers were subjected to qualitative content analysis methodology to be used in this review.

Results: The oxazolidines remain excellent candidates for antibacterial, presenting three compounds in clinical testing phase (Radezolide, Cadezolide and Sutezolide), besides being a good candidate as antitubercular agents. Other less explored activities have niches with a great therapeutic potential such as the oxazolidines acting on 5-HT receptors (anticonvulsant) and Zolmitriptan (anti-migraine), and also mefloquine-oxazolidine derivatives which may act as antineoplasic and antitubercular agents.

Conclusion: This review summarizes the versatility and great therapeutic potential that oxazolidines can offer, reinforcing the need for further studies and investments for this class of molecules.

The Role of microRNA in Ischemic and Hemorrhagic Stroke

Background: Stroke is the second leading cause of death worldwide. Understanding of gene expression dynamics could bring new approaches in diagnostics and therapy of stroke. Small noncoding molecules termed “microRNA” represent the most flexible network of gene expression regulators.

Method: The aim of this review was to briefly describe the structure and function of microRNA and summarize the current knowledge about the involvement of microRNAs in the pathophysiology of ischemic and hemorrhagic stroke based on both experimental and clinical studies.

Results: Numerous profiling studies identified candidate microRNAs and partially described dynamics of their expression after the stroke. However, complex associations of specific microRNAs expression with main clinical characteristics and deeper insight into mechanisms of their regulatory functions are still missing. In this review, we put special emphasis on several microRNA clusters involved in neuroprotection (miR-124, miR-181, miR-21, miR-29, miR-210 and let7). Potential application of microRNAs as biomarkers and diagnostic or therapeutic targets was also discussed.

Conclusion: Full understanding of the regulatory mechanisms of the microRNA networks represents a novel direction for stroke research. To date, we do not have effective tools to control pathophysiological processes associated with stroke. Thus the microRNAs have to be considered as a very promising target for future stroke therapies.

Pericyte: Potential Target for Hemorrhagic Stroke Prevention and Treatment

Background: Despite long-standing and worldwide efforts, hemorrhagic stroke remains a critical clinical syndrome that exerts a heavy toll on affected individuals and their families due to the lack of preventive and therapeutic targets.

Objective: To clarify the pathogenesis of hemorrhagic stroke and to identify novel therapeutic targets.

Method: Targeting pericytes, the typical mural cells of microvessels, could serve as a way to modulate microvascular permeability, development, and maturation by regulating endothelial cell functions and modulating tissue fibrosis and inflammatory responses.

Results: Pericytes in hemorrhagic stroke may exert the following functions: before bleeding, the morphological aberration and dysfunction of pericytes may lead to aneurysm formation, angiopsathyrosis, and hemodynamic disturbances, ultimately causing vasculature rupture. In the acute phase after hemorrhage, pericytes are faced with a complicated bleeding environment, which results in the death of pericytes, blood-brain barrier damage, pericyte-mediated inflammatory cascades, white matter impairment, and ultimately aggravated neural injury. In the recovery period post-hemorrhage, in situ pericytes are activated and differentiate into neurons, glia and endothelial cells to repair the neural vascular network. Moreover, many pericytes are recruited to the lesion and contribute to blood-brain barrier remodeling, thus facilitating neurovascular functional recovery after stroke.

Conclusion: Due to the multiple functions of pericytes in the development of vascular rupture and hemorrhagic stroke pathophysiology, additional drugs and trials targeting pericytes and evaluations of their effectiveness are required in future investigations to develop new strategies for the prevention and treatment of hemorrhagic stroke.

Inhibition of Angiogenesis as a Treatment Strategy for Neuroblastoma

Background: Angiogenesis stands as a symbol for the development of tumor as well as its metastasis. In this review, we discuss the various components that induce and enhance angiogenesis along with its several inhibitors in neuroblastoma. Angiogenesis is vital for tumor development and migration and it is dependent on the creation of angiogenic elements by tumor cell lines.

Methodology: Neuroblastoma (NB) is a general pediatric tumor which originates from neural crest that is biologically and physiologically diverse. As tumor vascular index increases, it leads to the unfavorable consequence of NB. Tumor vascularity is very much interrelated with an ill consequence of neuroblastoma. Hence, unique drugs which aim at the vascular endothelium are applicants for integration into clinical experimentation. As the quest for new anti-angiogenic compounds goes on, several angiogenic inhibitors get discovered whose progress needs to be scrutinized from time to time. Antiangiogenic activity of a drug gets elevated when used as combination therapy than monotherapy. Vascular targeting is yet another strategy to increase the efficacy of antiangiogenic therapy. In general for children having neuroblastoma, the anti-angiogenic therapy works as a boon when administered along with gene therapy.

Results: As a resulting discovery of unique molecular objective, several inhibition mediators are gaining attention of exploration by neuroblastoma researchers. The further discussion proceeds with understanding the process of angiogenesis, its clinical inferences, and future perspectives. Novel and more efficient methodologies are required to diagnose and treat extremely antagonistic neuroblastoma.

The Extracellular Bacterial HtrA Proteins as Potential Therapeutic Targets and Vaccine Candidates

Background: An increasing resistance of bacteria to the commonly used antimicrobials forces to search for alternative or supportive ways to cure infections. Targeting virulence factors is one of such approaches. The bacterial HtrA proteins are strongly involved in virulence and the lack of functional HtrA in many cases impairs invasiveness of pathogens. HtrAs act by protecting the cells under stressful conditions as well as they take direct part in invasion of the host. The latter function is played predominantly by the recently identified extracellular fraction of HtrA. This review aims to evaluate HtrAs as therapeutic targets, including design of chemical inhibitors and vaccines.

Methods: We undertook a thorough search of bibliographic databases for peer-reviewed scientific literature.

Results: One hundred and sixty-four papers were included in the review. First, we briefly summarized key structural and functional properties of known HtrA proteins with the special focus on the extracellular HtrA fraction. Then we provided an overview of efforts and advancements to target HtrAs of pathogenic bacteria as a promising antimicrobial therapy. In some cases, encouraging results were obtained and application of HtrAspecific inhibitors protected tissues from damage and killed bacteria. Also promising reports concerning the use of HtrA as a protective antigen in several disease models have recently been published.

Conclusion: The findings of this review suggest that the exported HtrA proteins are very attractive therapeutic targets due to their accessibility, significance in virulence and immunogenicity. However, further extensive studies are still needed to develop a safe antimicrobial treatment.

Recent Advances in Transcranial Focused Ultrasound (FUS) Triggered Brain Delivery

Background: Successful delivery of therapeutic agents in the brain is very challenging, which makes treatment of various brain disorders very difficult. One of the major causes of this difficulty is the presence of physiological barriers in the brain like blood brain barrier (BBB) and blood cerebrospinal fluid (CSF) barrier. These barriers are very specific and restrict the entry of water soluble agents and ionized molecule.

Objective: The current article focuses on the transcranial route, transcranial focused ultrasound (FUS), and the techniques involved in transcranial focused ultrasound (FUS) delivery and recent updates of this system.

Results: The study describes that the FUS in conjunction with various other techniques opens the BBB very effectively.

Conclusion: The administration of therapeutic agent using various FUS techniques opens a new perspective in treating CNS diseases.

Is there a Teratogenicity Risk Associated with Cannabis and Synthetic Cannabimimetics’ (‘Spice’) Intake?

Background: Substance use, including cannabis, has been documented amongst women both in the pre-conception period and during pregnancy, particularly during the 1st trimester, which is clearly the most critical period in the organogenesis. The recent emergence on the drug market of synthetic cannabimimetics/SC (‘spice’) may represent a new challenge for clinicians.

Objective: A literature overview on the teratogenicity profile of both cannabis and synthetic cannabimimetics was here carried out.

Method: The PubMed database was searched in order to collect all relevant cases and data regarding the possible evidence of teratogenicity issues associated with cannabis and SC intake.

Results: The use of cannabis in pregnant women has been associated with a plethora of both obstetrical/ gestational complications and neurobehavioral/neurological effects on newborns. Conversely, only few and conflicting data are related to SC misuse issues.

Conclusion: Although cannabis use may be considered a risk factor for the occurrence of pregnancyrelated morbidity issues, many studies relied on self-reports and showed inconsistent results when controlling for potential confounders, including tobacco use. Given the role of the endocannabinoid system in both pregnancy and delivery, SC potency at interacting with the endocannabinoid system may be a reason of concern. Clinicians should carefully assess each woman planning a pregnancy, or who is pregnant already, and who is at risk of persisting in her current cannabis and/or SC intake. A nonjudgmental approach, aiming at collecting both a history of drug/alcohol use and at providing information regarding the risks associated with cannabis/SC intake during pregnancy is here advised.

Vitamins B1, B2, B3 and B9 – Occurrence, Biosynthesis Pathways and Functions in Human Nutrition

Background: Vitamins are chemical compounds whose derivatives are involved in vital metabolic pathways of all living organisms. The complete endogenous biosynthesis of vitamins can be performed by many bacteria, yeast and plants, but humans need to acquire most of these essential nutrients with food. In recent years, new types of action of the well-recognized vitamins or their more sophisticated relationships have been reported.

Objectives: In this review we present the current knowledge of factors that can influence the yield and regulation of vitamin B1, B2, B3 and B9 biosynthesis in plants which can be important for human nutrition. A summary of modern methods applied for vitamin analysis in biological materials is also provided. Contributions of selected vitamins to the homeostasis of the human organism, as well as their relations to the progress or prevention of some important diseases such as cancer, cardiovascular diseases, diabetes and Alzheimer’s disease are discussed in the light of recent investigations. Better understanding of the mechanisms of vitamin uptake by human tissues and possible metabolic or genetic backgrounds of vitamin deficiencies can open new perspectives on the medical strategies and biotechnological processes of food fortification.

Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer’s Disease

Objectives: Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer’s disease.

Design: Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan.

Methods: Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 μg) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant. Safety, tolerability, and immunogenicity were assessed during active treatment and 6-month follow-up.

Results: ACC-001 + QS-21 was well tolerated in the United States (N=110) and European Union (N=50), and Japan (N=53) extension studies; safety profile was similar to that observed in the parent studies, and no new safety signals were identified. Overall, injection site reactions were the most common adverse event in these studies. Anti-amyloid antibody titers were elicited in all groups, with the highest titers observed in subjects who received ACC-001 + QS-21 in both the parent and extension studies.

Conclusions: Long-term exposure to ACC-001 + QS-21 was well tolerated in subjects with Alzheimer’s disease, suggesting that side effects do not pose a principal limitation for anti-amyloid active immunotherapy. The highest anti-amyloid-beta IgG titers are elicited during long-term therapy with ACC-001 + QS-21 compared with other regimens.

Low-Density Lipoprotein Cholesterol (LDL-C): How Low?

Low-density lipoprotein cholesterol (LDL-C) is a well-established major cardiovascular (CV) risk factor supported by clinical evidence showing decreased atherosclerotic disease events when LDL-C is therapeutically lowered. A reasonable approach is to tailor each patient’s LDL-C target level depending on the initial LDL-C level and the perceived risk. Multiple clinical entities such as the newborn, hypobetalipoproteinemia, proprotein convertase subtilisin/kexin type 9 (PCSK9) missense mutations, and an unexpected excess response to a statin or other medications, are associated with very low LDL-C levels in otherwise healthy individuals. Therefore, an issue of major interest to clinicians who buy into “lower is better” for LDL-C in the high-risk CV patient is how low can and should the LDL-C be taken? Available information is discussed and placed into context. A definite safe lowest LDL-C level cannot be specified but there appears to be support that a level as low as 20 mg/dL (0.52 mmol/l) can be justified in the highest CV risk patients with extensive atherosclerosis where plaque stabilization and regression are necessary.

Polyphenols Beyond Barriers: A Glimpse into the Brain

Background: Ageing can be simply defined as the process of becoming older, which is genetically determined but also environmentally modulated. With the continuous increase of life expectancy, quality of life during ageing has become one of the biggest challenges of developed countries. The quest for a healthy ageing has led to the extensive study of plant polyphenols with the aim to prevent age-associated deterioration and diseases, including neurodegenerative diseases. The world of polyphenols has fascinated researchers over the past decades, and in vitro, cell-based, animal and human studies have attempted to unravel the mechanisms behind dietary polyphenols neuroprotection.

Methods: In this review, we compiled some of the extensive and ever-growing research in the field, highlighting some of the most recent trends in the area.

Results: The main findings regarding polypolyphenols neuroprotective potential performed using in vitro, cellular and animal studies, as well as human trials are covered in this review. Concepts like bioavailability, polyphenols biotransformation, transport of dietary polyphenols across barriers, including the blood-brain barrier, are here explored.

Conclusion: The diversity and holistic properties of polypolyphenol present them as an attractive alternative for the treatment of multifactorial diseases, where a multitude of cellular pathways are disrupted. The underlying mechanisms of polypolyphenols for nutrition or therapeutic applications must be further consolidated, however there is strong evidence of their beneficial impact on brain function during ageing. Nevertheless, only the tip of the iceberg of nutritional and pharmacological potential of dietary polyphenols is hitherto understood and further research needs to be done to fill the gaps in pursuing a healthy ageing.

Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application

The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders.

Statins, Mevalonate Pathway and its Intermediate Products in Placental Development and Preeclampsia

The mevalonate pathway synthesizes intermediates and products such as cholesterol and nonsterol isoprenoids that are crucial for cell survival and function. In the human placenta, the prenylation of proteins, rather than cholesterol synthesis, represents the main "metabolic target" of mevalonate metabolism. Major cellular functions depend on isoprenylation including proliferation, migration, metabolism and protein glycosylation that are all crucial for proper development of the embryo and the placenta. Statins are inhibitors of HMG-CoA reductase, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid by NADPH. In vitro experiments using human placental explants suggest that statins elicit a detrimental effect on placental growth. However, animal and epidemiologic studies show no increase of fetal malformations after exposure to statins during pregnancy. Moreover, emerging evidence from mouse studies suggest that statins may be useful in preventing serious pregnancy complications like preeclampsia.

Melatonin: Pharmacology, Functions and Therapeutic Benefits

Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock.

Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed.

Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects.

Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

Pulmonary Disease in Beta-Thalassemia

The care of beta-thalassemia has improved dramatically over the last few decades mostly because of: i) improved blood transfusion regimens; ii) wide-spread use of deferoxamine; iii) surgical advances; and iv) allogeneic hematopoietic stem cell transplantation. Advanced healthcare standards, improved life expectancy, and complications specific to beta-thalassemia necessitate a renewed approach to the pulmonary issues of this disease.

While transfusion-related infections are expected, and Streptococcal, Staphylococcal, E. coli and Salmonella infections are common, a number of special problems are also reported. Mycoplasma pneumoniae infections associated with hemolytic anemia, Pneumocystis carinii pneumonia and necrotizing pneumonia caused by Klebsiella pneumoniae are indicative of the special susceptibility to infections in beta-thalassemia. The issue of immune function in the (non-transplanted) patient with thalassemia is brought up. Conditions associated with chronic airway inflammation, such as plastic bronchitis and allergic bronchopulmonary mycosis, are discussed as well as life-threatening complications.

In an attempt to organize the diagnostic approach to pulmonary disease in beta-thalassemia, four working entities are delineated, which, almost invariably, tend to overlap and aggravate each other: i) disorders inherent to the beta-thalassemia hemoglobinopathy; ii) chronic lung disease and its complications; iii) immunological corollaries of the therapy of beta-thalassemia, i.e. chronic transfusion, splenectomy and bone marrow transplantation; and iv) airway inflammation.

Is Intake of Flavonoid-Based Food Supplements During Pregnancy Safe for the Developing Child? A Literature Review

Due to potential health benefits and the general assumption that natural products are safe, there is an increasing trend in the general population – including pregnant women – to supplement their diet with flavonoid-based food supplements. In addition, preclinical studies aim to prevent developmental adverse effects induced by toxic substances, infections, maternal or genetic diseases of the unborn child by administration of flavonoids at doses far above those reached by normal diets. Because these substances do not undergo classical risk assessment processes, our aim was to review the available literature on the potential adverse effects of maternal diet supplementation with flavonoid-based products for the developing child. A systematic literature search was performed in three databases and screened following four exclusion criteria. Selected studies were classified into two groups: 1. Studies on the developmental toxicity of single flavonoids in vitro or in animals in vivo, and 2. Studies on the developmental toxicity of single flavonoids or on flavonoid-mixtures in humans. The data collected indicate that there is a concern for the safety of some flavonoids within realistic human exposure scenarios. This concern is accompanied by a tremendous lack of studies on safety of these compounds during development making definite safety decisions impossible. Besides studies of survival, especially the more specific developmental processes like nervous system development need to be addressed experimentally. Before new high-dose, flavonoid-based therapeutic strategies are developed for pregnant women further research on the safety of these compounds is clearly needed.

The Effects of Vitamin B in Depression

Vitamins are dietary components which are necessary for life. They play a major role in health and their deficiency may be linked to symptoms of psychiatric disorders. B vitamins are required for proper functioning of the methylation cycle, monoamine oxidase production, DNA synthesis and the repair and maintenance of phospholipids. Vitamin B deficiency could influence memory function, cognitive impairment and dementia. In particular, vitamins B1, B3, B6, B9 and B12 are essential for neuronal function and deficiencies have been linked to depression. We discuss the causes of depression and the neurochemical pathways in depression. In particular, we provide evidence that vitamin B contributes to the complexity of depressive symptoms.

ABC Transporters and Drug Resistance in Patients with Epilepsy

Resistance to antiepileptic drugs (AED) remains a major problem in clinical epileptology. This pharmacoresistance is independent of the choice of AEDs. Different hypotheses have been proposed to explain the neurobiological basis for pharmacoresistance in epilepsy. The transporter hypothesis is the mostly investigated theory. Hereby, overexpression of multidrug efflux transporters, such as P-glycoprotein (Pgp), at the blood-brain-barrier (BBB) is thought to be involved in pharmacoresistance in epilepsy by extruding AEDs from their target site. Accumulating evidence supports an overexpression of Pgp in pharmacoresistant epilepsy. Molecular Imaging studies provide unique opportunities for the in-vivo study of the transporter hypothesis in the central nervous system (CNS). Several studies demonstrated that positron emission tomography (PET) with [¹¹C]-radiolabled Pgp substrates is a promising tool for in vivo investigation of Pgp function at the rat, monkey and human BBB. Quantification of Pgp over activity in epilepsy patients by in vivo imaging could be highly useful because altered treatment strategies or novel AED could then be applied.

Editorial: Limited Utility of the Handgrip Test for the Diagnosis of Diabetic Cardiovascular Autonomic Neuropathy: “There’s Time Enough, But None to Spare”

Solving the Blood-Brain Barrier Challenge for the Effective Treatment of HIV Replication in the Central Nervous System

Recent decades mark a great progress in the treatment of HIV infection. What was once a deadly disease is now a chronic infection. However, HIV-infected patients are prone to develop comorbidities, which severely affect their daily functions. For example, a large population of patients develop a variety of neurological and cognitive complications, called HIV associated neurological disorders (HAND). Despite efficient repression of viral replication in the periphery, evidence shows that the virus can remain active in the central nervous system (CNS). This low level of replication is believed to result in a progression of neurocognitive dysfunction in infected individuals. Insufficient viral inhibition in the brain results from the inability of several treatment drugs in crossing the blood-brain barrier (BBB) and reaching therapeutic concentrations in the CNS. The current manuscript discusses several strategies that are being developed to enable therapeutics to cross the BBB, including bypassing BBB, inhibition of efflux transporters, the use of active transporters present at the BBB, and nanotechnology. The increased concentration of therapeutics in the CNS is desirable to prevent viral replication; however, potential side effects of anti-retroviral drugs need also to be taken into consideration.

Therapeutic Applications of Crocus sativus L. (Saffron): A Review

Saffron is an integral part of various traditional medicines containing several phytochemicals having disease preventing and health promoting properties. The antidepressant, cardio protective and chemopreventive properties of saffron can be attributed to its constinuent active phytochemicals and bioactive compounds like crocin, crocetin and safranal. Publicly available databases like NCBI-PubChem and ChEMBL have millions of bioactive compounds.This offers opportunity to mine the compound(s) of interest based on desired attributes in the therapeutic area of interest. The current review, attempts to identify potential of molecular basis of bioactive compounds of saffron.

Brain-metastatic Breast Cancer: Clinical Considerations and Pharmacological Approaches

Despite constant advances on breast cancer knowledge, the metastatic disease resulting from the spreading of this disease is still a challenge. This scenario is particularly critical in the more aggressive subtypes, as HER2-amplified and triple negative breast cancers, when often occurs the invasion of central nervous system (CNS) structures. In this situation, the survival of patients is drastically reduced, and the number of sequels and functional impairment is huge due to the small therapeutic arsenal available. In this context, it is necessary to understand the mechanisms involved in the process of metastasis of breast cancer to CNS, and how this process affects anatomically important structures for its functioning. This review aims to point out some mechanisms enrolled in the spread of breast cancer to CNS, discuss the clinical impact of such metastatisation and address the critical aspects related to the treatment of this condition.

Optic Nerve and Cerebral Edema in the Course of Diabetic Ketoacidosis

In the recent years we have been observing an increased incidence of type 1 diabetes in children and adolescents. This leads to a more frequent acute complication of type 1 diabetes among children with hyperglycemia. The most common of these is diabetic ketoacidosis (DKA), while cerebral edema is the most dangerous. In children with DKA, cerebral edema most often presents with clinical symptoms but may also appear in the so-called “subclinical” form. That is why the search continues for new methods of assessing and monitoring cerebral edema in the course of DKA treatment. Ultrasonographic optic nerve sheath diameter (US ONSD) assessment is performed in various clinical scenarios when cerebral edema is suspected. It is most often performed in adult patients but increasingly often in children. US ONSD assessment is useful in the treatment of DKA in children with type 1 diabetes. This manuscript provides an overview of research results available in PubMed and other available databases on the course of treatment of DKA in children with type 1 diabetes.

Future Targets in Endothelial Biology: Endothelial Cell to Mesenchymal Transition

Endothelial to mesenchymal transition (EndMT) is a poorly understood phenomenon that results in normal endothelial cells acquiring a mesenchymal phenotype. EndMT has been observed in a number of pathological conditions, from cancer to fibrosis to cardiovascular disease and the process itself may play an important mechanistic role in the development of these disease states.

Anticancer Mammalian Target of Rapamycin (mTOR) Signaling Pathway Inhibitors: Current Status, Challenges and Future Prospects in Management of Epilepsy

The role of phosphatidylinositol 3-kinase linked mammalian target of rapamycin (mTOR) pathway hyperactivation is well established in cancer pathogenesis. Several molecules inhibiting mTOR pathway, leading to inhibition of protein synthesis responsible for angiogenesis of tumor cells have emerged out to be potential anticancers. Similar hyperactivation of mTOR pathway has also reported in epilepsy during latent phase, following precipitating injury causing reorganization of neuronal networks and ultimately leading to induction of seizures. The mTOR inhibitors have also found to attenuate pathological changes in the brain associated with epilepsy, primarily suppression of mossy fiber sprouting. At the same time, a few antiepileptic molecules which have been studied against cancer showed anticancer activity, apart from their principal mechanism of action. These studies suggest mTOR signaling pathway to be a common pathogenic link between cancer and epilepsy. It has been found that, anticancer molecules acting on different molecular targets, that ultimately down regulate the expression of mTOR, can also be used in case of epilepsy to reduce its hyperactivation. There are several unexplored anticancer molecules that act by inhibiting mTOR directly or indirectly available which can be explored as antiepileptic in future. Majority of the molecules which are tested as anticancer do not reach the final phases of clinical trials due to less potency and efficacy, and ultimately a few of them reach the market. Since a lot of experimental/safety studies have already been conducted on such molecules, hence it is worthwhile to test these molecules for other disorders that share common pathogenic pathway like epilepsy, provided their pitfalls have been addressed, as proposed in the present review.

Current Progress of Reelin in Development, Inflammation and Tissue Remodeling: From Nervous to Visual Systems

Reelin is a matrix glycoprotein that plays a pivotal role for the positioning of neurons throughout brain development. In the early developing cortex Reelin regulates radial migration of cortical neurons while later in development, Reelin promotes maturation of dendrites and dendritic spines. Low Reelin levels characterize healthy adult brain while increased Reelin levels have been associated with cellular events underlying response to injury.

Reelin has been detected in structural and immune cells outside brain (liver, gut/colon tracts, kidney, testis, ovary, lung, retina and cornea). In the Visual system, Reelin was first described in the retina and thereafter in the cornea. Increased Reelin levels were observed during retinogenesis, low levels were found in adulthood and a significant increase was detected upon injury. Insult-driven Reelin changes occur after upregulation of adhesion molecules, cytokines, neurotrophins, growth factors, neuropeptides and other mediators as well as their receptors. These soluble factors contribute to the development of nervous and visual system and promote survival/recovery of neurons/accessory cells populating the injured visual system. Likewise, Reelin might modulate these factors by driving different multiple effects on homeostasis/plasticity, inflammation, healing and remodeling at different physiopathological levels. Very low-density lipoprotein receptor, apolipoprotein E receptor 2, integrins and the adaptor molecule Disabled 1 trigger Reelin pathway.

Recent advances highlight some Reelin activities during inflammation and tissue remodeling and point out to a crucial Reelin activity in the visual system. A better understanding of Reelin function in retinal development might open to new attractive perspective for counteracting retina degeneration.

Chaperone Therapy: New Molecular Therapy for Protein Misfolding Diseases with Brain Dysfunction

Chaperone therapy was proposed as a new molecular therapeutic approach almost simultaneously to lysosomal diseases and cystic fibrosis, caused by gene mutations resulting in misfolding of expressed proteins. In our original papers, we reported that unstable mutant lysosomal enzymes causing lysosomal diseases resulted in rapid intracellular degradation and loss of catalytic function. However, in the presence of some low molecular competitive inhibitors (chemical chaperones), after binding to enzyme active sites, paradoxically stabilized and enhanced catalytic activities in somatic cells (proteostasis) by correcting the enzyme protein folding. After oral administration, they were transferred to the bloodstream, reached the brain tissue through the blood-brain barrier, and normalized pathophysiology of the disease. Our reports of these inhibitory chaperones were followed by reports of non-competitive (or allosteric) chaperones without inhibitory bioactivity. Furthermore heat shock proteins and other endogenous proteins were recognized as candidates for the third-type chaperone therapy. Theoretically they could be utilized for handling abnormally accumulated intracellular mutant proteins, if they are overexpressed by small molecules particularly in neurodegenerative diseases. These three types of chaperone therapies are expected as promising approaches to a variety of diseases, genetic or nongenetic, and neurological or non-neurological, in addition to lysosomal diseases. Finally, in this article, possible chaperones for Gaucher disease are discussed, and preliminary clinical results of ambroxol therapy are summarized.

Antioxidants as a Potential Preventive and Therapeutic Strategy for Cadmium

Epidemiological studies provide a growing number of evidences that chronic exposure to relatively low levels of cadmium (Cd), nowadays taking place in industrialized countries, may cause health hazard. Thus, growing interest has been focused on effective ways of protection from adverse effects of exposure to this heavy metal. Because numerous effects to Cd’s toxic action result from its prooxidative properties, it seems reasonable that special attention should be directed to agents that can prevent or reduce this metal-induced oxidative stress and its consequences in tissues, organs and systems at risk of toxicity, including liver, kidneys, testes, ears, eyes, cardiovascular system and nervous system as well as bone tissue. This review discusses a wide range of natural (plant and animal origin) and synthetic antioxidants together with many plant extracts (e.g. black and green tea, Aronia melanocarpa, Allium sativum, Allium cepa, Ocimum sanctum, Phoenix dactylifera, Physalis peruviana, Zingiber officinale) that have been shown to prevent from Cd toxicity. Moreover, some attention has been focused on the fact that substances not possessing antioxidative potential may also prevent Cd-induced oxidative stress and its consequences. So far, most of the data on the protective effects of the natural and synthetic antioxidants and plant extracts come from studies in animals’ models; however, numerous of them seem to be promising preventive/therapeutic strategies for Cd toxicity in humans. Further investigation of prophylactic and therapeutic use of antioxidants in populations exposed to Cd environmentally and occupationally is warranted, given that therapeutically effective chelation therapy for this toxic metal is currently lacking.

Cellular Oxidative/Antioxidant Balance in γ-Irradiated Brain: An Update

Both epidemiological and experimental data indicate that ionizing radiation (IR) may disrupt developmental processes leading to deleterious effects on brain functions. A central role of reactive oxygen (ROS) and nitrogen species (RNS), as important mediators in neurotoxicity and neuroprotection, has been demonstrated. Primary ionization events triggered by IR are amplified and propagated by mechanisms involving ROS and RNS, which activate several signaling pathways leading to final radiation effects. The immature and adult brain display clear differences in the way they respond to insults. Moreover, a great deal of attention is being focus on the limited antioxidant capacity and the particular lipid composition of cell membranes of the developing brain that render it more vulnerable to oxidative stress. The goal of this review is to summarize the current knowledge on the role of alterations in the balance between oxidative/nitrosative stress and antioxidant capacity in the pathways involved in cellular radiation response, with particular focus on the possible therapies proposed to limit radiation-induced effects in the brain.

The Role of Therapeutic Drugs on Acquired Mitochondrial Toxicity

Background: Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms including deafness, neuropathy, myopathy, hyperlactatemia, lactic acidosis, pancreatitis and lipodystrophy, among others, which could even compromise the life of the patient.

Objectives: The aim of this work is to review the potential mitochondrial toxicity derived from drugs used in health care, including anesthetics, antiepileptics, neuroleptics, antidepressants, antivirals, antibiotics, antifungals, antimalarics, antineoplastics, antidiabetics, hypolipemiants, antiarrhythmics, anti-inflammatories and nitric oxide.

Methods: We herein have reviewed data from experimental and clinical studies to document the molecular mitochondrial basis, potential biomarkers and putative clinical symptoms associated to secondary effects of drugs.

Results: One hundred and forty-five articles were selected and the information was organized by means of the primary target to which pharmacologic drugs were directed. Adverse toxic events were classified depending on the mitochondrial offtarget effect and whether they had been demonstrated in the experimental or clinical setting. Conclusions: Since treatment of acquired mitochondriopathies remains supportive and therapeutic interventions cannot be avoided, information of molecular and clinical consequences of toxic exposure becomes fundamental to assess riskbenefit imbalance of treatment prescription. Additionally, there is a crucial need to develop less mitochondrial toxic compounds, novel biomarkers to follow up mitochondrial toxicity (or implement those already proposed) and new approaches to prevent or revert unintended mitochondrial damage.

Migraine and Central Sensitization: Clinical Features, Main Comorbidities and Therapeutic Perspectives

Migraine is a very common neurologic disorder, characterized by recurrent attacks of severe headache, autonomic nervous system dysfunction and in some patients by an aura.

Background: Migraine is a very common neurologic disorder of neuro-vascular origin, being amongst the 20 most disabling diseases. Migraine attacks are characterized by severe headache, associated to autonomic nervous system dysfunction and in some patients by aura.

Pathophysiology and Role of Central Sensitization: Abnormal neuronal excitability may subtend altered processing of sensory stimuli, leading to cortical spreading depression and trigeminal activation. A dysfunction of pain modulation enhances central sensitization phenomena, contributing to acute allodynia and headache persistence. The peculiarity of migraine pain facilitates the use of analgesics, and causes an adjunctive invalidating tendency toward drug over-use.

Comorbidity: Chronic migraine patients are frequently affected by diffuse pain, framed in fibromyalgia diagnosis. This comorbidity seems to be supported by common pathophysiological mechanisms. It may aggravate migraine invalidity being worth of consideration for therapeutic management.

Migraine Management: Acute and preventive treatments need to be tailored to single cases. Main comorbidity and factors facilitating central sensitization should be taken into account. The management of migraine patients should include a link between headache centers and general practitioner, in order to provide for a better patient information and treatment just at the onset of the disease.

Conclusions: Despite its high epidemiologic impact, migraine is frequently underestimated and destined to evolve into chronic form and drugs abuse. A more focused attention to factors facilitating central sensitization and invalidating comorbidities, should reduce the global burden of the disease. Key words: migraine, pathophysiology, central sensitization, fibromyalgia comorbidity, acute and preventive therapy, patients – centered approach.

Metabotropic Glutamate Receptors and Interacting Proteins in Epileptogenesis

Neurotransmitter and receptor systems are involved in different neurological and neuropsychological disorders such as Parkinson's disease, depression, Alzheimer’s disease and epilepsy. Recent advances in studies of signal transduction pathways or interacting proteins of neurotransmitter receptor systems suggest that different receptor systems may share the common signal transduction pathways or interacting proteins which may be better therapeutic targets for development of drugs to effectively control brain diseases. In this paper, we reviewed metabotropic glutamate receptors (mGluRs) and their related signal transduction pathways or interacting proteins in status epilepticus and temporal lobe epilepsy, and proposed some novel therapeutical drug targets for controlling epilepsy and epileptogenesis.

Therapeutic Potential of Neuregulin in Cardiovascular System: Can we Ignore the Effects of Neuregulin on Electrophysiology?

Neuregulin-1(NRG-1) has now been accepted to have therapeutic potential in cardiovascular disease. The preclinical and clinical researches of NRG-1 have demonstrated its advantage effects in cardiac function with multi-target cardiovascular biology and pathophysiology, but its influence on cardiac electrophysiology is rarely involved, which is a very important aspect and should not be ignored.

AMPK As A Target in Rare Diseases

The AMP-activated protein kinase (AMPK) has emerged as an important sensor of signals that control cellular energy balance in all eukaryotes. AMPK is also involved in fatty acid oxidation, glucose transport, antioxidant defense, mitochondrial biogenesis and the modulation of inflammatory processes. The numerous roles of AMPK in cell physiological and pathological states justified the notable increase in the number of publications in previous years, with almost 1500 scientific articles relative to this kinase in 2014. Due to its role in maintaining energy balance, a dysfunction in AMPK signalling pathway may result in perturbations at the systemic level that contribute to the development of many disease conditions. Among them, more than 7000 poorly-known rare diseases are particularly of social and scientific interest because they are usually chronically debilitating or even lifethreatening and lack effective and safe treatment. Several authors have demonstrated AMPK alterations and the beneficial effect of treatments with drugs regulating AMPK activity in some of these low prevalence pathologies. Among these rare diseases in which AMPK can play an important pathological role are mitochondrial disorders, muscular dystrophies, cardiovascular diseases, neurodegenerative pathologies, or even some types of cancer for the importance of AMPK as a suppressor of cell proliferation. This review focuses on current knowledge about the pathophysiological roles of AMPK and future approaches as therapeutic targeting in rare diseases.

Anesthesia Issues in Central Nervous System Disorders

Every year, millions of people affected by disorders of the central nervous system (CNS) undergo various diagnostic, therapeutic and surgical procedures requiring administration of anesthetic agents. Anesthetics exert their anesthetic, amnesic and analgesic effects by acting on multiple neuronal membrane proteins in the CNS. While some of the causal anesthetic targets have been identified, a large number of anesthetic targets remain unknown. The consequent longterm effect of anesthetic agents on expression of these various molecular targets has been implicated in mediating potentially long-lasting adverse effects. Recent work suggested that the effects of general anesthetics may not be entirely reversible, with animal studies demonstrating persistent changes in CNS protein expression post recovery from anesthesia. Age-associated or disease-induced alterations in the CNS can profoundly alter multiple aspects of brain structure, biochemistry, and function. Such maladaptive changes in the brain can render it increasingly vulnerable to the effects of various anesthetics. The selection of appropriate anesthesia drugs and protocol is mandatory, especially in individuals with pre-existing CNS disorders, so as to maximize anesthesia efficiency, avoid occurrence of adverse events, and ensure patient safety. This review aims to summarize and consider the effects and potential risks of commonly used anesthetic agents in patients with compromised CNS function. We provide a comprehensive review of the established as well as the implicated effects of anesthetic agents on the elderly as well as on the pathology and progression of common neurological conditions.

Novel Methods of Genetic Modification of Human Pluripotent Stem Cells

Genomic engineering has enormous potential along basic research, drug discovery and cell therapeutics. Many existing methods for targeted gene knockout mutagenesis or integration rely on homologous recombination. The low rate of spontaneous recombination in nearly all mammalian cell types, as well as the scale of screening, effort and time required to isolate the targeted events during genome modification, have hindered progress in this field. The present review has the objective to present latest improvements of technology to develop genetic modification to a clinical grade level so it can be used in human therapy.

Peroxisome Proliferator-Activated Receptor (PPAR) in Regenerative Medicine: Molecular Mechanism for PPAR in Stem Cells’ Adipocyte Differentiation

Regenerative medicine plays an indispensable role in modern medicine and many trials and researches have therefore been developed to fit our medical needs. Tissue engineering has proven that adipose tissue can widely be used and brings advantages to regenerative medicine. Moreover, a trait of adipose stem cells being isolated and grown in vitro is a cornerstone to various applications. Since the adipose tissue has been widely used in regenerative medicine, numerous studies have been conducted to seek methods for gaining more adipocytes. To investigate molecular mechanism for adipocyte differentiation, peroxisome proliferator-activated receptor (PPAR) has been widely studied to find out its functional mechanism, as a key factor for adipocyte differentiation. However, the precise molecular mechanism is still unknown. This review thus summarizes recent progress on the study of molecular mechanism and role of PPAR in adipocyte differentiation.

Targeted Drug Delivery and Imaging Using Mobile Milli/Microrobots: A Promising Future Towards Theranostic Pharmaceutical Design

Miniature untethered medical robots have been receiving growing attention due to technological advances in microactuation, microsensors, and microfabrication and have significant potential to reduce the invasiveness and improve the accessibility of medical devices into unprecedented small spaces inside the human body. In this review, we discuss therapeutic and diagnostic applications of untethered medical microrobots. Wirelessly controlled milli/microrobots with integrated sensors are revolutionizing micromanipulation based medical interventions and are enabling doctors to perform minimally invasive procedures not possible before. 3D fabrication technologies enabling milli/microrobot fabrication at the single cell scale are empowering high-resolution visual imaging and in vivo manipulation capabilities. Swallowable millirobots and injectabale ocular microrobots allow the gastric ulcer imaging, and performance of vitreoretinal microsurgery at previously inaccessible ocular sites. Many invasive excision and incision based diagnostic biopsy, prostrate, and nephrolgical procedures can be performed minimally or almost noninvasively due to recent advancements in microrobotic technology. Advances in biohybrid microrobot systems are pushing microrobotic systems even smaller, using biological cells as on-board microactuators and microsensors using the chemical energy. Such microrobotic systems could be used for local targeted delivery of imaging contrast agents, drugs, genes, and mRNA, minimally invasive surgery, and cell micromanipulation in the near future.

Drug Design Targeting the CXCR4/CXCR7/CXCL12 Pathway

Under physiological conditions, CXCL12 modulates cell proliferation, survival, angiogenesis, and migration mainly through CXCR4. Interestingly, the newly discovered receptor CXCR7 for CXCL12 is highly expressed in many tumor cells as well as tumor-associated blood vessels, although the level of CXCR7 in normal blood cells is low. Recently, many studies have suggested that CXCR7 promotes cell growth and metastasis in various cancers, including lymphoma and leukemia, hepatocecullar, ovarian, colorectal, breast and lung cancer. Compared to CXCR4, CXCR7 is a non-classical GPCR that is unable to activate G proteins. The function of CXCR7 is generally considered to be mediated by: (a) recruiting β-arrestin-2; (b) heterodimerizing with CXCR4; and (c) acting as a “scavenger” of CXCL12, thus lowering the level of CXCL12 to weaken the activity of CXCR4. However, the crosstalk between CXCL12/CXCR7/CXCR4 and other signaling pathways (such as the p38 MAPK pathway, the PI3K/mTOR pathway, the STAT3 signaling, and metalloproteinases MMP-9 and MMP-2) is more complicated. The function of CXCR7 is also involved in modulating tumor microenvironment, tumor cell migration and apoptosis. Understanding these complex interactions will provide insight in drug design targeting the CXCR7 as potential anticancer therapy.

Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma

While mortality is low for intraocular retinoblastoma patients in the developed world who receive aggressive multimodal therapy, partial or full loss of vision occurs in approximately 50% of patients with advanced bilateral retinoblastoma. Therapies that preserve vision and reduce late effects are needed. Because clinical trials for retinoblastoma are difficult due to the young age of the patient population and relative rarity of the disease, robust preclinical testing of new therapies is critical. The last decade has seen advances towards identifying new therapies including the development of animal models of retinoblastoma for preclinical testing, progress in local drug delivery to reach intraocular targets, and improved understanding of the underlying biological mechanisms that give rise to retinoblastoma. This review discusses advances in these areas, with a focus on discovery and development of small molecules for the treatment of retinoblastoma, including novel targeted therapeutics such as inhibitors of the MDMX-p53 interaction (nutlin-3a), histone deacetylase (HDAC) inhibitors, and spleen tyrosine kinase (SYK) inhibitors.

Melatonin in Pregnancy: Effects on Brain Development and CNS Programming Disorders

Melatonin is an important neuroprotective factor and its receptors are expressed in the fetal brain. During normal pregnancy, maternal melatonin level increases progressively until term and is highly transferred to the fetus, with an important role in brain formation and differentiation. Maternal melatonin provides the first circadian signal to the fetus. This indolamine is also produced de novo and plays a protective role in the human placenta. In pregnancy disorders, both maternal and placental melatonin levels are decreased. Alteration in maternal melatonin level has been associated with disrupted brain programming with long-term effects. Melatonin has strong antioxidant protective effects directly and indirectly via the activation of its receptors. The fetal brain is highly susceptible to oxygenation variation and oxidative stress that can lead to neuronal development disruption. Based on that, several approaches have been tested as a treatment in case of pregnancy disorders and melatonin, through its neuroprotective effect, has been recently accepted against fetal brain injury. This review provides an overview about the protective effects of melatonin during pregnancy and on fetal brain development.

Bevacizumab for Malignant Brain Gliomas. Which is the Current Evidence?

Recently, the improvement of innovative medications named focused treatments represents the consequence of a superior knowledge of the procedures implicated in the modification of physiological tissues in tumor. Focused treatment is known as the therapy which uses specific substances that affect selective mechanisms implicated in tumorigenesis and tumor development. Angiogenesis is important for tumor development and distant metastatic disease and represents a significant aim for modern biological substances. Bevacizumab belongs to humanized recombinant antibody family which obviates vascular endothelial growth factor (VEGF) receptor fastening, and suspending genesis of new vessels and tumor development. Bevacizumab represents the primary antiangiogenic treatment authorized for usage in tumor and has FDA authorization to treat the recurrent glioblastoma multiform since 2009. Bevacizumab’s efficiency for treating malignant brain gliomas along with correlated patent appliances related to this agent is discussed below.

Vasculogenic and Angiogenic Pathways in Moyamoya Disease

Background. Moyamoya disease (MMD) is a slowly progressing steno-occlusive cerebrovascular disease. The typical moyamoya vessels, which originate from an initial stenosis of the internal carotid, highlight that increased and/or abnormal angiogenic, vasculogenic and arteriogenic processes are involved in the disease pathophysiology. Objective. Herein, we summarize the current knowledge on the most important signaling pathways involved in MMD vessel formation, particularly focusing on the expression of growth factors and function of endothelial progenitor cells (EPCs). Methods and Results. Higher plasma concentrations of vascular endothelial growth factor, matrix metalloproteinase, hepatocyte growth factor, and interleukin-1β were reported in MMD. A specific higher level of basic fibroblast growth factor was also found in the cerebrospinal fluid of these patients. Finally, the number and the functionality of EPCs were found to be increased. In spite of the available data, the approaches and findings reported so far do not give an evident correlation between the expression levels of the aforementioned growth factors and MMD severity. Furthermore, the controversial results provided by studies on EPCs, do not permit to understand the true involvement of these cells in MMD pathophysiology. Conclusion. Further studies should thus be implemented to extend our knowledge on processes regulating both the arterial stenosis and the excessive formation of collateral vessels. Moreover, we suggest advances of integrated approaches and functional assays to correlate biological and clinical data, arguing for the development of new therapeutic applications for MMD.

New Perspectives in the Pharmacological Treatment of Non-Melanoma Skin Cancer

Non-melanoma skin cancers are the most common malignancy in humans, with a basal/squamous cell carcinoma incidence ratio of 4:1 in immunocompetent patients. Basal cell carcinoma rarely metastasizes but commonly causes significant local tissue destruction and disfigurement, whereas squamous cell carcinoma is associated with a substantial risk of recurrence and metastasis; the prognosis in metastatic patients is poor. Surgical approaches give a cure rate greater than 90% if appropriately applied, on the basis of the characteristics of the primary tumors and of the patients, but in selected cases, medical treatment (5-fluorouracil, imiquimod, diclofenac and, more recently, ingenol mebutate) is preferable to invasive procedures and provides a good chance of cure, with generally excellent cosmetic outcomes. In case of advanced and metastatic non-melanoma skin cancer, newly developed molecularly targeted therapy represents a reasonably promising alternative to classical cytostatics. In particular, the monoclonal antibody cetuximab, directed against the epidermal growth factor receptor, is effective and well-tolerated in squamous cell carcinoma patients. Moreover, the recent identification of mutations in the Hedgehog signaling pathway in basal cell carcinoma lead to the development of the smoothened Hedgehog pathway inhibitor vismodegib, that was recently approved for the treatment of locally advanced or metastatic basal cell carcinoma. In this review we provide an overview of the molecular pathways involved in NMSC pathogenesis, focusing on the mechanisms of action, indications, efficacy, side effects and contraindications of new medical treatments that specifically tackle molecular targets of these pathways.

Cyclooxygenase-2 and Prostaglandin E2 are Associated with Middle Cerebral Artery Occlusion and Hemorrhage in Patients with Moyamoya Disease

Some inflammatory proteins, such as cyclooxygenase (COX)-2 and prostaglandin (PG) E2 are hypothesized to be implicated in the development of moyamoya disease (MMD). However, the functional roles of COX-2/PGE2 in the pathogenesis of MMD remain elusive. In this study, tiny pieces of middle cerebral artery (MCA) and superficial temporal artery (STA) were surgically harvested from 18 adult MMD patients and 5 surgical control patients. The expression levels of COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1) in the vascular walls were immunohistochemically detected. With additional 10 healthy controls, the plasma levels of PGE2 were also measured by enzyme-linked immunosorbent assay (ELISA). Obvious intimal thickening was observed in both STA and MCA of MMD patients, but not in the controls. However, the MCA had a thicker intima than the STA (P < 0.01). Although plasma concentrations of PGE2 had no differences among the MMD patients, surgical controls and healthy controls, MCA of most MMD patients (15/18, 83.3%) were stained positively for COX-2 and all patients for mPGES-1. Staining of both COX-2 and mPGES-1 was more abundant in the MCA of hemorrhagic patients than those in their ischemic counterparts (P = 0.001 and 0.029, respectively). The expression levels of COX-2 were positively correlated with those of mPGES-1 (r = 0.647, P = 0.004). Positive COX-2 and mPGES-1 expressions were detected neither in the MCA samples from the surgical controls nor in all STA specimens. Our findings indicate that COX-2/PGE2 may be associated with the MCA occlusion and the hemorrhagic stroke in patients with MMD.

Relation Between Obstructive Sleep Apnea Syndrome and Resistant Hypertension - The Tip of the Iceberg

Obstructive sleep apnea (OSA) and hypertension (HT) are widespread, sometimes associated disorders that enhance each other and result in high morbidity and mortality rates. Resistant hypertension (RHT) is a specific condition defined as high blood pressure that remains uncontrolled despite treatment with at least three antihypertensive drugs (including a diuretic) at optimal doses. Given that RHT is very common in OSA patients, OSA is now considered one of the leading causes of RHT and RHT screening is mandatory in such cases. Some of the mechanisms seen in HT pathogenesis are also present (with specific particularities) in the OSA-HT association. Thus, factors like increased sympathetic tone, renin-angiotensinaldosterone system, endothelial dysfunction, vasoactive substances, inflammation, oxidative stress, nocturnal rostral fluid shift and excessive daytime sleepiness add their burden to the pathological chain, leading to both resistance and nondipping profile of HT. Consequently, we can assume that continuous positive airway pressure (CPAP) therapy in OSA patients has an impact on HT and HT resistance. This review describes the effect of CPAP on the above-mentioned links of the pathological chain, while providing information on new methods of assessing the cardiovascular risk in these patients, a history of the most important studies on the OSA-RHT association and the outcomes of a recent meta-analysis showing a positive effect of CPAP on 24-hour BP monitoring in patients with OSA and RHT compared to standard antihypertensive treatment.

Integrins as Therapeutic Targets for Respiratory Diseases

Integrins are a large family of transmembrane heterodimeric proteins that constitute the main receptors for extracellular matrix components. Integrins were initially thought to be primarily involved in the maintenance of cell adhesion and tissue integrity. However, it is now appreciated that integrins play important roles in many other biological processes such as cell survival, proliferation, differentiation, migration, cell shape and polarity. Lung cells express numerous combinations and permutations of integrin heterodimers. The complexity and diversity of different integrin heterodimers being implicated in different lung diseases present a major challenge for drug development. Here we provide a comprehensive overview of the current knowledge of integrins from studies in cell culture to integrin knockout mouse models and provide an update of results from clinical trials for which integrins are therapeutic targets with a focus on respiratory diseases (asthma, emphysema, pneumonia, lung cancer, pulmonary fibrosis and sarcoidosis).

Nutri-epigenomic Studies Related to Neural Tube Defects: Does Folate Affect Neural Tube Closure Via Changes in DNA Methylation?

Neural tube defects (NTDs), affecting 1-2 per 1000 pregnancies, are severe congenital malformations that arise from the failure of neurulation during early embryonic development. The methylation hypothesis suggests that folate prevents NTDs by stimulating cellular methylation reactions. Folate is central to the one-carbon metabolism that produces pyrimidines and purines for DNA synthesis and for the generation of the methyldonor S-adenosyl-methionine. This review focuses on the relation between the folate-mediated one-carbon metabolism, DNA methylation and NTDs. Studies will be discussed that investigated global or locus-specific DNA methylation differences in patients with NTDs. Folate deficiency may increase NTD risk by decreasing DNA methylation, but to date, human studies vary widely in study design in terms of analyzing different clinical subtypes of NTDs, using different methylation quantification assays and using DNA isolated from diverse types of tissues. Some studies have focused mainly on global DNA methylation differences while others have quantified specific methylation differences for imprinted genes, transposable elements and DNA repair enzymes. Findings of global DNA hypomethylation and LINE-1 hypomethylation suggest that epigenetic alterations may disrupt neural tube closure. However, current research does not support a linear relation between red blood cell folate concentration and DNA methylation. Further studies are required to better understand the interaction between folate, DNA methylation changes and NTDs.

Diagnostic Imaging of Fetal and Neonatal Abdominal and Soft Tissue Tumors

Imaging plays a key role in the diagnosis and staging of prenatal and neonatal tumors, and is essential in treatment planning. Though obstetrical ultrasound is the first choice prenatally, fetal MRI continues to play an increasing role as experience with this imaging modality increases. In the neonate, in addition to ultrasound and MRI, CT and nuclear medicine studies can also play an important role. We describe the prenatal and neonatal imaging findings of some of the most common congenital abdominal and soft tissue neoplasms including neuroblastoma, renal, liver and soft tissue tumors.

Current Management of Neonatal Soft-tissue Sarcomas and Benign Tumors with Local Aggressiveness

Neonatal soft-tissue tumors are rare and comprise a heterogeneous group of neoplasms with substantial histological diversity. Treatment options include careful observation, primary surgical resection or medical therapy. Although histologically benign, some neoplasms do exhibit an aggressive local behavior. The most common soft-tissue sarcomas in this age group include rhabdomyosarcoma, fibrosarcoma, malignant rhabdoid tumor and hemangiopericytoma. Prenatal diagnosis on routine ultrasound or in the context of a known predisposition syndrome is increasingly becoming more common. Management of neonatal tumors requires a multidisciplinary team that includes obstetricians, neonatologists, pediatric oncologists, pediatric surgical specialists and psychological support for the family members. Treatment is particularly challenging due to the difficulty in appropriate dosing of chemotherapeutic agents or the limitations of the use of radiation therapy. Although surgical treatment is predominant in this age group, close observation may be appropriate, since spontaneous regression has been reported for certain histological subtypes.