Noonan Syndrome

RASopathies and Cardiac Complications: Insights into Mechanisms, Diagnosis, and Innovative Treatments

RAS proteins are critical in cellular signal transduction, influencing cell proliferation, differentiation, and survival. While extensively studied for their role in cancer, RAS gene mutations also contribute significantly to cardiovascular diseases, such as hypertrophic cardiomyopathy, pulmonary valve stenosis, and atrial septal defects. Despite their similar primary structures, RAS proteins exhibit distinct functions in cardiac biology: H-RAS regulates cardiomyocyte size, K-RAS governs proliferation, and N-RAS, less associated with cardiac defects, is understudied in cardiac cells. Congenital RAS mutations, collectively known as RASopathies, include syndromes, like Noonan syndrome and cardio-facio-cutaneous syndrome, which often lead to severe cardiac complications, including heart failure. Genetic testing and imaging advances have improved the diagnosis and management of these conditions. Recent research has shown promise with MEK inhibitors and other targeted therapies, offering potential improvements in managing RAS-related cardiac conditions. This review explores the role of the RAS subfamily in heart disease, highlighting key concepts and potential therapeutic targets. PubMed database was searched using keywords, such as RASopathies, RAS gene mutations, cardiac hypertrophy, cardiovascular disease, RAS/MAPK pathway, congenital heart disease, and more. Relevant literature up to June 2024 was examined and summarized, consisting of data from various clinical trials, metaanalyses, retrospective/prospective cohort studies, and current guidelines.

PaSTe. Blockade of the Lipid Phenotype of Prostate Cancer as Metabolic Therapy: A Theoretical Proposal

Background: Prostate cancer is the most frequently diagnosed malignancy in 112 countries and is the leading cause of death in eighteen. In addition to continuing research on prevention and early diagnosis, improving treatments and making them more affordable is imperative. In this sense, the therapeutic repurposing of low-cost and widely available drugs could reduce global mortality from this disease. The malignant metabolic phenotype is becoming increasingly important due to its therapeutic implications. Cancer generally is characterized by hyperactivation of glycolysis, glutaminolysis, and fatty acid synthesis. However, prostate cancer is particularly lipidic; it exhibits increased activity in the pathways for synthesizing fatty acids, cholesterol, and fatty acid oxidation (FAO).

Objective: Based on a literature review, we propose the PaSTe regimen (Pantoprazole, Simvastatin, Trimetazidine) as a metabolic therapy for prostate cancer. Pantoprazole and simvastatin inhibit the enzymes fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), therefore, blocking the synthesis of fatty acids and cholesterol, respectively. In contrast, trimetazidine inhibits the enzyme 3-β-Ketoacyl- CoA thiolase (3-KAT), an enzyme that catalyzes the oxidation of fatty acids (FAO). It is known that the pharmacological or genetic depletion of any of these enzymes has antitumor effects in prostatic cancer.

Results: Based on this information, we hypothesize that the PaSTe regimen will have increased antitumor effects and may impede the metabolic reprogramming shift. Existing knowledge shows that enzyme inhibition occurs at molar concentrations achieved in plasma at standard doses of these drugs.

Conclusion: We conclude that this regimen deserves to be preclinically evaluated because of its clinical potential for the treatment of prostate cancer.

Nuchal Translucency and Congenital Heart Defects

Nuchal translucency comprises a temporary accumulation of fluid in the subcutaneous tissue on the back of a fetus’s neck, which accompanies the crown-rump length and is observed through an ultrasound performed between 11 and 13 weeks + 6 days gestation. Nuchal translucency is considered to be above normal when values are higher than the 95th/99th percentile or equal to or higher than 2.5/3.5 mm. The first connection between increased nuchal translucency and the presence of congenital heart defects is described in the study of Hyett et al., who observed that they are directly proportional. Since that time, several studies have been conducted to understand if nuchal translucency measurements can be used for congenital heart defect screening in euploid fetuses. However, there is great variability in the estimated nuchal translucency cutoff values for congenital heart defect detection. The purpose of this review was to understand how increased nuchal translucency values and congenital heart defects are related and to identify which of these defects are more frequently associated with an increase in these values.

Repurposing Metformin for Vascular Disease

Metformin has been used as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom Prospective Diabetes Study (UKPDS), metformin use rapidly increased and today is the first-choice anti-hyperglycaemic drug for patients with type 2 diabetes (T2D). Metformin is in daily use by an estimated 150 million people worldwide. Historically, the benefits of metformin as an anti-diabetic and cardiovascular-protective drug have been linked to effects in the liver, where it acts to inhibit gluconeogenesis and lipogenesis, as well as reduce insulin resistance and enhance peripheral glucose utilization. However, direct protective effects on the endothelium and effects in the gut prior to metformin absorption are now recognized as important. In the gut, metformin modulates the glucagon-like peptide- 1 (GLP-1) - gut-brain axis and impacts the intestinal microbiota. As the apparent number of putative tissue and cellular targets for metformin has increased, so has the interest in re-purposing metformin to treat other diseases that include polycystic ovary syndrome (PCOS), cancer, neurodegenerative diseases, and COVID-19. Metformin is also being investigated as an anti-ageing drug. Of particular interest is whether metformin provides the same level of vascular protection in individuals other than those with T2D, including obese individuals with metabolic syndrome, or in the setting of vascular thromboinflammation caused by SARS-CoV-2. In this review, we critically evaluate the literature to highlight clinical settings in which metformin might be therapeutically repurposed for the prevention and treatment of vascular disease.

Cannabinoids Receptors in COVID-19: Perpetrators and Victims

COVID-19 is caused by SARS-CoV-2 and leads to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severely affected cases. However, most of the affected cases are mild or asymptomatic. Cannabinoids (CBs) such as tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on G-protein-coupled receptors called CB1 and CB2, have anti-inflammatory effects. Many published studies show that CBs are effective in various inflammatory disorders, viral infections, and attenuation of ALI and ARDS. Therefore, the present narrative review aimed to summarize the possible immunological role of CBs in COVID-19. The effects of CBs are controversial, although they have beneficial effects via CB2 receptors and adverse effects via CB1 receptors against ALI, ARDS, and hyperinflammation, which are hallmarks of COVID-19. The present narrative review has shown that CBs effectively manage ALI and ARDS by suppressing pro-inflammatory cytokines, which are common in COVID-19. Therefore, CBs may be used to manage COVID-19 because of their potent anti-inflammatory effects, suppressing pro-inflammatory cytokines and inhibiting inflammatory signaling pathways.

Structure based Drug Designing Approaches in SARS-CoV-2 Spike Inhibitor Design

The COVID-19 outbreak and the pandemic situation have hastened the research community to design a novel drug and vaccine against its causative organism, the SARS-CoV-2. The spike glycoprotein present on the surface of this pathogenic organism plays an immense role in viral entry and antigenicity. Hence, it is considered an important drug target in COVID-19 drug design. Several three-dimensional crystal structures of this SARS-CoV-2 spike protein have been identified and deposited in the Protein DataBank during the pandemic period. This accelerated the research in computer- aided drug designing, especially in the field of structure-based drug designing. This review summarizes various structure-based drug design approaches applied to this SARS-CoV-2 spike protein and its findings. Specifically, it is focused on different structure-based approaches such as molecular docking, high-throughput virtual screening, molecular dynamics simulation, drug repurposing, and target-based pharmacophore modelling and screening. These structural approaches have been applied to different ligands and datasets such as FDA-approved drugs, small molecular chemical compounds, chemical libraries, chemical databases, structural analogs, and natural compounds, which resulted in the prediction of spike inhibitors, spike-ACE-2 interface inhibitors, and allosteric inhibitors.

Key miRNAs in Modulating Aging and Longevity: A Focus on Signaling Pathways and Cellular Targets

Aging is a multifactorial process accompanied by gradual deterioration of most biological procedures of cells. MicroRNAs (miRNAs) are a class of short non-coding RNAs that post-transcriptionally regulate the expression of mRNAs through sequence-specific binding, contributing to many crucial aspects of cell biology. Several miRNAs are expressed differently in various organisms through aging. The function of miRNAs in modulating aging procedures has been disclosed recently with the detection of miRNAs that modulate longevity in the invertebrate model organisms through the IIS pathway. In these model organisms, several miRNAs have been detected to both negatively and positively regulate lifespan via commonly aging pathways. miRNAs modulate age-related procedures and disorders in different mammalian tissues by measuring their tissue- specific expression in older and younger counterparts, including heart, skin, bone, brain, and muscle tissues. Moreover, several miRNAs have contributed to modulating senescence in different human cells, and the roles of these miRNAs in modulating cellular senescence have allowed illustrating some mechanisms of aging. The review discusses the available data on the role of miRNAs in the aging process, and the roles of miRNAs as aging biomarkers and regulators of longevity in cellular senescence, tissue aging, and organism lifespan have been highlighted.

Pediatrics for Disability: A Comprehensive Approach to Children with Syndromic Psychomotor Delay

Intellectual disability is the impairment of cognitive, linguistic, motor and social skills that occurs in the pediatric age and is also described by the term “mental retardation”. Intellectual disability occurs in 3-28 % of the general population due to a genetic cause, including chromosome aberrations. Among people with intellectual disabilities, the cause of the disability was identified as a single gene disorder in up to 12 %, multifactorial disorders in up to 4 %, and genetic disorders in up to 8.5 %. Children affected by a malformation syndrome associated with mental retardation or intellectual disability represent a care challenge for the pediatrician. A multidisciplinary team is essential to manage the patient, thereby controlling the complications of the syndrome and promoting the correct psychophysical development. This requires continuous follow-up of these children by the pediatrician, which is essential for both the clinical management of the syndrome and facilitating the social integration of these children.

In Vitro and In Vivo Approaches for Screening the Potential of Anticancer Agents: A Review

Background: Anticancer drug development is a tedious process, requiring several in vitro, in vivo, and clinical studies. In order to avoid chemical toxicity in animals during an experiment, it is necessary to envisage toxic doses of screened drugs in vivo at different concentrations. Several in vitro and in vivo studies have been reported to discover the management of cancer.

Materials and Methods: This study focused on bringing together a wide range of in vivo and in vitro assay methods developed to evaluate each hallmark feature of cancer.

Result: This review provides detailed information on target-based and cell-based screening of new anticancer drugs in the molecular targeting period. This would help in inciting an alteration from the preclinical screening of pragmatic compound-orientated to target-orientated drug selection.

Conclusion: Selection methodologies for finding anticancer activity have importance for tumor- specific agents. In this study, advanced rationalization of the cell-based assay is explored along with broad applications of the cell-based methodologies considering other opportunities.

Impact of Sitagliptin on Non-diabetic Covid-19 Patients

Objectives: In coronavirus disease 2019 (Covid-19), SARS-CoV-2 may use dipeptidyl peptidase 4 (DPP4) as an entry-point in different tissues expressing these receptors. DPP4 inhibitors (DPP4Is), also named gliptins, like sitagliptin, have anti-inflammatory and antioxidant effects, thereby lessen inflammatory and oxidative stress in diabetic Covid-19 patients. Therefore, the present study aimed to illustrate the potential beneficial effect of sitagliptin in managing Covid-19 in non-diabetic patients.

Methods: A total number of 89 patients with Covid-19 were recruited from a single center at the time of diagnosis. The recruited patients were assigned according to the standard therapy for Covid-19 and our interventional therapy into two groups; Group A: Covid-19 patients on the standard therapy (n=40) and Group B: Covid-19 patients on the standard therapy plus sitagliptin (n=49). The duration of this interventional study was 28 days according to the guideline in managing patients with Covid-19. Routine laboratory investigations, serological tests, Complete Blood Count (CBC), C-reactive Protein (CRP), D-dimer, lactate dehydrogenase (LDH), and serum ferritin were measured to observed Covid-19 severity and complications. Lung Computed Tomography (CT) and clinical scores were evaluated.

Results: The present study illustrated that sitagliptin as an add-on to standard therapy improved clinical outcomes, radiological scores, and inflammatory biomarkers than standard therapy alone in non-diabetic patients with Covid-19 (P<0.01).

Conclusion: Sitagliptin as an add-on to standard therapy in managing non-diabetic Covid-19 patients may have a robust beneficial effect by modulating inflammatory cytokines with subsequent good clinical outcomes.

Harnessing the Natural Pool of Polyketide and Non-ribosomal Peptide Family: A Route Map towards Novel Drug Development

The emergence of communicable and non-communicable diseases has posed a health challenge for millions of people worldwide and is a major threat to the economic and social development in the coming century. The occurrence of the recent pandemic, SARS-CoV-2, caused by lethal severe acute respiratory syndrome coronavirus 2, is one such example. Rapid research and development of drugs for the treatment and management of these diseases have become an incredibly challenging task for the pharmaceutical industry. Although, substantial attention has been paid to the discovery of therapeutic compounds from natural sources having significant medicinal potential, their synthesis has made a slow progress. Hence, the discovery of new targets by the application of the latest biotechnological and synthetic biology approaches is very much the need of the hour. Polyketides (PKs) and non-ribosomal peptides (NRPs) found in bacteria, fungi and plants are a diverse family of natural products synthesized by two classes of enzymes: polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS). These enzymes possess immense biomedical potential due to their simple architecture, catalytic capacity, as well as diversity. With the advent of the latest in-silico and in-vitro strategies, these enzymes and their related metabolic pathways, if targeted, can contribute highly towards the biosynthesis of an array of potentially natural drug leads that have antagonist effects on biopolymers associated with various human diseases. In the face of the rising threat from multidrug-resistant pathogens, this will further open new avenues for the discovery of novel and improved drugs by combining natural and synthetic approaches. This review discusses the relevance of polyketides and non-ribosomal peptides and the improvement strategies for the development of their derivatives and scaffolds, and how they will be beneficial for future bioprospecting and drug discovery.

Therapeutic Options for the Management of Aromatase Inhibitor- Associated Bone Loss

Background: Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy. Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease- free survival and overall survival; it involves several endocrine treatment regimens, including Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women.

Objectives: The objective of this review is to evaluate the therapeutic options in the management of Aromatase Inhibitor-Associated Bone Loss (AIBL).

Methods: We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL.

Results: Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease- free survival.

Conclusions: AI, that are the pillar of the systemic treatment for patients with hormone receptorpositive breast cancer, are associated with different side effects, and in particular, osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.

Role of Protein Tyrosine Phosphatase in Regulation of Cell Signaling Cascades Affecting Tumor Cell Growth: A Future Perspective as Anti-Cancer Drug Target

Protein Tyrosine Phosphatase (PTP) superfamily is a key enzyme involved in the regulation of growth-related cell signaling cascades, such as the RAS/MAPK pathway, that directly affect cancer cell growth and metastasis. Several studies have indicated that the drug resistance observed in several late-stage tumors might also be affected by the levels of PTP in the cell. Hence, these phosphatases have been in the limelight for the past few decades as potential drug targets and several promising drug candidates have been developed, even though none of these drugs have reached the market yet. In this review, we explore the potential of PTP as a viable anti-cancer drug target by studying PTPs, their regulation of several key cancer cell signaling pathways, and how their levels affect various types of cancer. Furthermore, we present the current scenario of PTP as a molecular target and the various challenges faced in the development of PTP-targeting anti-cancer drugs.

In-Silico and In-Vitro Analysis of Human SOS1 Protein Causing Noonan Syndrome - A Novel Approach to Explore the Molecular Pathways

Aims: Perform in-silico analysis of human SOS1 mutations to elucidate their pathogenic role in Noonan syndrome (NS).

Background: NS is an autosomal dominant genetic disorder caused by single nucleotide mutation in PTPN11, SOS1, RAF1, and KRAS genes. NS is thought to affect approximately 1 in 1000. NS patients suffer different pathogenic effects depending on the mutations they carry. Analysis of the mutations would be a promising predictor in identifying the pathogenic effect of NS.

Methods: We performed computational analysis of the SOS1 gene to identify the pathogenic nonsynonymous single nucleotide polymorphisms (nsSNPs) th a t cause NS. SOS1 variants were retrieved from the SNP database (dbSNP) and analyzed by in-silico tools I-Mutant, iPTREESTAB, and MutPred to elucidate their structural and functional characteristics.

Results: We found that 11 nsSNPs of SOS1 that were linked to NS. 3D modeling of the wild-type and the 11 nsSNPs of SOS1 showed that SOS1 interacts with cardiac proteins GATA4, TNNT2, and ACTN2. We also found that GRB2 and HRAS act as intermediate molecules between SOS1 and cardiac proteins. Our in-silico analysis findings were further validated using induced cardiomyocytes (iCMCs) derived from NS patients carrying SOS1 gene variant c.1654A>G (NSiCMCs) and compared to control human skin fibroblast-derived iCMCs (C-iCMCs). Our in vitro data confirmed that the SOS1, GRB2 and HRAS gene expressions as well as the activated ERK protein, were significantly decreased in NS-iCMCs when compared to C-iCMCs.

Conclusion: This is the first in-silico and in vitro study demonstrating that 11 nsSNPs of SOS1 play deleterious pathogenic roles in causing NS.

Natural Substances in the Fight of SARS-CoV-2: A Critical Evaluation Resulting from the Cross-Fertilization of Molecular Modeling Data with the Pharmacological Aspects

The recent pandemic due to SARS-CoV-2, the last isolated human betacoronavirus, has revolutionized modern knowledge of the pathogenesis of viral pneumonia. The lack of specific antiviral drugs and the need to develop adequate research for new antiviral drugs capable of treating this new form of the disease undertook three different research paths quickly. The first one is aimed to test antiviral molecules already present in therapeutic use, with a mechanism of action directed towards viral proteins functional to replication or adsorption; the second one, it is the repositioning of molecules with known pharmacological activity for which various chemistry studies have been prepared in an attempt to find new and specific viral targets; the third, it is the search for molecules of natural origin for which to demonstrate a specific anti-coronavirus activity. Many databases of natural and synthetic substances have been used for the identification of potent inhibitors of various viral targets. The field of computer-aided drug design seems to be promising and useful for the identification of SARS-CoV-2 inhibitors; hence, different structure- and ligand- based computational approaches have been used for their identification. This review analyzes in-depth and critically the most recent publications in the field of applied computational chemistry to find out molecules of natural origin with potent antiviral activity. Furthermore, a critical and functional selection of some molecules with the best hypothetical anti-SARS-CoV-2 activity is made for further studies by biological tests.

Protein-Ligand Docking Simulations with AutoDock4 Focused on the Main Protease of SARS-CoV-2

Background: The main protease of SARS-CoV-2 (M^pro) is one of the targets identified in SARS-CoV-2, the causative agent of COVID-19. The application of X-ray diffraction crystallography made available the three-dimensional structure of this protein target in complex with ligands, which paved the way for docking studies.

Objective: Our goal here is to review recent efforts in the application of docking simulations to identify inhibitors of the M^pro using the program AutoDock4.

Methods: We searched PubMed to identify studies that applied AutoDock4 for docking against this protein target. We used the structures available for M^pro to analyze intermolecular interactions and reviewed the methods used to search for inhibitors.

Results: The application of docking against the structures available for the M^pro found ligands with an estimated inhibition in the nanomolar range. Such computational approaches focused on the crystal structures revealed potential inhibitors of M^pro that might exhibit pharmacological activity against SARS-CoV-2. Nevertheless, most of these studies lack the proper validation of the docking protocol. Also, they all ignored the potential use of machine learning to predict affinity.

Conclusion: The combination of structural data with computational approaches opened the possibility to accelerate the search for drugs to treat COVID-19. Several studies used AutoDock4 to search for inhibitors of M^pro. Most of them did not employ a validated docking protocol, which lends support to critics of their computational methodology. Furthermore, one of these studies reported the binding of chloroquine and hydroxychloroquine to M^pro. This study ignores the scientific evidence against the use of these antimalarial drugs to treat COVID-19.

The Impact of Crystallographic Data for the Development of Machine Learning Models to Predict Protein-Ligand Binding Affinity

Background: One of the main challenges in the early stages of drug discovery is the computational assessment of protein-ligand binding affinity. Machine learning techniques can contribute to predicting this type of interaction. We may apply these techniques following two approaches. Firstly, using the experimental structures for which affinity data is available. Secondly, using protein-ligand docking simulations.

Objective: In this review, we describe recently published machine learning models based on crystal structures, for which binding affinity and thermodynamic data are available.

Method: We used experimental structures available at the protein data bank and binding affinity and thermodynamic data was accessed through BindingDB, Binding MOAD, and PDBbind databases. We reviewed machine learning models to predict binding created using open source programs, such as SAnDReS and Taba.

Results: Analysis of machine learning models trained against datasets, composed of crystal structure complexes indicated the high predictive performance of these models when compared with classical scoring functions.

Conclusion: The rapid increase in the number of crystal structures of protein-ligand complexes created a favorable scenario for developing machine learning models to predict binding affinity. These models rely on experimental data from two sources, the structural and the affinity data. The combination of experimental data generates computational models that outperform the classical scoring functions.

Elucidation of Abnormal Extracellular Regulated Kinase (ERK) Signaling and Associations with Syndromic and Non-syndromic Autism

Autism is a highly inherited and extremely complex disorder in which results from various cases indicate chromosome anomalies, unusual single-gene mutations, and multiplicative effects of particular gene variants, characterized primarily by impaired speech and social interaction and restricted behavior. The precise etiology of Autism Spectrum Disorder (ASD) is currently unclear. The extracellular signal-regulated kinase (ERK) signaling mechanism affects neurogenesis and neuronal plasticity during the development of the central nervous mechanism. In this regard, the pathway of ERK has recently gained significant interest in the pathogenesis of ASD. The mutation occurs in a few ERK components. Besides, the ERK pathway dysfunction lies in the upstream of modified translation and contributes to synapse pathology in syndromic types of autism. In this review, we highlight the ERK pathway as a target for neurodevelopmental disorder autism. In addition, we summarize the regulation of the ERK pathway with ERK inhibitors in neurological disorders. In conclusion, a better understanding of the ERK signaling pathway provides a range of therapeutic options for autism spectrum disorder.

Allosteric Inhibitors of SHP2: An Updated Patent Review (2015-2020)

Srchomology-2-domain-containing PTP 2 (SHP2) is a nonreceptor phosphatase encoded by the PTPN11 gene. Over expression of SHP2 is associated with various human diseases, such as Noonan syndrome, LEOPARD syndrome, and cancers. To overcome the shortcomings of existing orthosteric inhibitors, novel inhibitors targeting the allosteric site of SHP2 with high selectivity and low toxicity are under development. This paper reviews allosteric inhibitors of SHP2 published in patents from 2015 to 2020. The molecules are classified according to the chemical structure of the central core. SHP2 has long been considered as an ‘undruggable’ protein. Fortunately, a critical breakthrough was made by researchers from Novartis AG Ltd., who identified SHP099 as a highly potent, selective, soluble, and orally bioavailable SHP2 allosteric inhibitor. Currently, there are several allosteric inhibitors of SHP2 in clinical development. However, drug resistance is still a major challenge. The combination of SHP2 allosteric inhibitors and immunotherapy drugs or molecular targeted drugs is emerging as a promising therapeutic strategy against drug resistance.

Tanshinones: An Update in the Medicinal Chemistry in Recent 5 Years

Tanshinones are an important type of natural products isolated from Salvia miltiorrhiza Bunge with various bioactivities. Tanshinone IIa, cryptotanshinone and tanshinone I are three kinds of tanshinones which have been widely investigated. Particularly, sodium tanshinone IIa sulfonate is a water-soluble derivative of tanshinone IIa and it is used in clinical in China for treating cardiovascular diseases. In recent years, there are increasing interests in the investigation of tanshinones derivatives in various diseases. This article presents a review of the anti-atherosclerotic effects, cardioprotective effects, anticancer activities, antibacterial activities and antiviral activities of tanshinones and structural modification work in recent years.

Newborn Screening through TREC, TREC/KREC System for Primary Immunodeficiency with limitation of TREC/KREC. Comprehensive Review

Introduction: Newborn screening (NBS) by quantifying T cell receptor excision circles (TRECs) and Kappa receptor excision circles in neonatal dried blood spots (DBS) enables early diagnosis of different types of primary immune deficiencies. Global newborn screening for PID, using an assay to detect T-cell receptor excision circles (TREC) in dried blood spots (DBS), is now being performed in all states in the United States. In this review, we discuss the development and outcomes of TREC, TREC/KREC combines screening, and continued challenges to implementation.

Objective: To review the diagnostic performance of published articles for TREC and TREC/ KREC based NBS for PID and its different types.

Methods: Different research resources were used to get an approach for the published data of TREС and KREC based NBS for PID like PubMed, Scopus, Google Scholar, Research gate EMBASE. We extracted TREC and KREC screening Publisher with years of publication, content and cut-off values, and a number of retests, repeat DBS, and referrals from the different published pilot, pilot cohort, Case series, and cohort studies.

Results: We included the results of TREC, combined TREC/KREC system based NBS screening from different research articles, and divided these results between the Pilot studies, case series, and cohort. For each of these studies, different parameter data are excluded from different articles. Thirteen studies were included, re-confirming 89 known SCID cases in case series and reporting 53 new SCID cases in 3.15 million newborns. Individual TREC contents in all SCID patients were <25 TRECs/μl (except in those evaluated with the New York State assay).

Conclusion: TREC and KREC sensitivity for typical SCID and other types of PID was 100 %. It shows its importance and anticipating the significance of implementation in different undeveloped and developed countries in the NBS program in upcoming years. Data adapting the screening algorithm for pre-term/ill infants reduce the amount of false-positive test results.

Diabetes and Its Complications: Therapies Available, Anticipated and Aspired

Worldwide, diabetes ranks among the ten leading causes of mortality. Prevalence of diabetes is growing rapidly in low and middle income countries. It is a progressive disease leading to serious co-morbidities, which results in increased cost of treatment and over-all health system of the country. Pathophysiological alterations in Type 2 Diabetes (T2D) progressed from a simple disturbance in the functioning of the pancreas to triumvirate to ominous octet to egregious eleven to dirty dozen model. Due to complex interplay of multiple hormones in T2D, there may be multifaceted approach in its management. The ‘long-term secondary complications’ in uncontrolled diabetes may affect almost every organ of the body, and finally may lead to multi-organ dysfunction. Available therapies are inconsistent in maintaining long term glycemic control and their long term use may be associated with adverse effects. There is need for newer drugs, not only for glycemic control but also for prevention or mitigation of secondary microvascular and macrovascular complications. Increased knowledge of the pathophysiology of diabetes has contributed to the development of novel treatments. Several new agents like Glucagon Like Peptide - 1 (GLP-1) agonists, Dipeptidyl Peptidase IV (DPP-4) inhibitors, amylin analogues, Sodium-Glucose transport -2 (SGLT- 2) inhibitors and dual Peroxisome Proliferator-Activated Receptor (PPAR) agonists are available or will be available soon, thus extending the range of therapy for T2D, thereby preventing its long term complications. The article discusses the pathophysiology of diabetes along with its comorbidities, with a focus on existing and novel upcoming antidiabetic drugs which are under investigation. It also dives deep to deliberate upon the novel therapies that are in various stages of development. Adding new options with new mechanisms of action to the treatment armamentarium of diabetes may eventually help improve outcomes and reduce its economic burden.

The Therapeutic Potential and Usage Patterns of Cannabinoids in People with Spinal Cord Injuries: A Systematic Review

Background: People with spinal cord injuries (SCI) commonly experience pain and spasticity; limitations of current treatments have generated interest in cannabis as a possible therapy.

Objectives: We conducted this systematic review to: 1) examine usage patterns and reasons for cannabinoid use, and 2) determine the treatment efficacy and safety of cannabinoid use in people with SCI.

Methods: PubMed, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature databases were queried for keywords related to SCI and cannabinoids.

Results: 7,232 studies were screened, and 34 were included in this systematic review. Though 26 studies addressed cannabinoid usage, only 8 investigated its therapeutic potential on outcomes such as pain and spasticity. The most common method of use was smoking. Relief of pain, spasticity and recreation were the most common reasons for use. A statistically significant reduction of pain and spasticity was observed with cannabinoid use in 83% and 100% of experimental studies, respectively. However, on examination of randomized control trials (RCTs) alone, effect sizes ranged from - 0.82 to 0.83 for pain and -0.95 to 0.09 for spasticity. Cannabinoid use was associated with fatigue and cognitive deficits.

Conclusion: Current evidence suggests that cannabinoids may reduce pain and spasticity in people with SCI, but its effect magnitude and clinical significance are unclear. Existing information is lacking on optimal dosage, method of use, composition and concentration of compounds. Long-term, double-blind, RCTs, assessing a wider range of outcomes should be conducted to further understand the effects of cannabinoid use in people with SCI.

Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis

Background: Hepatocellular carcinoma (HCC) is among the world’s most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab).

Aim: The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways.

Methods: The Food and Drug Administration (FDA)’s and European Medicines Agency (EMA)’s datasheets, results from clinical trials and observational studies have been reviewed.

Results: This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients.

Conclusion: The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.

Bioactive Compounds of the PVPP Brewery Waste Stream and their Pharmacological Effects

Beer, one of the most commonly consumed alcoholic beverages, is rich in polyphenols and is the main dietary source of xanthohumol and related prenylflavonoids. However, to avoid haze formation caused by the interaction between polyphenols and proteins, most phenolic compounds are removed from beer and lost in the brewery waste stream via polyvinylpolypyrrolidone (PVPP) adsorption. This waste stream contains several polyphenols with high antioxidant capacity and pharmacological effects; that waste could be used as a rich, low-cost source of these compounds, though little is known about its composition and potential attributes. This work aims to review the polyphenols present in this brewery waste stream, as well as the health benefits associated with their consumption.

Oxidative Stress-Induced Brain Damage Triggered by Voluntary Ethanol Consumption during Adolescence: A Potential Target for Neuroprotection?

Alcohol consumption, in particular ethanol (EtOH), typically begins in human adolescence, often in a “binge like” manner. However, although EtOH abuse has a high prevalence at this stage, the effects of exposure during adolescence have been less explored than prenatal or adult age exposure.

Several authors have reported that EtOH intake during specific periods of development might induce brain damage. Although the mechanisms are poorly understood, it has been postulated that oxidative stress may play a role. In fact, some of these studies revealed a decrease in brain antioxidant enzymes’ level and/or an increase in reactive oxygen species (ROS) production. Nevertheless, although existing literature shows a number of studies in which ROS were measured in developing animals, fewer reported the measurement of ROS levels after EtOH exposure in adolescence. Importantly, neuroprotective agents aimed to these potential targets may be relevant tools useful to reduce EtOH-induced neurodegeneration, restore cognitive function and improve treatment outcomes for alcohol use disorders (AUDs).

The present paper reviews significant evidences about the mechanisms involved in EtOH-induced brain damage, as well as the effect of different potential neuroprotectants that have shown to be able to prevent EtOH-induced oxidative stress. A selective inhibitor of the endocannabinoid anandamide metabolism, a flavonol present in different fruits (quercetin), an antibiotic with known neuroprotective properties (minocycline), a SOD/catalase mimetic, a potent antioxidant and anti-inflammatory molecule (resveratrol), a powerful ROS scavenger (melatonin), an isoquinoline alkaloid (berberine), are some of the therapeutic strategies that could have some clinical relevance in the treatment of AUDs. As most of these works were performed in adult animal models and using EtOH-forced paradigms, the finding of neuroprotective tools that could be effective in adolescent animal models of voluntary EtOH intake should be encouraged.

Immunosuppression and Immunotargeted Therapy in Acute Myeloid Leukemia - The Potential Use of Checkpoint Inhibitors in Combination with Other Treatments

Introduction: Immunotherapy by using checkpoint inhibitors is now tried in the treatment of several malignancies, including Acute Myeloid Leukemia (AML). The treatment is tried both as monotherapy and as a part of combined therapy.

Methods: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of checkpoint inhibition; (ii) published articles describing the immunocompromised status of AML patients; and (iii) published studies of antileukemic immune reactivity and immunotherapy in AML.

Results: Studies of monotherapy suggest that checkpoint inhibition has a modest antileukemic effect and complete hematological remissions are uncommon, whereas combination with conventional chemotherapy increases the antileukemic efficiency with acceptable toxicity. The experience with a combination of different checkpoint inhibitors is limited. Thalidomide derivatives are referred to as immunomodulatory drugs and seem to reverse leukemia-induced immunosuppression, but in addition, they have direct inhibitory effects on the AML cells. The combination of checkpoint targeting and thalidomide derivatives thus represents a strategy for dual immunotargeting together with a direct antileukemic effect.

Conclusion: Checkpoint inhibitors are now tried in AML. Experimental studies suggest that these inhibitors should be combined with immunomodulatory agents (i.e. thalidomide derivatives) and/or new targeted or conventional antileukemic treatment. Such combinations would allow dual immunotargeting (checkpoint inhibitor, immunomodulatory agents) together with a double/triple direct targeting of the leukemic cells.

Herb-Drug Interactions and Hepatotoxicity

Background: In recent times, herbals or phytomedicines have become very popular due to their global acceptance as a complementary and alternative remedy. While modern drugs are commercially available only after laboratory validations, clinical trials, as well as approval from drug regulatory authorities, majority of the marketed herbal products lack such scientific evidence of efficacy and safety. This results in herb or herb-drug interaction induced unfavorable clinical outcomes without crucial documentation on their temporal relations and concomitant use.

Methods: An online literature search for peer-reviewed articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using the phrases: complementary & alternative medicine, traditional Chinese medicine, herb-drug interaction, mechanisms of herb-drug interaction, herb-induced toxicity, herbal hepatotoxicity and causality, traditional medicine, viral hepatitis, etc.

Results: The retrieved data showed that globally, patients are attracted to herbal remedies with the misconception that these are completely safe and therefore, use them simultaneously with prescription drugs. Notably, there exists a potential risk of herb-drug interactions leading to some adverse side effects, including hepatotoxicity. The toxicological effect of a drug or herb is due to the inhibition of drug metabolizing enzymes (e.g., cytochrome P450), including interactions with certain prescription drugs through various mechanisms. Several cases of hepatotoxicity due to use of herbals in viral hepatitis-related liver diseases have been recently reported. However, limited experimental data and clinical evidence on herbal pharmacokinetics hamper the evaluation and reporting of adverse reactions and the underlying mechanisms.

Conclusion: Herb-drug interaction related morbidity is thus an emerging serious public health issue with broad implications for clinicians, pharmaceutical industries and health authorities. Nonetheless, despite increasing recognition of herb-drug interaction, a standard system for interaction prediction and evaluation is still nonexistent. This review article discusses the herb-drug interactions related hepatotoxicity and underlying mechanisms, including drug metabolizing enzymes and their regulation.

Nutraceuticals and "Repurposed" Drugs of Phytochemical Origin in Prevention and Interception of Chronic Degenerative Diseases and Cancer

Background: Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy.

Objectives: The validation of novel (chemo)preventive and interceptive approaches, and the use of new or repurposed agents, alone or in combination with registered drugs, are urgently required.

Results: Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, nonsteroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing antiangiogenic and anti-anti-inflammatory proprieties. Many of them target AMPK and metabolic pathways such as the mTOR axis. We summarize the beneficial effects of several compounds in conferring protection and supporting therapy, and as a paradigm, we present data on terpenoids & biquanides on beer hop xanthohumol and hydroxytryrosol from olive mill waste waters.

Conclusions: These molecules could be employed for combinatorial chemoprevention and interception approaches or chemoprevention/therapy regimens for cancer and other chronic complex diseases.

The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer

Role of Shp2: The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic have been recognized as the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain.

Conclusion: The current study was designed to focus on the allosteric regulation (autoinhibition) of the of Shp2 protein. Subsequently, it will cover the last 10-year recap of Shp2 protein, their role in cancer, and regulation in numerous ways (allosteric regulation).

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.

GH Supplementation Effects on Cardiovascular Risk in GH Deficient Adult Patients: A Systematic Review and Meta-analysis

Background and Objective: The current meta-analysis aims at evaluating whether the existing clinical evidence may ascertain the effects of growth hormone (GH) replacement therapy on cardiovascular risk, both in isolated GH deficiency (GHD) and in compensated panhypopituitarism including GH deficit.

Methods: Original articles published from 1991 to 2015 were searched on Medline (Pubmed). Among an overall number of 181 potentially suitable studies, 24 fulfilled the selection criteria and were included in the analysis. Data aggregation was carried out through the calculation of the absolute risk reduction. The meta-analysis was then conducted by means of a fixed-effects model, according to the heterogeneity test (Chi-square statistic).

Results: Fat-free mass (FFM) increase and fat mass (FM) reduction were found, together with a C-LDL reduction, a wide variation in glycaemia and a neutral effect on glycated haemoglobin (HbA1c) and blood pressure. These effects were valid both for isolated GHD patients and for those with compensated panhypopituitarism. The global outcome D showed a nonsignificant reduction of the overall cardiovascular risk (0.53; 95% C.I. -1.23, 2.85).

Conclusion: Our meta-analysis shows no signnificatly positive trend in cardiovascular risk after both short and long-term GH supplementation therapy in adult GHD patients. However, a reduction of LDL cholesterol levels has been found. No differences were found between isolated GHD participants and those affected by panhypopituitarism well compensated since at least 3 months.

Protein Tyrosine Signaling and its Potential Therapeutic Implications in Carcinogenesis

Protein tyrosine phosphorylation is a crucial signaling mechanism that plays a role in epithelial carcinogenesis. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, metabolism, and motility by activating major signaling pathways including STAT3, AKT, and MAPK. Genetic mutation of PTKs and/or prolonged activation of PTKs and their downstream pathways can lead to the development of epithelial cancer. Therefore, PTKs became an attractive target for cancer prevention. PTK inhibitors are continuously being developed, and they are currently used for the treatment of cancers that show a high expression of PTKs. Protein tyrosine phosphatases (PTPs), the homeostatic counterpart of PTKs, negatively regulate the rate and duration of phosphotyrosine signaling. PTPs initially were considered to be only housekeeping enzymes with low specificity. However, recent studies have demonstrated that PTPs can function as either tumor suppressors or tumor promoters, depending on their target substrates. Together, both PTK and PTP signal transduction pathways are potential therapeutic targets for cancer prevention and treatment.

Immunomodulatory Activity of MicroRNAs: Potential Implications for Multiple Myeloma Treatment

Multiple myeloma (MM) is an incurable plasma cell neoplasm accounting for about 10% of all hematologic malignancies. Recently, emerging evidence is disclosing the complexity of bone marrow interactions between MM cells and infiltrating immune cells, which have been reported to promote proliferation, survival and drug resistance of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules with regulatory functions in the cell, whose expression has predictive and prognostic value in different malignancies. MiRNAs are gaining increasing interest due to their capability to polarize the immune-response through different mechanisms, which include the molecular reprogramming of immune cells. This characteristic, together with the antitumor activity of miRNA mimics or inhibitors, make the miRNA network an attractive area of investigation for novel anti-MM therapeutic approaches. In this review, we will discuss the recent advances in the understanding of the interplay between MM cells and bone marrow resident immune cells, with special focus on the molecular and functional changes induced by miRNA network modulation. We will finally indicate potential targets for therapeutic intervention.

Targeting the Immune Niche within the Bone Marrow Microenvironment: The Rise of Immunotherapy in Multiple Myeloma

Background: Multiple Myeloma (MM) cells inhibit the development of an effective anti- MM immune response via defects in T cell function, ineffective antigen presentation; reduced phagocytic capacity; natural killer and dendritic cell dysfunction; decreased responsiveness to IL-2 and defects in B cell immunity; upregulation of inhibitory pathways; and production of excessive proinflammatory cytokines. Moreover, immune cells including plasmacytoid dendritic cells and macrophages trigger tumor cell proliferation, survival, and drug resistance. The usefulness of immunotherapies in MM patients has first been supported by the identification of the graft-versus-myeloma effect in the context of allogeneic bone marrow (BM) transplantation. Subsequently, the inclusion of thalidomide and its derivatives, the Immunomodulatory Drugs (IMiDs) as well as of (immuno) proteasome inhibitors into MM regimens dramatically improved MM patients outcome during the last 15 years. Despite these unprecedented therapeutic advances MM remains an incurable disease.

Objective: This article reviews novel immunotherapeutic approaches, which aim to restore the balance within the immunologic niche of the MM BM microenvironment.

Method: A systematic search was conducted of the Pubmed Medline, Embase, and Cochrane Library databases for primary articles, as well as of conference abstracts (e.g., of the American Society of Hematology, the American Society of Clinical Oncology, the American Association of Cancer Research, the European Hematology Association, and the Multiple Myeloma Workshop), practice guidelines, and registries of clinical trials.

Results: The inclusion of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor-engineered (CAR) T cells, genetically engineered T cells, and vaccination, dendritic cellbased cancer vaccines in particular, into existing regimens is likely to significantly improve MM patient outcome in the near future.

Conclusion: Given continuing efforts to target the immune niche within the bone marrow microenvironment we are confident that the rise of immunotherapies in MM will result in long-lasting responses in many of our patients within the next decade.

Molecular Dynamics Simulations, Challenges and Opportunities: A Biologist’s Prospective

Molecular dynamics (MD) is a computational technique which is used to study biomolecules in virtual environment. Each of the constituent atoms represents a particle and hence the biomolecule embodies a multi-particle mechanical system analyzed within a simulation box during MD analysis. The potential energies of the atoms are explained by a mathematical expression consisting of different forces and space parameters. There are various software and force fields that have been developed for MD studies of the biomolecules. MD analysis has unravelled the various biological mechanisms (protein folding/unfolding, protein-small molecule interactions, protein-protein interactions, DNA/RNA-protein interactions, proteins embedded in membrane, lipid-lipid interactions, drug transport etc.) operating at the atomic and molecular levels. However, there are still some parameters including torsions in amino acids, carbohydrates (whose structure is extended and not well defined like that of proteins) and single stranded nucleic acids for which the force fields need further improvement, although there are several workers putting in constant efforts in these directions. The existing force fields are not efficient for studying the crowded environment inside the cells, since these interactions involve multiple factors in real time. Therefore, the improved force fields may provide the opportunities for their wider applications on the complex biosystems in diverse cellular conditions. In conclusion, the intervention of MD in the basic sciences involving interdisciplinary approaches will be helpful for understanding many fundamental biological and physiological processes at the molecular levels that may be further applied in various fields including biotechnology, fisheries, sustainable agriculture and biomedical research.

Molecular Targets and Angiogenesis in Renal Cell Carcinoma, A Multitarget Approach: Mini Review

Background: Renal cell carcinoma (RCC) accounts for 2% of all adult malignancies and is associated with a case fatality rate as high as 40%. RCC has been on the rise for the last 6 decades at a steady increase of 2% per annum. Much work has been done to uncover the pathogenesis of the disease and the role of angiogenesis has been a recurrent denominator connected to vascular endothelial growth factor (VEGF) and its downstream effectors along with the mammalian target of rapamycin (mTOR) mediated signal transduction pathway.

Objective: This review will discuss relevant inhibitors of key biomarkers to the disease in hopes of paving the way for novel treatments geared towards improving RCC morbidity and mortality rates.

Results and Conclusion: Currently, treatment of advanced RCC includes one or more of the following: partial or radical nephrectomy, systemic therapy, immunotherapy and targeted therapy. Still drug resistance continues to be a challenge to many of the approved drugs and those undergoing clinical trials. However, the inclusion of targeted therapies has improved advanced RCC treatment success rates over that of surgery alone, and over that of the use of traditional chemotherapy for this relatively chemo-resistant disease. In an era of personalized medicine, research utilizing a polypharmacology approach could enhance efficacy of drug leads to treating RCC.

DephosSitePred: A High Accuracy Predictor for Protein Dephosphorylation Sites

Aim and Objective: Protein tyrosine phosphatases (PTPs) are responsible for protein phosphorylation. Because the level of protein phosphorylation is correlated with tumor transformation, PTPs have been considered as candidate transformation suppressors. In this study, we developed a novel PTP site prediction model, DephosSitePred, based on bi-profile sequence features.

Materials and Method: A dataset which contains 63-, 50- and 51-positive samples, and 868-, 856-, and 731-negative samples with less than 70% sequence identity for the three phosphatases was constructed in this study. Based on the dataset, a predictor model DephosSitePred was constructed, by applying the sequence-based bi-profile Bayes feature extraction technique to identify three phosphatases, PTP1B, SHP-1, and SHP-2. Concerning the imbalance of datasets used in our study, the weight parameters (W1 and W-1) of the support vector machine (SVM) were selected according to jackknife cross-validation.

Results: DephosSitePred yielded Matthews correlation coefficients of 0.686 for protein tyrosine phosphatase 1B (PTP1B), 0.668 for Src homology region 2 domain-containing phosphatase (SHP)-1, and 0.748 for SHP-2 substrate sites, which significantly outperformed other existing predictors. Moreover, 30 times of 5-fold cross-validations showed that DephosSitePred achieved average area under the curve values of 0.968, 0.968, and 0.982 for PTP1B, SHP-1 and SHP-2, respectively, which were 0.115, 0.105 and 0.105 higher than those of the second best model, MGPS-DEPHOS, respectively.

Conclusion: DephosSitePred is indeed an effective auxiliary tool for in silico identification of dephosphorylation sites and may help to reveal the physiological and pathological role of dephosphorylation protein.

microRNAs-based Predictor Factor in Patients with Migraine-ischemic Stroke

Among the clinical spectrum of neurological diseases, migraine is often associated with cerebro-vasculopathy. Impairment of neuroimmune mediators in the central nervous system has been recognized in the pathophysiology of migraine-related stroke. Although genetic correlation was found in patients with migraine-related stroke, the epidemiology of this disease indicates a need in biomarker searching discovery and validation. In this view, small molecule, called microRNAs (miRNAs), able to regulate immune and neuronal processes has been reported in patients with migraine and ischemic stroke and unambiguous miRNAs related to these diseases could be established as new molecular indicator of precocity for clinical and/or pharmacological intervention. Therefore, further exploration of this area is necessary, as greater understanding of these biomarkers could reveal the common mechanisms involved in the pathophysiology of migraine in patients with cerebral infarct.

Joint Occurrence of Pain and Sleep Disturbances in People with Dementia. A Systematic Review

Background: Advancing age is associated with high prevalence of pain, sleep problems and dementia. Dementia is frequently accompanied by distressing behavioral and psychological symptoms, including sleep problems. The etiology of sleep problems in dementia is multifactorial. It has been suggested that untreated pain may contribute to sleep problems, and pain treatment has been shown to reduce sleep problems in people with dementia.

Objective: This systematic review aims to provide an overview of the studies that have investigated the association and/or possible interaction between pain and sleep in dementia.

Methods: A systematic search was performed in MEDLINE, EMBASE, Cochrane and PsychINFO, including text words and MESH terms covering dementia, pain and sleep. Also, reference lists in the included publications were examined to retrieve publications. Publications had to investigate sleep and pain in relation to dementia to be included in this review.

Results: The search produced 1750 independent hits. Out of the 49 publications studied in full text, 11 publications were included. Only one controlled trial was identified and represented the only insights to the possible interactional relationship between pain, sleep and dementia. Pain or pain intensity were related to sleep in 6 of the included studies, while the remaining studies could neither support nor contradict a relationship between sleep and pain in people with dementia. None of the studies employed objective sleep assessment.

Conclusion: There is a need for high quality studies investigating the interaction between sleep and pain in people with dementia, using objective sleep measurements and pain assessment suitable for people with dementia.

Orofacial Pain and Mastication in Dementia

Orofacial pain is a common condition in the general population. It is likely that this is also the case in older persons with a dementia. However, the assessment of (orofacial) pain in non-verbal individuals is hampered by the subjective nature of pain, and their limited communicative abilities. To overcome this drawback, several tools have been developed for the assessment of pain based on observations of pain-specific facial activities, body movements, and vocalizations. Unfortunately, none of the so far developed observational tools have been designed specifically for the assessment of orofacial pain. While the recent psychometric testing of the Orofacial MOBID Pain Scale did not yield reliable outcomes, the subsequently developed Orofacial Pain Scale for Non-Verbal Individuals (OPS-NVI) is currently being evaluated and shows good promise to be reliable and valid. Besides the assessment of orofacial pain, an important application of this instrument will be the investigation of the probable causal association between impaired chewing and cognitive decline, in which orofacial pain plays a mediating role by its negative influence on chewing ability. The identification of this negative influence will urge opinion leaders and policy makers to improve the oral health status in older persons with a dementia. Ultimately, pain-free oral functioning may lead to a higher quality of life and might help stabilizing or improving cognition in this frail and vulnerable patient population.

Immunomodulatory Drugs: IMiDs in Acute Myeloid Leukemia (AML)

AML patients have an aberrant and dysfunctional immune state, paving the way for novel agents targeting pathways that integrate with immune signaling, function, and response. Small molecule immunomodulatory drugs (IMiDs) represent a class of agents derived from the parent compound, thalidomide. There are currently 3 IMiDs approved for a variety of malignancies: thalidomide, lenalidomide, and the newest agent, pomalidomide. IMiDs lead to a multitude of immunobiologic effects such as cytokine modulation, co-stimulation of T cells, down-regulation of co-inhibitory molecules, enhancing natural killer cell activity, inhibition of regulatory T cells, and repairing perturbed synapse formation on T cells. IMiDs have been extensively studied in various AML settings with promising clinical activity. This review discusses the immunologic effects of IMiDs, the rationale for studying IMiDs in AML, and the published and ongoing clinical trials investigating IMiD activity in AML.

Anti-inflammatory Action of Green Tea

Background: Green tea has been shown to have beneficial effects against a variety of diseases such as cancer, obesity, diabetes, cardiovascular disease, and neurodegenerative diseases. Through cellular, animal, and human experiments, green tea and its major component, epigallocatechin-3-gallate (EGCG) have been demonstrated to have anti-inflammatory effects. Our previous findings have indicated that green tea and EGCG suppress the gene and/or protein expression of inflammatory cytokines and inflammation-related enzymes.

Methods: Using bibliographic databases, particularly PubMed (provided by the http://www.ncbi.nlm.nih.gov/pubmed, US National Library of Medicine, National Institutes of Health, United States), we examined the potential usefulness of green tea/EGCG for the prevention and treatment of inflammatory diseases in human clinical and epidemiological studies. We also reviewed results from cellular and animal experiments and proposed action mechanisms.

Results: Most of the results from the human studies indicated the beneficial effects of green tea and tea catechins against inflammatory diseases. The cellular and animal studies also provided evidence for the favorable effects of green tea/EGCG. These results are compatible with our previous findings and can be largely explained by a mechanism wherein green tea/EGCG acts as an antioxidant to scavenge reactive oxygen species, leading to attenuation of nuclear factor-κB activity.

Conclusion: Since green tea and EGCG have multiple targets and act in a pleiotropic manner, we may consider their usage to improve the quality of life in patients with inflammatory disease. Green tea and EGCG have beneficial health effects and no severe adverse effects; however, care should be taken to avoid overdosage, which may induce deleterious effects including hepatic injury.

Protein Tyrosine Phosphatase SHP-2 as Drug Target

Protein tyrosine kinase (PTK) and tyrosine phosphatase (PTP) regulate various cellular processes. SHP-2, a ubiquitous non receptor type protein belongs to tyrosine phosphatase family. SHP-2 consists of two SH2 domain (N-SH2 and C-SH2), one C-terminal tail and a phosphatase domains. SHP2 is involved in regulating JAK-STAT and MAPK signaling pathways required for cell growth and differentiation. In the inactive form, SHP-2 is available in the closed conformation and gets activated after phosphorylation of tyrosine residues. SHP-2 protein is encoded with PTPN11 gene. Germline mutation in PTPN11 gene causes disruption in its closed conformation and causes over-expression of SHP-2 phosphatase activity. Deregulation of phosphatase activity leads to pathogenesis of cancer and diseases like Noonan and Leopard syndrome. Thus, SHP-2 inhibitors have been developed as a novel target for treating cancer and diseases caused due to abnormal cellular signaling. This review is a description of role of SHP-2 in cell physiology, diseases caused due to SHP-2 deregulation along with some SHP-2 inhibitors.

Synthetic and Medicinal Prospective of Structurally Modified Curcumins

Curcumin, a natural yellow phenolic compound, is present in various types of herbs, particularly in Turmeric, Curcuma longa Linn. (Zingiberaceae family) rhizomes. Curcumin is a polyphenolic natural compound with diverse and attractive biological activities. In the last decade curcumine and its various synthetic analogues have been prepared and evaluated for various pharmacological activities that prove it as a lead molecule against several biological targets. It is a natural antioxidant and exhibited many pharmacological activities such as anti-inflammatory, anti-microbial, anticancer, anti-Alzheimer in both preclinical and clinical studies. Moreover, Curcumin and its analogues have anti-tubercular, cardioprotective, anti-diabetic, hepatoprotective, neuroprotective, nephroprotective, antirheumatic and anti-viral activities. The substitutions of 1,6-heptadiene linkage moiety via carbonyl group sustituion and addition of heterocyclic linker; isoxazole, 1H-pyrazole, cyclopentanone, piperidin-4-one, N-methylpiperidin-4-one enhance biological activities. The structure activity relationship of various curcumin analogues is studied for medicinal purposes and it reveals that monocarbonyl linkage analogues have anticancer properties. The current review gives an insight of the history, chemistry, analogues and most interesting in vitro and in vivo studies on the biological effects of Curcumin and its analogues.

OPMSP: A Computational Method Integrating Protein Interaction and Sequence Information for the Identification of Novel Putative Oncogenes

Oncogenes are genes that have the potential to cause cancer. Oncogene research can provide insight into the occurrence and development of cancer, thereby helping to prevent cancer and to design effective treatments. This study proposes a network method called the oncogene prediction method based on shortest path algorithm (OPMSP) for the identification of novel oncogenes in a large protein network built using protein-protein interaction data. Novel putative genes were extracted from the shortest paths connecting any two known oncogenes. Then, they were filtered by a randomization test, and the linkages among them and known oncogenes were measured by protein interaction and sequence data. Thirty-seven new putative oncogenes were identified by this method. The enrichment analysis of the 37 putative oncogenes indicated that they are highly associated with several biological processes related to the initiation, progression and metastasis of tumors. Six of these genes—ESR1, CDK9, SEPT2, HOXA10, LMX1B, and NR2C2—are extensively discussed. Several lines of evidence indicate that they may be novel oncogenes.

Overview on the Tricks of HIV Tat to Hit the Blood Brain Barrier

HIV infection among AIDS patients is associated with dysfunctions in the central nervous system (CNS) at the late stages of the disease. HIV Tat protein is released extracellularly from the productively infected cells and play important role in successful HIV replication and activates the neighboring uninfected cells in the bystander fashion. The structural flexibility of Tat protein is one of the unique features, responsible for the diverse functions. The RNA binding ability and interacting domains are very important characteristic of the HIV-Tat protein. HIV Tat protein adversely affects the integrity of the blood brain barrier by a variety of mechanisms. Such compromise in the integrity of the blood brain barrier could affect the neuro-immune interactions within the brain, which results to the neuroinflammation.

Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality

Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.

Indoleamine 2,3-dioxygenase (IDO): Biology and Target in Cancer Immunotherapies

Indoleamine 2,3-dioxygenase (IDO) is a heme-containing oxidoreductase that catalyzes the initial and rate-limiting step in the breakdown of non-dietary tryptophan. The biology and immunomodulatory role for IDO is discussed in this review with a focus on its interaction with immune cells and its potential therapeutic target in the clinic. IDO has been revealed to be a central regulator of immune responses in a broad variety of physiological and pathological settings, mostly serving as a multifaceted negative feedback mechanism, to self-regulate immune responses. IDO is considered a therapeutic target in cancer and the use of IDO inhibitors as single agent or in combination with other treatment modalities are under active investigation.

Recent Patents for the Treatment of Asthma

Background: Despite adequate adherence and completion of anti-asthmatic treatment, many patients remain poorly controlled or uncontrolled. Asthma management is based on the use of medication to reverse the bronchial obstruction and eliminate the airway inflammation. New drug development is expected in the future as a consequence of discoveries in the pathophysiology and mechanisms of asthma. Currently, a good and effective set of treatments is available for these diseases. However, the search for new treatment modalities to improve the currently available is especially important for those patients unresponsive to current therapy.

Objective: In this review, we summarize new anti-cytokines therapies, anti-leucotrienes molecules, immunomodulatory and anti-inflammatory agents, researched for treatment of asthma.

Method: Database patents were used for searching new patents from 2015 and from the beginning of 2016 about treatment of asthma.

Conclusion: Pharmacogenomic point of view is now being considered by most major pharmaceutical companies as line of investigation without end in the nearest horizon. Pharmacogenomics has the potential to notably improve the safety and effectiveness of medications.

Mechanistic and Clinical Aspects of Lenalidomide Treatment for Chronic Lymphocytic Leukemia

There have been significant advances in our understanding of the pathogenesis of chronic lymphocytic leukemia (CLL) over the last decade, which has been accompanied by a rapid increase in treatment options. Inhibitors of BCRsignaling such as ibrutinib and idelalisib, and pro-apoptotic agents such as ABT- 199 have shown great promise in initial clinical trials and have been at the forefront of recent developments. However, despite the encouraging early data, these agents do not appear to represent a “cure” for CLL and mechanisms of resistance to these agents have already been identified. In light of these considerations there remains a need for alternative treatment strategies. Lenalidomide, a second-generation derivative of thalidomide, has been demonstrated to have significant clinical activity in CLL. Its effect appears to be mediated by reduction of CLL-cell proliferation, improvement of anti-tumor immune responses and reduction of pro-tumoral factors in the CLL microenvironment. This review discusses our current understanding of the mechanism of action of lenalidomide on both healthy cells and in CLL. It also summarises the published clinical trial experience with this drug, and proposes an ongoing role for this agent in the CLL armamentarium.

Human Induced Pluripotent Stem Cells for Inherited Cardiovascular Diseases Modeling

Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery.

Biochemical Markers of Renal Function

Kidney damage can be induced by ischemia, autoimmune diseases, hypertension, allograft rejection, metabolic or genetic disorders, infections or toxins. The influence of these factors could result in acute kidney injury (AKI) defined as an unexpected decrease in urine output or renal function, or encourage the development of chronic kidney disease (CKD). Biomarkers of renal function, measured in urine and serum, are in increasing use in order to estimate the severity and nature of kidney injury, and consequently apply appropriate therapy and improve patient management. The determined values of biomarkers can suggest the potential risk of kidney disease and the type of renal injury, predict the disease progression, as well as be helpful for assessing the response to an applied therapy. Although novel biomarkers are in practical use, serum creatinine, the indicator of glomerular filtration rate is still the most frequently used biomarker of renal function despite its known limitations. In recent decades, numerous studies resulted in discovering urinary and serum proteins that can serve as biomarkers for early and accurate detection of AKI and its development, as well as the identification of CKD. This review gives an overview of the most important renal biomarkers investigated in kidney diseases, classified in following types: functional biomarkers, up-regulated proteins, enzymes, and cycle arrest biomarkers. It describes their properties, physiological roles, and discusses the utility of these molecules in different clinical settings.

Psychosocial Vulnerability and Early Life Adversity as Risk Factors for Central Sensitivity Syndromes

The aim of this narrative review of the epidemiology of central sensitivity syndromes is to provide a summary of the role of early life adversity and psychosocial / psychological factors, in the epidemiology of six main syndromes: (i) fibromyalgia / chronic widespread pain; (ii) headache / migraine; (iii) irritable bowel syndrome; (iv) temporomandibular joint disorder; (v) interstitial cystitis; and (vi) endometriosis / vulvodynia / chronic pelvic pain.

The occurrence of each of the above syndromes vary between each other, and between studies. Prevalence ranges from interstitial cystitis, with a prevalence of approximately 14.5 per 100,000, to headache, with some estimates of lifetime prevalence to be around 66%.

Precise risk estimates vary between studies, conditions, and exposures, although there is consistent evidence to suggest an association between early life adversity and central sensitivity syndromes (based on the six syndromes under investigation). In further support of this, a number of studies have also demonstrated dose-risk associations. There is also considerable consistency in the literature to suggest a strong association between negative psychological and psychosocial factors, and the occurrence of central sensitivity syndromes and, again, there is some evidence of a dose-risk relationship.

The majority of studies in this field are cross-sectional or retrospective in design, and caution is advised when interpreting results. It is possible – indeed there is some evidence – that some findings may be subject to recall bias, and reverse causation is also a potential concern. However, there are also a number of prospective studies which provide more robust evidence.

Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise

Background: β-Caryophyllene (BCP) is a natural bicyclic sesquiterpene abundantly found in essential oils from various spices, fruits and medicinal as well as ornamental plants. It is approved by United States Food and Drug Administration and European agencies as food additive, taste enhancer and flavoring agent and termed as a phytocannabinoid. Methods: All the available literature on BCP and its synonyms were collected through different literature databases. Results: BCP was found to elicit a full agonist action on cannabinoid type 2 (CB2) receptors, a G-protein coupled receptor representing important therapeutic target in several diseases. Activation of CB2 receptors notably appeared devoid of psychotropic adverse effect of cannabinoids contrary to the CB1 receptors. In addition, it activates peroxisome proliferated activator receptors (PPARs) isoforms; PPAR-α &-γ and inhibits pathways triggered by the activation of toll like receptor complex; CD14/TLR4/MD2, reduce immuneinflammatory processes and exhibit synergy with µ-opioid receptor dependent pathways. Additionally, it found as potent antagonist of homomeric nicotinic acetylcholine receptors (α7-nAChRs) and devoid of effects mediated by serotonergic and GABAergic receptors. It also modulates numerous molecular targets by altering their gene expression, signaling pathways or through direct interaction. Various pharmacological activities such as cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, anti-inflammatory, antimicrobial and immune-modulator have been reported in experimental studies. It has shown potent therapeutic promise in neuropathic pain, neurodegenerative and metabolic diseases. Conclusion: The present review provides a comprehensive insight of pharmacological and therapeutic potential of BCP, its molecular mechanism and signaling pathways in different pathological conditions. The review also examines the possibility of its further development as a novel candidate for various pathologies considering the polypharmacological and multifaceted therapeutic properties potential along with favorable oral bioavailability, lipophilicity and physicochemical properties.

Commercially Available, FDA-approved Epigenetic Modifiers As Therapeutic Agents in Bacterial Infection

Epigenetics represents a relatively new but burgeoning field with implications and applications in a wide variety of fields. Heritable post-translational epigenetic modifications (PTEMs) of chromatin can be induced by an ever-increasing list of biological factors, including those produced by bacteria. Of particular interest are the PTEMs induced by bacterial pathogens in host cells, in an attempt by the pathogen to promote survival and suppress host defence mechanisms. To date, a number of pharmacological agents have been used to reverse PTEMs, especially in cancer treatment. These Food and Drug Administration (FDA)-approved, commercially available epigenetic modifying agents (EMAs) include: 5- azacytidine (AZA), decitabine, suberoylanilide hydroxamic acid (SAHA) and romidepsin. AZA and decitabine have been used successfully to treat myeloblastic syndromes; likewise both SAHA and romidepsin have proven effective in the treatment of cutaneous T-cell lymphoma (CTL). There is accumulating evidence from rodent and in vitro studies, which point to the possibility that pathogen-induced PTEMs in host cells represent viable therapeutic opportunities for intervention with epigenetic drugs. However, the same commercially available EMAs used in cancer treatment remain untested in bacterial infection of humans. Here, we review current studies that have revealed PTEMs of host cells, induced by a number of pathogenic bacteria and discuss whether or not commercially available EMAs might represent realistic options in the treatment of these infections in humans.

Natural Products as Farnesoid X Receptor (FXR) Agonists: Their Interactions with FXR Ligand Binding Region

Nuclear receptors (NRs) are ligand-activated transcription factors modulating significant biological functions including cell growth, lipid metabolism, and glucose homeostasis, so they are frequently to be utilized as important drug targets to develop therapeutic reagents. Farnesoid X receptor (FXR) with bile acids as the natural ligands, plays an essential role in regulation of bile acid and glucose metabolism, and is involved in the pathologies of human diseases including diabetes and chronic liver diseases. Thus, FXR is a promising pharmacological target for these diseases. Synthetic FXR agonists like INT-747 developed by Intercept Pharmaceutical Company is in the clinical trial phase III for non-alcoholic steatohepatitis and can be approved as the treatment of primary biliary cirrhosis in 2016. Due to the promising clinical trial results of INT-747, the naturally occurring FXR ligands may be utilized as the preventive nutraceuticals or treatments of the chronic liver diseases and diabetes. In this review, the natural FXR agonists are summarized and their possible interactions with FXR ligand binding region are discussed.

Furocoumarins from Cnidium monnieri Act as Peroxisome Proliferatoractivated R and Farnesoid X Receptor Agonists

The fruit of Cnidium monnieri (L) Cusson is an important traditional medicine employed in Taiwan and China as the treatments of impotence, sterilization, renal disease, dermatosis, colpitis, inflammation and gynecological disease. Peroxisome Proliferator-activated Receptor γ (PPARγ) and Farnesoid X receptor (FXR) are the members of nuclear receptor superfamily that have been targeted for developing treatments for chronic liver diseases. In this study, the furocoumarins isolated from the fruit of Cnidium monnieri (L) Cusson were evaluated for their PPARγ and FXR agonism. Indeed, in transient transfection reporter assays, these furocoumarins transactivated PPARγ and FXR to respectively modulate promoter action including ABCA1 and SHP promoters in dose-dependent manner. Through the molecular modeling docking studies these furocoumarins were shown to bind to PPARγ or FXR ligand binding pocket fairly well. All these results indicate that Cnidium monnieri (L) Cusson might possess therapeutic effects through the activation of PPARγ and FXR pathways.

The Heat Stress Response and Diabetes: More Room for Mitochondrial Implication

Heat preconditioning is a rapid cellular adaptive mechanism shared by many cells/ organs / organisms that results in synthesis and accumulation of heat shock proteins (HSPs), which are responsible for increased tolerance and survival of animals during and after heat stress (HS). HSPs function as molecular chaperones by restoring cellular homeostasis and promoting cell survival, and their major functions include protection of cells from injury by preventing protein damage and aggregation. Abundant evidence points to the ability of one kind of stress caused by external factors that induce primary adaptations in the organism to provide protection against additional stress of the same or another type, a phenomenon known as cross-tolerance.

Diabetes mellitus (DM) is one of the diseases which have been associated with increased tissue sensitivity and vulnerability due to incorrect protein folding. Thus, HSPs may play an important role in minimizing the protein damage that can occur under the stressful conditions created by the disease. By increasing HSP production, heat preconditioning may be a promising therapy for patients with lifestylerelated diseases such as hypercholesterolemia, hypertension, DM and obesity. Also, pancreatic β-cells exposed to acute HS activate defence mechanisms which include HSP synthesis and are less sensitive to the effects of cytotoxic agents such as NO, oxygen radicals and -cytotoxic diabetogenic agents, such as streptozotocin (STZ).

Mitochondrial dysfunction and mitochondria-specific cell stress are associated and can even be a primary abnormality caused by DMinduced hyperglycaemia and oxidative stress. There are an increasing number of genetic and/or pharmacological modulations of HSPs that have revealed the connection between HSPs, mitochondria and diabetes. HSPs may affect mitochondrial function in multiple ways, but the influence on skeletal muscle and adipose tissue, as well as on the pancreas, has attracted most interest as a key element in the development of novel pharmacological approaches to treating DM and associated metabolic conditions.

mTOR, a Potential Target to Treat Autism Spectrum Disorder

Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.

Clinical Characteristics and Treatment of Cardiomyopathies in Children

Cardiomyopathies are diseases of the heart muscle, a term introduced in 1957 to identify a group of myocardial diseases not attributable to coronary artery disease. The definition has since been modified to refer to structural and or functional abnormalities of the myocardium where other known causes of myocardial dysfunction, such as systemic hypertension, valvular disease and ischemic heart disease, have been excluded. In this review, we discuss the pathophysiology, clinical assessment and therapeutic strategies for hypertrophic, dilated and hypertrophic cardiomyopathies, with a particular focus on aspects unique to children.

Biomarkers in Post-stroke Depression

Depression is the most frequent neuropsychiatric complication after a stroke. Post-stroke depression has a significant impact on the outcome and prognosis of affected patients. Its diagnosis is complex and currently based only on clinical parameters. In recent years, efforts have been made to find biomarkers related to post-stroke outcomes, including complications such as depression. We carried out a systematic review of the literature looking for studies that investigated biomarkers associated with post-stroke depression (PSD) in Medline, Lilacs and PsycInfo databases. The results of 37 studies are discussed, describing the evidence for each evaluated biomarker. In conclusion, no evidence was found supporting the use of a particular biomarker for PSD. However, several changes were observed in inflammatory balance, oxidative stress, glutamatergic neurotransmission, production of neurotrophic factors, and genetic susceptibility that can be related to PSD. Research in the area of post-stroke biomarkers has the potential to provide personalized approach of stroke patients, also aiding in the diagnosis and understanding of the pathophysiology of this common neuropsychiatric complication.

Nutrigenomics and its Impact on Life Style Associated Metabolic Diseases

Post-human genome revelation observes the emergence of ‘Nutigenomics’ as one of the exciting scientific advancement influencing mankind around the world. Food or more precisely ‘nutrition’ has the major impact in defining the cause-response interaction between nutrient (diet) and human health. In addition to substantial understanding of nutrition-human-health interaction, bases of ‘nutrigenomic’ development foster on advent in transcriptomics, genomics, proteomics and metabolomics as well as insight into food as health supplement. Interaction of selected nutrient with associated genes in specific organ or tissue necessary to comprehend that how individual's genetic makeup (DNA transcribed into mRNA and then to proteins) respond to particular nutrient. It provided new opportunities to incorporate natural bioactive compounds into food for specific group of people with similar genotype. As inception of diabetes associated with change in gene expression of, not limited to, protein kinase B, insulin receptor, duodenal homeobox and glucokinase, thus, targeting such proteins by modifying or improving the nutritional availability or uptake may help to devise novel food, supplements, or nutraceuticals. In this article, various aspects of R&D in nutrigenomics are reviewed to ascertain its impact on human health, especially with lifestyle associated diseases.

Cancellers - Exploring the Possibility of Receptor Decoy Traps As a Superior Anti-Retroviral Strategy

The global Human Immunodeficiency Virus (HIV) pandemic is still spreading due to the lack of ideal anti-retroviral measures and their availability. Till date, all attempts to produce an efficient vaccine have ended with unsatisfactory results. The highly active anti-retroviral therapy (HAART) is the only effective weapon currently available and is widely being used for curtailing the HIV pandemic. However, the HAART is also expected to fail in the near future due to the emergence and dissemination of antiviral resistance. This review sheds light on the reasons for the failure of the conventional anti-viral measures against HIV and the novel anti-retroviral strategies currently being developed. The various principles to be considered for the success of a novel anti-retroviral strategy are elaborately emphasized and an innovative concept is proposed on these lines. The proposed concept intends to use receptor decoy traps (RDT) called cancellers which are erythrocytes expressing the HIV entry receptors on their surface. If successfully developed, the cancellers would be capable of active targeting of the free HIV particles leading to the trapping of the viruses within the canceller, resulting in the neutralization of infectivity of the trapped virus. The possible ways of translating this concept into reality and the probable hurdles that can be encountered in the process are subsequently discussed. Also, the scope of cancellers in therapeutic and/or preventive strategies against HIV infection is envisaged upon their successful development.

Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism

Introduction: The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission.

Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia.

Highlights: This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

Epigenetic MicroRNA Regulation of Multiple Chromatin Functions: A Perspective in Cancer

MicroRNAs (miRNAs) are a group of small noncoding RNAs of about 19-25 nucleotides (nt) in length. miRNAs act as a binary switch and play a key role in RNAi-mediated gene silencing by inhibiting translation and/or triggering subsequent degradation of their target mRNAs. Recent advances in the field of molecular biology have highlighted the role of miRNAs in different biological functions, including embryogenesis, developmental pattern formation and differentiation, organogenesis, growth control and cell death like brain development, including patterning, neurogenesis, neuronal differentiation, subtype specification, and neuronal activity which is scripted via menus. DNA methylation and Histone modifications facilitating epigenetic manipulations in the genome were already a precursor for tumorigenic development. But recently miRNA mediated regulatory mechanisms also have been implicated in malignancy by regulation of DNA methyltion. Keeping these facts in mind, we have summarized the emerging roles of miRNAs in modulating gene function and affecting signaling pathways. We have tried to focus into cancer cell physiology caused by miRNA mediated processes, and discuss the precise roles of miRNAs in modulating both DNA methylation and histone modifications.

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.

Ocular Drug Delivery - New Strategies for Targeting Anterior and Posterior Segments of the Eye

The ocular delivery of drugs encounters several limitations because of the dynamic and static barriers of the human’s eye anatomy and physiology. The poor bioavailability of drugs are mainly related to the topical administration, i.e. eye drops which is the most common drug dosage form for the treatment of eye pathologies. Precorneal factors and drug limitations related to its solubility and susceptibility for physicochemical degradation could be the main reasons for the poor permeation and uptake in the ocular mucosa. Pathologies affecting the anterior and posterior segment of the eye are thereafter difficult to be treated and, given the chronic and degenerative nature of some of these injuries, it is crucial to improve drugs therapeutic effect. Nanotechnology-based delivery systems could be a suitable approach to overcome these limitations. Some of the most important colloidal systems are highlighted in this review, such as the use of mucoadhesive polymers, prodrugs, nanogels, liposomes, microemulsions, lipid and polymeric nanoparticles, cyclodextrins, dendrimers and nanocrystals, along with their clinical and therapeutic relevance for the administration of drugs for ocular delivery.

The Many Neuroprogressive Actions of Tryptophan Catabolites (TRYCATs) that may be Associated with the Pathophysiology of Neuro-Immune Disorders

Many, if not all, chronic medical, neurodegenerative and neuroprogressive illnesses are characterised by chronic immune activation, oxidative and nitrosative stress (O&NS) and systemic inflammation. These factors, notably elevated pro-inflammatory cytokines, activate indoleamine 2,3-dioxygenase (IDO) leading to an upregulated tryptophan catabolite (TRYCAT) pathway of tryptophan degradation in the periphery and in the brain. In such conditions the TRYCAT pathway becomes the predominant system for tryptophan degradation in all body compartments. In this paper we review the pathways whereby TRYCATs may play a role in neuro-inflammatory and neuroprogressive disease. Thus chronic activation of the TRYCAT pathway leads to the production of a range of neuroactive, neuroprotective and neurotoxic TRYCATs. Some TRYCATs such as quinolinic acid act as potent neurotoxins which inhibit ATP production by mitochondria, provoke increases in O&NS, disrupt neuron glial communication and blood brain barrier integrity, induce apoptosis of glial cells, directly damage neurons and function as a N-methyl D-aspartate (NMDA) receptor agonist. Other TRYCATs such as kynurenic acid function as antagonists of NMDA, - amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors and act to regulate levels of glutamate and dopamine. The neuroprotective functions of this TRYCAT are likely exercised via engagement with alpha7 nicotinic acetylcholine and aryl hydrocarbon receptors but the neuroprotective effects stemming from elevated kynurenic acid levels come at the price of severely compromised neurocognitive function and emotional processing. Other TRYCATS also possess neurotoxic or neuroprotective properties via pro-oxidant and antioxidant effects. Here we discuss the involvement of the abovementioned TRYCAT pathways in schizophrenia, Alzheimer’s disease and chronic fatigue syndrome.

Memantine and Kynurenic Acid: Current Neuropharmacological Aspects

Glutamatergic neurotransmission, of special importance in the human brain, is implicated in key brain functions such as synaptic plasticity and memory. The excessive activation of N-methyl- D-aspartate (NMDA) receptors may result in excitotoxic neuronal damage; this process has been implicated in the pathomechanism of different neurodegenerative disorders, such as Alzheimer’s disease (AD). Memantine is an uncompetitive antagonist of NMDA receptors with a favorable pharmacokinetic profile, and is therefore clinically well tolerated. Memantine is approved for the treatment of AD, but may additionally be beneficial for other dementia forms and pain conditions. Kynurenic acid (KYNA) is an endogenous antagonist of NMDA receptors which has been demonstrated under experimental conditions to be neuroprotective. The development of a well-tolerated NMDA antagonist may offer a novel therapeutic option for the treatment of neurodegenerative disease and pain syndromes. KYNA may be a valuable candidate for future drug development.

Recent Patents of Complementary and Alternative Medicine for Allergic Rhinitis

Allergic rhinitis (AR) is a common respiratory disease affecting both adults and children worldwide. Affected patients may experience nasal congestion/stuffiness, rhinorrhea (anterior and/or posterior), nasal/ nasopharyngeal itching and sneezing. Allergen avoidance is the principal step in the management. Nasal saline irrigation to remove allergen (s) in the nose is a useful adjunctive therapy in the management of moderate to severe AR. Symptomatic relief and improved quality of life may be achieved in the majority of patients with appropriate pharmacotherapy. Mild-to-moderate cases are usually managed with either an oral second generation antihistamine or an intranasal corticosteroid. More severe cases may require treatment with an intranasal corticosteroid in combination with various oral medications. Patients who require medications for more than 6 months per year or have intolerable side effects from pharmacotherapy can be considered for immunotherapy. A wide range of complementary and alternative medicines (CAM) have also been proposed. This overview evaluates the evidence of use of CAM for AR. Some methods including acupuncture and herbal medicine have supportive evidence, but the efficacy of other CAM is controversial. Conversely, possible side effects of different modalities are often inadequately documented. The herbal formulae include Butterbur, Nigella sativa, Shi-Bi-Lin, Polyherbal formula, Grapeseed extract, Rosmarinic acid, Spirulina, Biminne, and Bhu-zhong-yi-qi-tong. Further research is needed to assess the efficacy and safety before they are employed in treating AR. This review article also discusses recent CAM patents for use in AR, which are exclusively traditional Chinese medicine (TCM) concoctions primarily for oral consumption but two as topical spray. Only 8 pertinent patents, all TCM compositions for treating AR and registered in 2014, were obtained. Description about their efficacy is impressive but objective outcome evaluation tools are lacking.

Saffron-Based Crocin Prevents Early Lesions of Liver Cancer: In vivo, In vitro and Network Analyses

Background: The angiogenesis inhibitor, sorafenib, remains the only available therapy of hepatocellular carcinoma (HCC). Only recently patents of VEGF receptors-3 inhibitors are developed. Thus, a novel approach against HCC is essential for a better therapeutic outcome. Objective: The aims of this study were to examine the chemopreventive action of saffron’s main biomolecule, crocin, against chemically-induced liver cancer in rats, and to explore the mechanisms by which crocin employs its anti-tumor effects. Method: We investigated the anti-cancer effect of crocin on an experimental carcinogenesis model of liver cancer by studying the anti-oxidant, anti-inflammatory, anti-proliferation, pro-apoptotic activities of crocin in vivo. In addition, we provided a network analysis of differentially expressed genes in tissues of animals pre-treated with crocin in comparison to induced-HCC animals’ tissues. To further support our results, in vitro analysis was carried out. We assessed the effects of crocin on HepG2 cells viability by treating them with various concentrations of crocin; in addition, effects of crocin on cell cycle distribution of HepG2 cells were investigated. Results: Findings reported herein demonstrated the anti-proliferative and pro-apoptotic properties of crocin when administrated in induced- HCC model. Crocin exhibited anti-inflammatory properties where NF-_κB, among other inflammatory markers, was inhibited. In vitro analysis confirmed crocin’s effect in HepG2 by arresting the cell cycle at S and G2/M phases, inducing apoptosis and down regulating inflammation. Network analysis identified NF-_κB as a potential regulatory hub, and therefore, a candidate therapeutic drug target. Conclusion: Taken together, our findings introduce crocin as a candidate chemopreventive agent against HCC.

The Medical Complications of Anorexia Nervosa and Their Treatments

Anorexia nervosa is a chronic mental health disorder associated with multiple medical complications. Intensive preoccupation with body weight and shape are the hallmarks of anorexia nervosa as defined by DSM-5. As a result of malnutrition and weight loss there develop major organ dysfunction and complications. No body system is immune to the ravages of this illness despite the typically young age of those affected. Most unfortunately, some of these complications are known now to be irreversible. However, the vast majority of these complications are reversible with timely and effective services. These patients are often co-managed by an internist and a mental health professional. Thus, the need for familiarity with the medical complications associated with anorexia nervosa.

Targeting TNF-Alpha in HIV-1 Infection

Highly active antiretroviral therapy (HAART) has dramatically extended the lifespan and quality of life of individuals infected with human immunodeficiency virus type 1 (HIV-1). HAART comprises of a cocktail of various pharmacological inhibitors which interfere with almost every stages of HIV-1 life cycle. However, constant application of drugs often results in the evolution of hostpathogen relationship resulting in the emergence of drug resistant viral strains. Drug resistant HIV-1 is a potent threat for the humankind. Therefore, there is a constant need to search for novel therapeutic molecules. HIV-1 infection results in the depletion of CD4+/CD8+T cells and alters the cytokine network in the infected individuals. Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, plays a critical role in HIV-1 pathogenesis. HIV-1 utilizes the TNF-alpha signaling pathway for expanding its reservoir. Several HIV-1 proteins mimic and regulate the TNF-alpha signaling pathway. TNF-alpha inhibitors have been used in several inflammatory pathologies with success to some extent. In the present mini review we will discuss the role of TNF-alpha in HIV-1 pathogenesis. Furthermore we will evaluate the TNF-alpha inhibitors as an additional therapeutic option for HIV-1 infection.

HIV-1 TAT and IMMUNE DYSREGULATION in AIDS PATHOGENESIS: a THERAPEUTIC TARGET

The HIV-1 transactivator Tat protein plays a key role in AIDS pathogenesis. Besides the Tat role as activator of HIV-1 transcription, it exerts several important functions on infected and uninfected cells. In fact, HIV-1 Tat is released by infected cells and is taken up by neighboring cells. In this way it regulates expression of viral and cellular genes and it modulates several cellular pathways leading to HIV-1 infection spreading and immune dysregulation. So far, Tat protein and the cellular pathways targeted by Tat may represent potential targets for new anti-HIV therapeutic approaches and vaccine development against AIDS.

The Role of the Metabolism of Anticancer Drugs in Their Induced-Cardiotoxicity

Cardioncology is a major topic of the day, since cardiotoxicity of chemotherapy agents can limit its real use and it can also become a clinical problem years after the end of anticancer therapy. These cardiac problems largely increase the mortality and morbidity of cancer-treated patients. Actually, as the number of cancer survivors is increasing each decade, late cardiotoxicity related to anticancer therapy is expected to grow exponentially in the fore coming years. The mechanisms of cardiotoxicity of anticancer drugs are still largely unknown. The metabolism of some drugs can lead to more active anticancer metabolites but those metabolites can likewise contribute to the observed cardiotoxicity. The alcohols and aglycone metabolites of anthracyclines are known to be cardiotoxic, while regarding 5-fluorouracil, fluoroacetate is considered one of the major metabolites responsible for its cardiotoxicity. Regarding mitoxantrone, the toxicity of the majority of the metabolites has not been assessed so far and concerning cyclophosphamide metabolites, both hydroxycyclophosphamide and acrolein are shown to be more cardiotoxic than the parent drug. Still, the contribution of drug metabolism to the cardiotoxicity of chemotherapy agents is largely unknown and poorly discussed. This review presents a new link between several cardiotoxic anticancer drugs and their drug metabolites, as they can play an important role in the widely reported heart damage inflicted by chemotherapy. Anthracyclines, cyclophosphamide, mitoxantrone, and 5- fluorouracil will be mainly focused, given the vast literature and clinical use. The current knowledge shows the possible involvement of drug metabolism in bioactivation mechanisms that can contribute to their cardiotoxicity.

Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers

Post-translational modifications can affect gene expression in a long-term manner without changes in the primary nucleotide sequence of the DNA. These epigenetic alterations involve dynamic processes that occur in histones, chromatin-associated proteins and DNA. In response to environmental stimuli, abnormal epigenetic alterations cause disorders in the cell cycle, apoptosis and other cellular processes and thus contribute to the incidence of diverse diseases, including cancers. In this review, we will summarize recent studies focusing on certain epigenetic readers, writers, and erasers associated with cancer development and how newly discovered natural compounds and their derivatives could interact with these targets. These advances provide insights into epigenetic alterations in cancers and the potential utility of these alterations as therapeutic targets for the future development of chemopreventive and chemotherapeutic drugs.

DNA Methyltransferases Inhibitors from Natural Sources

DNA methyltransferases (DNMTs) catalyze the methylation at cytosine-C5 mainly in a CpG dinucleotide context. Although DNA methylation is essential for fundamental processes like embryonic development or differentiation, aberrant expression and/or activities of DNMTs are involved in several pathologies, from neurodegeneration to cancer. DNMTs inhibition can arrest tumor growth, cells invasiveness and induce differentiation, whereas their increased expression is shown in numerous cancer types. Moreover, hypermethylated promoters of tumor suppressor genes lead to their silencing. Hence, the use of specific inhibitors of DNMT might reactivate those genes and stop or even reverse the aberrant cell processes. To date, the only approved DNMTs inhibitors for therapy belong to the nucleoside-based family of drugs, but they display relevant side effects as well as high chemical instability. Thus, there is a keen interest actually exists to develop novel, potent and safe inhibitors possessing a nonnucleoside structure. Increasing literature evidence is highlighting that natural sources could help the researchers to achieve this goal. Indeed, several polyphenols, flavonoids, antraquinones, and others are described able to inhibit DNMTs activity and/or expression, thus decreasing the methylation/silencing of different genes involved in tumorigenesis. These events can lead to re-expression of such genes and to cell death in diverse cancer cell lines. Epigallocatechin-3-gallate (1) and laccaic acid A (11) resulted the most effective DNMT1 inhibitors with submicromolar IC50 values, acting as competitive inhibitors. Compound 1 and 11 both displayed gene demethylation and re-activation in several cancers. However, all of the natural compounds described in this review showed important results, from gene reactivation to cell growth inhibition. Moreover, some of them displayed interesting activity even in rodent cancer models and very recently entered clinical trials .

Contextualizing the Genes Altered in Bladder Neoplasms in Pediatric and Teen Patients Allows Identifying Two Main Classes of Biological Processes Involved and New Potential Therapeutic Targets

Research on bladder neoplasms in pediatric and teen patients (BNPTP) has described 21 genes, which are variously involved in this disease and are mostly responsible for deregulated cell proliferation. However, due to the limited number of publications on this subject, it is still unclear what type of relationships there are among these genes and which are the chances that, while having different molecular functions, they i) act as downstream effector genes of well-known pro- or anti- proliferative stimuli and/or interplay with biochemical pathways having oncological relevance or ii) are specific and, possibly, early biomarkers of these pathologies. A Gene Ontology (GO)-based analysis showed that these 21 genes are involved in biological processes, which can be split into two main classes: cell regulation-based and differentiation/development-based. In order to understand the involvement/ overlapping with main cancer-related pathways, we performed a meta-analysis dependent on the 189 oncogenic signatures of the Molecular Signatures Database (OSMSD) curated by the Broad Institute. We generated a binary matrix with 53 gene signatures having at least one hit; this analysis i) suggests that some genes of the original list show inconsistencies and might need to be experimentally re- assessed or evaluated as biomarkers (in particular, ACTA2) and ii) allows hypothesizing that important (proto)oncogenes (E2F3, ERBB2/HER2, CCND1, WNT1, and YAP1) and (putative) tumor suppressors (BRCA1, RBBP8/CTIP, and RB1-RBL2/p130) may participate in the onset of this disease or worsen the observed phenotype, thus expanding the list of possible molecular targets for the treatment of BNPTP.

Genetics of Bladder Malignant Tumors in Childhood

Bladder masses are represented by either benign or malignant entities. Malignant bladder tumors are frequent causes of disease and death in western countries. However, in children they are less common. Additionally, different features are found in childhood, in which non epithelial tumors are more common than epithelial ones. Rhabdomyosarcoma is the most common pediatric bladder tumor, but many other types of lesions may be found, such as malignant rhabdoid tumor (MRT), inflammatory myofibroblastic tumor and neuroblastoma. Other rarer tumors described in literature include urothelial carcinoma and other epithelial neoplasms. Rhabdomyosarcoma is associated to a variety of genetic syndromes and many genes are involved in tumor development. PAX3-FKHR and PAX7-FKHR (P-F) fusion state has important implications in the pathogenesis and biology of RMS, and different genes alterations are involved in the pathogenesis of P-F negative and embryonal RMS, which are the subsets of tumors most frequently affecting the bladder. These genes include p53, MEF2, MYOG, Ptch1, Gli1, Gli3, Myf5, MyoD1, NF1, NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, IGF1R, PDGFRA, ERBB2/4, MET, BCOR. Malignant rhabdoid tumor (MRT) usually shows SMARCB1/INI1 alterations. Anaplastic lymphoma kinase (ALK) gene translocations are the most frequently associated alterations in inflammatory myofibroblastic tumor (IMT). Few genes alterations in urothelial neoplasms have been reported in the paediatric population, which are mainly related to deletion of p16/lnk4, overexpression of CK20 and overexpression of p53. Here, we reviewed available literature to identify genes associated to bladder malignancies in children and discussed their possible relationships with these tumors.

Myalgic Encephalomyelitis: Symptoms and Biomarkers

Myalgic Encephalomyelitis (ME) continues to cause significant morbidity worldwide with an estimated one million cases in the United States. Hurdles to establishing consensus to achieve accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions, slow progress in development of standardized diagnostic approaches, and issues surrounding research priorities. Because there are other medical problems, such as early MS and Parkinson’s Disease, which have some similar clinical presentations, it is critical to accurately diagnose ME to make a differential diagnosis. In this article, we explore and summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to elucidate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME for clinicians and researchers. This review, therefore, represents a synthesis of key discussions in the literature, and has important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear need for more longitudinal studies in this area with larger data sets, which correct for multiple testing.

Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections

In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis.

Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.

Genetic Predisposition to Neonatal Tumors

The development of tumors within the first month of life is extremely rare and this very young age at presentation should raise concern for an underlying cancer predisposition syndrome. This chapter discusses genetic predisposition to neonatal solid tumors, specifically those involving the eyes, kidneys, liver, adrenal glands and lungs. For each tumor type, we discuss the most common associated predisposition syndromes and for eye and lung tumors, we also review the approach to diagnosis and management. The reader is referred to the other chapters of this volume for an overview of management details for the other tumor types. The management of neonates with cancer predisposing syndromes is challenging, with many patients demonstrating multisystem involvement. Accordingly, it is critical to use a team approach, where providers with expertise in neonatology, oncology, genetics, surgery and other pediatric subspecialties can appropriately tailor management of the patient and coordinate genetic evaluation of the family.

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.

Current Indications for Implantable Cardioverter Defibrillators in Non-Ischemic Cardiomyopathies and Channelopathies

Current indications for implantable cardioverter defibrillators (ICDs) in patients with channelopathies and cardiomyopathies of non-ischemic origin are mainly based on non-randomized evidence. In patients with nonischemic dilated cardiomyopathy (NIDCM), there is a tendency towards a beneficial effect on total mortality of ICD therapy in patients with significant left ventricular (LV) dysfunction. Although an important reduction in sudden cardiac death (SCD) seems to be clearly demonstrated in these patients, a net beneficial effect on total mortality is unclear mostly in cases with good functional status. Risk stratification has been changing over the last two decades in patients with hypertrophic cardiomyopathy (HCM). Its risk profile has been delineated in parallel with the beneficial effect of ICD in high risk patients. Observational results based on “appropriate” ICD interventions do support its usefulness both in primary and secondary SCD prevention in these patients. Novel risk models quantify the rate of sudden cardiac death in these patients on individual basis. Less clear risk stratification is available for cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) and in other uncommon familiar cardiomyopathies. Main features of risk stratification vary among the different channelopathies (long QT syndrome -LQTS-, Brugada syndrome, etc) with great debate on the management of asymptomatic patients. For most familiar cardiomyopathies, ICD therapy is the only accepted strategy in the prevention of SCD. So far, genetic testing has a limited role in risk evaluation and management of the individual patient. This review aims to summarize these criticisms and to refine the current indications of ICD implantation in patients with cardiomyopathies and major channelopathies.

Anti-cancer and Anti-angiogenic Properties of Various Natural Pentacyclic Tri-terpenoids and Some of their Chemical Derivatives

Pentacyclic triterpenes are natural substances, synthesized and present in variable amounts in a large number of terrestrial and aquatic plants, which act not only as antioxidants and antimicrobials but also as poisons, antibiotics, protease inhibitors, and so on. From the organic chemistry point of view, they are compounds derived from isoprene. These compounds consist of 30 carbons with different substituents, which facilitate their chemical identification and confer different physico-chemical and molecular properties. During the last ten years, most of them have been reported to have a variety of interesting and significant biological properties, such as analgesic, anti-allodynic, anti-diabetic, anti-oxidant, anti-parasitic, antimicrobial, anti-viral, anti-atherogenic, anti-inflammatory, anti-proliferative, anti-tumour, growth-stimulating activities as well as cardioand neuro-protective activity. However, special attention has been focused on the study of their anti-tumour capacity, fundamentally, on the various molecular mechanisms involved in the induction of programmed cell death and the inhibition of metastatic activity, in different types of cancers. Researchers have also focused on the role that different RNA molecules play in the anti-tumour activity of the major triterpenes studied.

In this review, we look at the recent advances reported on the anti-tumorigenic roles of the main representatives of this group of compounds, such as betulinic (BA), ursolic (UA), oleanolic (OA) and maslinic (MA) acids and some of their derivatives, with a special emphasis on cell apoptosis and angiogenesis.

Impact of Epigenetic Dietary Components on Cancer through Histone Modifications

Epigenetics, the study of heritable changes in gene expression without modifying the nucleotide sequence, is among the most important topics in medicinal chemistry and cancer prevention and therapy. Among those changes, DNA methylation and histone modification have been shown to be associated with various types of cancers in a number of ways, many of which are regulated by dietary components that are mostly found in plants. Although mechanisms of nutrient components affecting histone acetylation/deacetylation in cancer are widely studied, how those natural compounds affect cancer through other histone modifications, such as methylation, phosphorylation and ubiquitylation, is rarely reviewed. Thus, this review article discusses impacts on histone acetylation as well as other histone modifications by nutrient components, such as genistein, resveratrol, curcumin, epigallocatechin-3-gallate (EGCG), 3,3’-diindolylmethane (DIM), diallyl disulfide, garcinol, procyanidin B3, quercetin, sulforaphane and other isothiocyanates that have been recently reported in vivo as well as in various types of cancer cell lines.

The N-Terminal Region of HIV-1 Tat Protein Binds CD127 in Human CD8 T Cells to Target the Receptor for Down Regulation Through Tat's Basic Region

We have previously shown that soluble HIV-1 Tat protein down regulates surface expression of the interleukin (IL)-7 receptor alpha-chain (CD127) on human CD8 T cells resulting in impaired T cell proliferation and cytolytic capacity. Once taken up by CD8 T cells, Tat translocates to the inner leaflet of the plasma membrane where it interacts with the cytoplasmic tail of CD127 inducing receptor internalization and degradation by the proteasome. Here we characterized the regions of Tat required to interact with CD127 and induce receptor down regulation from the cell surface. To do this, a series of histidine-tagged Tat deletion mutants were generated and expressed as purified soluble protein, or cloned into a DNA expression vector and transfected into primary human CD8 T cells and a CD127 expressing Jurkat cell line. Protein-protein interactions were assessed by co-immunoprecipitation. Substitution of the first 10 Nterminal residues or deletion of residues 17-21 prevented Tat from interacting with and down regulating CD127 from the cell surface. Deletion of the basic region also prevented Tat from down regulating CD127 but did not prevent Tat from binding to the receptor. Notably, an endogenously expressed Tat variant lacking the basic region caused an accumulation of CD127 at the cell surface. We propose a model where Tat interacts with CD127 via its N-terminal region and recruits cellular factors via its basic region to down regulate CD127 from the cell surface.

Multitarget Network Strategies to Influence Memory and Forgetting: The Ras/Mapk Pathway as a Novel Option

The Ras/mitogen activated protein kinase (MAPK) pathway has key importance in development, cell differentiation and senescence, tumorigenesis, learning and memory. The clinical manifestations associated with this highly conserved pathway are called RASopathies. Phenotypic features are diverse and overlapping, but cognitive impairment is a common symptom. Here, we propose an approach based on molecular networks that link learning, memory and forgetting to the RASopathies and various neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease and autism spectrum disorders. We demonstrate the cross-talks of the molecular pathways in RASopathies and memory and the role of compartmentalization in these processes. The approved drugs are also overviewed, and C. elegans is proposed as a viable model system for experimental exploration and compound target prediction.n

Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.

Monoclonal Antibodies in Allergy; Updated Applications and Promising Trials

Allergic disorders, as asthma, allergic rhinitis/rhinoconjunctivitis, atopic dermatitis, food allergies and anaphylaxis have an increasing burden in the general population and a growing body of evidence has shown that an increased interest has aroused to seek for more effective treatment strategies. Conventional pharmacotherapy by antihistamines, anti-leukotrienes, corticosteroids and bronchodilators can routinely control most of the cases, in addition to allergen avoidance which saves the date. Furthermore, allergen specific immunotherapy stands as the only curative method to treat the underlying cause of allergic immune response by induction of immune tolerance. However, response to pharmacotherapies can show diversity depending on the genotype and phenotype of the allergic disorders, which are known to be under the influence of multifactorial triggers. Thus, understanding the mechanisms of development of allergic disorders, in addition to selective description of the phenotypes can provide access to development of more specific therapies in order to control the disease progression. Monoclonal antibodies can be the major actors in this targeting process. Concerns about the safety, efficacy and long-term tolerability of these molecules always stand as a question for them, in order to gain indications for the treatment of allergic disorders. This review includes most recent developments and patents on usage of monoclonal antibodies for the treatment of allergic disorders.

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecortin [DCX] and MEF2. We also present new data showing that Tat interferes with the trafficking of CDK5 between the nucleus and cytoplasm. This results in prolonged presence of CDK5 in the cytoplasm leading to accumulation of aberrantly phosphorylated cytoplasmic targets [e.g.: Tau, CRMP2, DCX] that impair neuronal function and eventually lead to cell death. Novel therapeutic approaches with compounds that block Tat mediated hyper-activation of CDK5 might be of value in the management of HAND.

Involvement of Hypoxia-Inducible Factors in the Dysregulation of Oxygen Homeostasis in Sepsis

Sepsis is a state of infection with serious systemic manifestations, and if severe enough, can be associated with multiple organ dysfunction and systemic hypotension, which can cause tissues to be hypoxic. Inflammation, as part of the multifaceted biological response to injurious stimuli, such as pathogens or damaged tissues and cells, underlies these biological processes. Prolonged and persistent inflammation, also known as chronic inflammation, results in progressive alteration in the various types of cells at the site of inflammation and is characterized by the simultaneous destruction and healing of tissue during the process. Tissue hypoxia during inflammation is not just a simple bystander process, but can considerably affect the development or attenuation of inflammation by causing the regulation of hypoxia-dependent gene expression. Indeed, the study of transcriptionally regulated tissue adaptation to hypoxia requires intense investigation to help control hypoxia-induced inflammation and organ failure. In this review, I have described the pathophysiology of sepsis with respect to oxygen metabolism and expression of hypoxia-inducible factor 1.

Genetics of Cardiomyopathies: Novel Perspectives with Next Generation Sequencing

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium usually of genetic origin and with familial presentation. The identification of multiple genetic causes for these diseases has opened a new window for early diagnosis, understanding of their natural history and improvement in risk stratification and management. However, in the past years, the clinical application of genetics has been limited by the prohibiting cost and restricted yield of the available genotyping technologies. The emergence of Next Generation Sequencing (NGS) has completely changed this scenario. This group of sequencing technologies allow the evaluation of hundreds or even thousands of genes in parallel at an affordable cost. Now the challenge is not genotyping per se but the interpretation of the complex results that NGS generates. In this paper we review the main aspects related to the application and impact of Next Generation Sequencing in the study of cardiomyopathies: technology, analysis procedures, bioinformatics, clinical validation and interpretation of results.

Beyond Bile Acids: Targeting Farnesoid X Receptor (FXR) with Natural and Synthetic Ligands

The modulation of FXR receptor remains an attractive area in drug discovery to develop novel therapeutic opportunities for liver and metabolic disorders. Despite the large variety of FXR ligands reported so far, only a very restricted number of agonists have entered in clinical settings. In this review article we provide the reader with an overview on the different classes of natural and synthetic ligands that have been developed by academic groups and pharmaceutical companies to target FXR. We discuss their structure-activity relationships, analyzing the binding modes that some of these compounds adopt to interact with the receptor.

Knocking on FXR's Door:The "Hammerhead"-Structure Series of FXRs Agonists - Amphiphilic Isoxazoles with Potent In Vitro and In Vivo Activities

The Farnesoid X Receptor (FXR) was recently validated in clinical studies using the bile acid analogue Obeticholic Acid (OCA) as an attractive drug target for liver diseases such as Primary Biliary Cirrhosis (PBC) or Non-alcoholic Steatohepatitis (NASH). OCA, however, turned out to induce cholesterol- related side effects upon prolonged treatment and it shows bile acid like pharmacokinetics. The quest for synthetic non-steroidal FXR agonists with general drug likeliness and improved pharmacokinetic and – dynamic properties has started more than a decade ago: The first non-steroidal and selective FXR agonist with decent submicromolar potency, GW4064, was patented in 1998 and published in 2000. Since then, many pharmaceutical companies have taken GW4064 as a structural template for their efforts in identifying novel patentable FXR agonists with the GW-derived trisubstituted isoxazole general structure. However, so far only one compound out of these different series has made it into the early stages of clinical development: The Px-102/Px-104 from Phenex is currently tested in a phase IIa study in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). In this review we try to summarize from the patent and scientific literature the attempts to improve the GW4064 structure into different directions. Furthermore, we suggest directions for further improvements of this special class of synthetic FXR agonists which all display the typical “hammerhead”-conformation in the FXR ligand binding pocket that provides the basis for their impressive in vitro and in vivo potencies.

Bile Acid Derivatives as Ligands of the Farnesoid X Receptor: Molecular Determinants for Bile Acid Binding and Receptor Modulation

Bile acids are a peculiar class of steroidal compounds that never cease to amaze. From being simple detergents with a primary role in aiding the absorption of fats and fat-soluble vitamins, bile acids are now widely considered as crucial hormones endowed with genomic and non-genomic functions that are mediated by their interaction with several proteins including the nuclear receptor Farnesoid X Receptor (FXR). Taking advantages of the peculiar properties of bile acids in interacting with the FXR receptor, several biliary derivatives have been synthesized and tested as FXR ligands. The availability of these compounds has contributed to characterize the receptor from a structural, patho-physiological and therapeutic standpoint. Among these, obeticholic acid is a first-in-class FXR agonist that is demonstrating hepatoprotective effects upon FXR activation in patients with liver diseases such as primary biliary cirrhosis and nonalcoholic steatohepatitis. This review provides an historical overview of the rationale behind the discovery of obeticholic acid and chemical tools generated to depict the molecular features and bio-pharmacological relevance of the FXR receptor, as well as to summarize structure-activity relationships of bile acid-based FXR ligands so far reported.

Recent Advances in Non-Steroidal FXR Antagonists Development for Therapeutic Applications

Farnesoid X receptor (FXR, NR1H4), a nuclear receptor (NR) highly expressed in the liver, intestine, kidney, adrenal glands and other cholesterol-rich tissues, functions as the master regulator for bile acid homeostasis. FXR, which regulates the expression of genes encoding proteins involved in cholesterol homeostasis, plays an essential role in regulating cholesterol, lipid, and glucose metabolism. Recently, some FXR agonists are reported to have low selectivity on NRs, which forces the researchers to move their eyes onto the development of FXR antagonists with high selectivity. The development of non-steroidal FXR antagonists with different scaffolds including AGN34, tuberatolides, atractylenolides, andrographolides, GW4064 derivatives and 1,3,4-trisubstitutedpyrazolones, provides us a prospect for the therapy of in ammation, metabolic syndrome, diabetes, cholesterol gallstones, and cancer.

Medicinal Chemistry and Pharmacological Effects of Farnesoid X Receptor (FXR) Antagonists

The nuclear bile acid sensor farnesoid X receptor (FXR) constitutes a rising target for the treatment of a variety of diseases including metabolic disorders, inflammation and certain forms of cancer. While the research on FXR agonists has yielded many compounds and first clinical candidates, only few FXR antagonists have been discovered so far and the knowledge about their in vivo effects is quite narrow. We have evaluated available in vitro and in vivo studies with FXR antagonists as well as FXR knockout models to elucidate a potential pharmacological use of FXR antagonism. To date, the in vitro and in vivo data suggests that FXR inhibition by knockout or the use of antagonists causes beneficial effects on cholesterol metabolism, ameliorates liver toxicity in cholestasis and can reduce the proliferation and migration of some cancer cell lines. Unfortunately, also many disadvantageous effects are connected with FXR antagonists.

Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Incorporating Fatty Acid-Modified Polyethylenimine

Antisense oligonucleotides (ASOs) have promising therapeutic potential in oncotherapy. However, low stability and efficacy limit their application in the clinic. Cationic liposomes have been investigated as delivery vehicles for ASOs. Here, we report the synthesis and evaluation of an ASO delivery vehicle comprising cationic liposomes incorporating fatty acid-modified polyethylenimine. An oleic acid derivative of branched polyethylenimine (PEI-OA) and a linoleic acid derivative of branched polyethylenimine (PEI-LA) were synthesized and incorporated into liposomes. The PEImodified liposomes were synthesized by an ethanol injection method with composition of PEI-modified lipid/Chol/TPGS. The properties of these liposomes, including cytotoxicity, cellular uptake, ASO target silencing activity, based on mRNA and protein downregulation, were investigated. LOR-2501, an ASOs targeting ribonucleotide reductase R1 subunit (R1) was used as the therapeutic cargo. The PEI-modified liposomes showed relatively compact particle size and excellent colloidal stability for at least 25 days. PEI-modified liposomes effectively delivered LOR-2501 into KB cells and efficiently induced down-regulation of R1 mRNA and protein. Compared with regular cationic liposomes, PEI-modified liposomes was more effective, reducing R1 mRNA and protein by ~10%.