MSX1 Gene Polymorphisms in Patients with non-Syndromic Cleft lip and Palate: A Tertiary Care Centre Based Case-Control Study from Central Kerala.

OBJECTIVE: The purpose of this study was to investigate the contribution of MSX1 gene polymorphisms to the risk of developing NSCLP. DESIGN: Case-Control Study. SETTING: A tertiary care centre. PATIENTS/PARTICIPANTS: The sample consisted of 200 subjects (100 cases and 100 controls). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Genotyping was performed by restriction fragment length polymorphism. Allele and genotype frequencies were calculated between patients and controls and analyzed using online Web Tools such as SISA and SNPstats. The MSX1 gene polymorphisms c. 799 GT, c.458 CA can be risk factors in the development of orofacial clefts. RESULTS: In the cases, an association was found between NSCLP and c.799 and c.458 of the MSX1 gene when compared with the control. The dominant and overdominant models, c. 799 GT, c.458 CA genotypes and c. 799 T, c.458 A alleles in the population are said to be the main risk factors to develop the NSCLP in our study population. The genotype variation of c 799 G/T and c.458 C/A are revealed to be specifically contributing to an NSCLP-type Cleft lip and Palate. It is worth noting that NSCLP females in the study population showed a stronger association with heterozygous genotypes of c.799 and c.458. However, further investigation with a larger cohort is necessary to confirm these findings. CONCLUSION: Overall the results of the study revealed that MSX1 c 799 G > T and c.458 C > A can be considered as one of the genetic risk factors in the formation of Non-Syndromic Cleft Lip and Palate in the study population.

Death associated protein kinases: molecular structure and brain injury.

Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk) family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1.

Neuroprotective effects of dietary plants and phytochemicals against radiation-induced cognitive and behavioral deficits: a comprehensive review of evidence and prospects for future research.

Exposure to ionizing radiation (IR) is a common occurrence in clinical practice and incidents involving nuclear detonation or nuclear reactor accidents. IR triggers cellular events that result in oxidative stress and damage to macromolecules, rendering it harmful. While the central nervous system (CNS) was once believed to be resistant to radiation, emerging evidence suggests that even small doses of IR can adversely impact the brain. Exposure to an unsafe dose of radiation can cause increased permeability of the blood-brain barrier (BBB), neuronal apoptosis, reduced neurogenesis, impaired synaptic plasticity, and cognitive dysfunction. In recent years, the potential benefits of dietary agents and phytochemicals for mental health and radiation-induced damage have been widely investigated. Despite this, few studies have explored the protective effects of plants against radiation-induced brain damage. Here, we present a review collating evidence on the beneficial effects of dietary plants on radiation-induced brain damage based on behavioral studies. Notably, Amaranthus paniculatus, Grewia asiatica, Lycium barbarum, and phytochemicals such as vitamin E, corilagin, curcumin, resveratrol, and ursolic acid have demonstrated potential in mitigating radiation-induced damage to the CNS. Furthermore, preliminary studies have indicated that alpha-tocopherol and the micronutrient selenium have neuroprotective effects in cancer survivors previously treated with radiation to the brain. This review focuses exclusively on behavioral outcomes to assess the impact of ionizing radiation on the CNS and the effectiveness of dietary plants and phytochemicals as neuroprotective agents against radiation-induced neuronal damage.

In situ engineering of Au-Ag alloy embedded PEDOT nanohybrids at a solvent/non-solvent interface for the electrochemical enzyme-free detection of histamine.

Steadfast efforts have been made to develop novel materials and incorporate them into functional devices for practical applications, pushing the research on electroactive materials to the forefront of nano electronics. Liquid/liquid interface-assisted polymerization offers a scalable methodology to fabricate hybrid materials with multifunctional applications, in contrast to the conventional and ubiquitous routes. Here, we explored this efficient and versatile approach toward the in situ tailoring of Au-Ag alloy nanostructures with a conducting polymer, poly(3,4-ethylene-dioxythiophene) (PEDOT). With the appropriate choice of organic and inorganic phases for the distribution of monomer and oxidant, the miscibility restraints of the reactants in a single phase were alleviated. Effective nanostructure tuning of highly crystalline and electroactive PEDOT/Au-Ag alloy has been achieved by varying the molar ratio of Au3+/Ag+ in the reaction mixture. The as-synthesized composite is further explored to detect neuromodulator histamine (HA), which displays high sensitivity with a limit of detection (LOD) of 1.5 nM, and selectivity even in the presence of various interfering analogs of 10-fold concentration. Subsequently, density functional theory (DFT) simulations are employed to assess the mode of interaction between HA and the electroactive surfaces. The competency to detect HA in preserved food entails its potential in food spoilage monitoring. Furthermore, the detection of histamine generated by sub-cultured human neuronal cells SH-SY5Y proves its practical viability in health monitoring devices.

An integrated chemo-informatics and in vitro experimental approach repurposes acarbose as a post-ischemic neuro-protectant.

The increasing prevalence of ischemic stroke combined with limited therapeutic options highlights the compelling need for continued research into the development of future neuro-therapeutics. Death-Associated Protein Kinase 1 (DAPK1) and p53 protein-protein interaction serve as a signaling point for the convergence of apoptosis and necrosis in cerebral ischemia. In this study, we used an integrated chemo-informatics and in vitro experimental drug repurposing strategy to screen potential small-molecule inhibitors of DAPK1-p53 interaction from the United States of America Food and Drug Administration (FDA) approved drug database exhibiting post-ischemic neuroprotective and neuro-regenerative efficacy and mechanisms. The computational docking and molecular dynamics simulation of FDA-approved drugs followed by an in vitro experimental validation identified acarbose, an anti-diabetic medication and caloric restriction mimetic as a potential inhibitor of DAPK1-p53 interaction. The evaluation of post-ischemic neuroprotective and regenerative efficacy and mechanisms of action for acarbose was carried out using a set of experimental methods, including cell viability, proliferation and differentiation assays, fluorescence staining, and gene expression analysis. Post-ischemic administration of acarbose conferred significant neuroprotection against ischemia-reperfusion injury in vitro. The reduced fluorescence emission in cells stained with pS20 supported the potential of acarbose in inhibiting the DAPK1-p53 interaction. Acarbose prevented mitochondrial and lysosomal dysfunction, and favorably modulated gene expression related to cell survival, inflammation, and regeneration. BrdU staining and neurite outgrowth assay showed a significant increase in cell proliferation and differentiation in acarbose-treated group. This is the first study known to provide mechanistic insight into the post-ischemic neuroprotective and neuro-regenerative potential of acarbose. Our results provide a strong basis for preclinical studies to evaluate the safety and neuroprotective efficacy of acarbose against ischemic stroke. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-022-03130-5.

Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia.

Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or beta-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood-brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood-brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia.

Rodent Gymnastics: Neurobehavioral Assays in Ischemic Stroke.

Despite years of research, most preclinical trials on ischemic stroke have remained unsuccessful owing to poor methodological and statistical standards leading to "translational roadblocks." Various behavioral tests have been established to evaluate traits such as sensorimotor function, cognitive and social interactions, and anxiety-like and depression-like behavior. A test's validity is of cardinal importance as it influences the chance of a successful translation of preclinical results to clinical settings. The mission of choosing a behavioral test for a particular project is, therefore, imperative and the present review aims to provide a structured way to evaluate rodent behavioral tests with implications in ischemic stroke.

ISCHEMIRs: Finding a Way Through the Obstructed Cerebral Arteries.

MicroRNAs (miRNAs) are small (19-25 nucleotides) non-coding single-stranded RNAs that control post-transcriptional gene expression. miRNAs are abundantly expressed in the brain, where they play key roles during neuronal differentiation, synaptogenesis, and plasticity. It is also becoming increasingly evident that miRNAs are involved in the etiology of several neurological disorders. Mounting evidence indicates that miRNAs have the ability to regulate the expression profiles of genes in signaling pathways associated with cerebrovascular diseases such as ischemic stroke, subarachnoid hemorrhage, and vascular dementia. For instance, miR-21 is involved in ischemic stroke pathology through atherosclerosis and provides neuroprotection by its anti-apoptotic features. miR-497 induces neuronal death and miR-210 is upregulated in hypoxic cells. Deregulated expression of miRNAs in response to ischemic stroke has enabled the use of miRNA as an efficient non-invasive biomarker. Antagomirs are often effective against neuronal apoptosis and can induce neuroregeneration following ischemia. Moreover, the advent of systems biology has introduced novel computational tools to identify the link between miRNAs, target genes and transcription factors involved in the stroke pathology and its treatment. This review describes the emerging role of miRNAs in neuroprotection and focuses on a subset of miRNAs that act as central players in ischemic stroke.

Role of KCa3.1 Channels in CNS Diseases: A Concise Review.

KCa3.1 protein is part of a heterotetrameric voltage-independent potassium channel, the activity of which depends on the intracellular calcium binding to calmodulin. KCa3.1 is immensely significant in regulating immune responses and primarily expressed in cells of hematopoietic lineage. It is one of the attractive pharmacological targets that are known to inhibit neuroinflammation. KCa3.1 blockers mediate neuroprotection through multiple mechanisms, such as by targeting microglia-mediated neuronal killing. KCa3.1 modulators may provide alternative treatment options for neurological disorders like ischemic stroke, Alzheimer disease, glioblastoma multiforme, multiple sclerosis and spinal cord injury. This review is an attempt to draw attention towards KCa3.1 channel, which was never exploited to its full potential as a viable therapeutic candidate against various neurological disorders.

CypD: The Key to the Death Door.

Numerous studies have deciphered the importance of Cyclophilin D (CypD/ peptidyl prolyl cis-trans isomerase F) in the formation and regulation of mitochondrial permeability transition pore (MPTP), implicated in the cell death mechanisms in various neurological diseases. Decrease in the ATP and increase in the calcium levels are the most common aftermath consequences that are observed in these diseases. Increased calcium level leads to the persistent opening of MPTP and cell death, which is mediated by CypD. However, the underlying mechanisms that contribute to the abnormal calcium homeostasis in different diseases remain elusive. In this review, we attempted to connect the disruption of mitochondrial bioenergetics with abnormal calcium levels and MPTP. Further, various proteins that interact with the CypD and the subsequent consequences have been described. All the cell death pathways in various neurological disorders merge at CypD, which acts as a key regulatory protein in cellular demise. Agents inhibiting CypD may have a therapeutic potential for treating neurological disorders such as Alzheimer's disease, Parkinson's disease and cerebral ischemia. Further, the knowledge regarding the pathophysiological processes involved in CypD-regulated MPTP and cell death would assist in battling with these diseases.

Glycogen synthase kinase-ß3 in ischemic neuronal death.

Glycogen synthase kinase 3ß (GSK-3ß) is implicated in diverse cellular processes such as cell signaling and survival. Accumulating lines of evidence indicate that increased GSK-3ß activity contributes to neuronal death and pathogenesis of ischemic stroke. Considering predominant roles of GSK-3ß in neuronal apoptosis, modulation of this protein kinase is a reliable strategy for ischemic neuroprotection. In this review, we survey and synthesize the current knowledge about the role of GSK-3ß in neuroprotection following the ischemic stroke.

A combination of 3D-QSAR modeling and molecular docking approach for the discovery of potential HIF prolyl hydroxylase inhibitors.

Suppression of HIF prolyl hydroxylase (PHD) activity by small molecule inhibitors leads to the stabilization of HIF and offers a potential therapeutic option for treating ischemic disorders. In this study, pharmacophore based QSAR modeling, virtual screening and molecular docking approaches were concurrently used to identify target-specific PHD inhibitors with better ADME properties and to readily minimize false positives and false negatives. A 3D-QSAR based method was used to generate a pharmacophore hypothesis (AAAN). The obtained 3D-QSAR model has an excellent correlation coefficient value (r2 = 0.99), Fisher ratio (F = 386) and exhibited good predictive power (q2 = 0.64). The hypothesis was validated and utilized for chemical database screening and the retrieved compounds were subjected to molecular docking for further refinement. Quantitative AAAN hypothesis comprised three H-bond accepter and one negative ionizable group feature and it give good predictive ability because all the QSAR information it was providing matched with the active site information. The hypothesis was validated and used as a 3D query for database screening. After manual selection, molecular docking and further refinement, based on the molecular interactions of inhibitors with the essential amino acids residues, 12 candidates with good ADME and blood brain barrier permeability values were selected as potential PHD inhibitors.

In silico prediction of novel inhibitors of the DNA binding activity of FoxG1.

Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. FoxG1 is a transcriptional repressor, whose function has been elucidated recently. FoxG1 overexpression was found to be associated with medulloblastoma and hepatoblastoma. It was suggested that the inhibition of FoxG1 could be a potential target for the development of molecular therapeutics in such type of cancers. Since, experimentally derived structure for FoxG1 is unavailable in any of the structural databases, modeling of the DNA binding domain of this protein was carried out. Potential binding sites on the protein surface were predicted. Pharmacophoric features were derived from the binding site that lies near the protein-DNA binding interface and this pharmacophore was employed for virtual screening of compounds. To the best of our knowledge, this is the first pharmacophore model proposed for screening inhibitors of FoxG1, which may interfere with its transcriptional repressor functionality. The interactions of the binding site residues with the top scoring ligand hits were analyzed. These ligands may be used for the development of potential inhibitors of FoxG1 protein.

Generation of pharmacophore and atom based 3D-QSAR model of novel isoquinolin-1-one and quinazolin-4-one-type inhibitors of TNFα.

In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R2=0.9965, Q2=0.6185, Root Mean Squared Error=0.4284 and Pearson-R=0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFα that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1-ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFα inhibitors.