Validating the temporal performance of genetic biomarkers in an animal model of recurrence/ non-recurrence myocardial infarction persuades by bioinformatics tools.

With a global towering prevalence of index acute myocardial infarction (nonrecurrent MI, NR-MI), a high incidence of recurrent MI (R-MI) has emerged in recent decades. Despite the extensive occurrence, the promising predictors of R-MI have been elusive within the cohort of survivors. This study investigates and validates the involvement of distinct gene expressions in R-MI and NR-MI. Bioinformatics tools were used to identify DEGs from the GEO dataset, functional annotation, pathway enrichment analysis, and the PPI network analysis to find hub genes. The validation of proposed genes was conceded by qRT-PCR and Western Blot analysis in experimentally induced NR-MI and R-MI models on a temporal basis. The temporal findings based on RT-PCR consequences reveal a significant and constant upregulation of the UBE2N in the NR-MI model out of the proposed three DEGs (UBE2N, UBB, and TMEM189), while no expression was reported in the R-MI model. Additionally, the proteomics study proposed five DEGs (IL2RB, NKG7, GZMH, CXCR6, and GZMK) for the R-MI model since IL2RB was spotted for significant and persistent downregulation with different time points. Further, Western Blot analysis validated these target genes' expressions temporally. I/R-induced NR-MI and R-MI models were confirmed by the biochemical parameters (CKMB, LDH, cTnI, serum nitrite/nitrate concentration, and inflammatory cytokines) and histological assessments of myocardial tissue. These results underscore the importance of understanding genetic mechanisms underlying MI and highlight the potential of UBE2N and IL2RB as biomarkers for non-recurrent and recurrent MI, respectively.

Artificial intelligence derived categorizations significantly improve HOMA IR/ß indicators: Combating diabetes through cross-interacting drugs.

Improvements in the homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-ß) significantly reduce the risk of disabling diabetic pathies. Nanoparticle (AuNP-AgNP)-metformin are concentration dependent cross-interacting drugs as they may have a synergistic as well as antagonistic effect(s) on HOMA indicators when administered concurrently. We have employed a blend of machine learning: Artificial Neural Network (ANN), and evolutionary optimization: multiobjective Genetic Algorithms (GA) to discover the optimum regime of the nanoparticle-metformin combination. We demonstrated how to successfully employ a tested and validated ANN to classify the exposed drug regimen into categories of interest based on gradient information. This study also prescribed standard categories of interest for the exposure of multiple diabetic drug regimen. The application of categorization greatly reduces the time and effort involved in reaching the optimum combination of multiple drug regimen based on the category of interest. Exposure of optimum AuNP, AgNP and Metformin to Diabetic rats significantly improved HOMA ß functionality (∼63 %), Insulin resistance (HOMA IR) of Diabetic animals was also reduced significantly (∼54 %). The methods explained in the study are versatile and are not limited to only diabetic drugs.

SARS-CoV-2 inhibitory potential of fish oil-derived 2-pyrone compounds by acquiring linoleic acid binding site on the spike protein.

Traditional medicines have reportedly treated SARS-CoV-2 infection. Substantial evidence shows that fish oil supplements promote human immune function, suggesting they may lessen susceptibility to SARS-CoV-2 infection and suppress viral replication by inducing interferon. Fish oil was subjected to partition chromatography and separated into two compounds (EP01 and DH01). Isolated compounds were purified and characterized using UV, FTIR, NMR, and mass spectrometry to confirm their identity. Molecular docking was studied on the SARS CoV-2 variants of concern; SARS CoV-2 WT (PDB: 6VXX), SARS CoV-2 Alpha variant (PDB: 7LWS), SARS CoV-2 Delta variant (PDB: 7TOU), SARS CoV-2 Gamma variant (PDB: 7V78), SARS CoV-2 Kappa variant (PDB: 7VX9), and SARS CoV-2 Omicron variant (PDB: 7QO7) and TMPRSS2 (PDB: 7Y0E). Further selected protein-ligand complexes were subjected to 100 ns MD simulations to predict their biological potential in the SARS-CoV-2 treatment. In-vitro biological studies were carried out to support in-silico findings. Isolated compounds EP01 and DH01 were identified as 5-Tridecyltetrahydro-2H-pyran-2-one and 5-Heptadecyltetrahydro-2H-pyran-2-one, respectively. The compound EP01 significantly reduced (93.24 %) the viral RNA copy number with an IC50 of ~8.661 µM. EP01 proved to be a potent antiviral by in-vitro method against the SARS-CoV-2 clinical isolate, making it a promising antiviral candidate, with a single dose capable of preventing viral replication.

Computational Screening of Repurposed Drugs for HMG-CoA Synthase 2 in Alzheimer's Disease.

Background: HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) plays a pivotal role as a control enzyme in ketogenesis, and its association with the amyloid-ß protein precursor (AßPP) in mitochondria implicates a potential involvement in Alzheimer's disease (AD) pathophysiology. Objective: Our study aimed at identifying repurposed drugs using the DrugBank database capable of inhibiting HMGCS2 activity. Methods: Exploiting the power of drug repurposing in conjunction with virtual screening and molecular dynamic (MD) simulations against 'HMGCS2', we present new in-silico insight into structure-based drug repurposing. Results: The initial molecules were screened for their binding affinity to HMGCS2. Subsequent interaction analyses and extensive 300 ns MD simulations were conducted to explore the conformational dynamics and stability of HMGCS2 in complex with the screened molecules, particularly Penfluridol and Lurasidone. Conclusions: The study revealed that HMGCS2 forms stable protein-ligand complexes with Penfluridol and Lurasidone. Our findings indicate that Penfluridol and Lurasidone competitively bind to HMGCS2 and warrant their further exploration as potential repurposed molecules for anti-Alzheimer's drug development.

Antifungal potential of multi-drug-resistant Pseudomonas aeruginosa: harnessing pyocyanin for candida growth inhibition.

Introduction: Pseudomonas aeruginosa is notorious for its multidrug resistance and its involvement in hospital-acquired infections. In this study, 20 bacterial strains isolated from soil samples near the Hindan River in Ghaziabad, India, were investigated for their biochemical and morphological characteristics, with a focus on identifying strains with exceptional drug resistance and pyocyanin production. Methods: The isolated bacterial strains were subjected to biochemical and morphological analyses to characterize their properties, with a particular emphasis on exopolysaccharide production. Strain GZB16/CEES1, exhibiting remarkable drug resistance and pyocyanin production. Biochemical and molecular analyses, including sequencing of its 16S rRNA gene (accession number LN735036.1), plasmid-curing assays, and estimation of plasmid size, were conducted to elucidate its drug resistance mechanisms and further pyocynin based target the Candida albicans Strain GZB16/CEES1 demonstrated 100% resistance to various antibiotics used in the investigation, with plasmid-curing assays, suggesting plasmid-based resistance gene transmission. The plasmid in GZB16/CEES1 was estimated to be approximately 24 kb in size. The study focused on P. aeruginosa's pyocyanin production, revealing its association with anticandidal activity. The minimum inhibitory concentration (MIC) of the bacterial extract against Candida albicans was 50 µg/ml, with a slightly lower pyocyanin-based MIC of 38.5 µg/ml. Scanning electron microscopy illustrated direct interactions between P. aeruginosa strains and Candida albicans cells, leading to the destruction of the latter. Discussion: These findings underscore the potential of P. aeruginosa in understanding microbial interactions and developing strategies to combat fungal infections. The study highlights the importance of investigating bacterial-fungal interactions and the role of pyocyanin in antimicrobial activity. Further research in this area could lead to the development of novel therapeutic approaches for combating multidrug-resistant infections.

Field emission from two-dimensional (2D) CdSSe flake flowers structure grown on gold coated silicon substrate: An efficient cold cathode.

Field emission finds a vital space in numerous scientific and technological applications, including high-resolution imaging at micro- and nano-scales, conducting high-energy physics experiments, molecule ionization in spectroscopy, and electronic uses. A continuous effort exists to develop new materials for enhanced field emission applications. In the present work, two-dimensional (2D) well-aligned CdSSe flake flowers (CdSSe-FFs) were successfully grown on gold-coated silicon substrate utilizing a simple and affordable chemical bath deposition approach at ambient temperature. The time-dependent growth mechanism from nanoparticles to FFs was observed at optimized parameters such as concentration of precursors, pH (~11), deposition time, and solution temperature. The crystalline nature of CdSSe-FFs is confirmed by high-resolution transmission electron microscopy (HRTEM) results, and selected area electron diffraction (SAED) observations reveal a hexagonal crystal structure. Additionally, the CdSSe-FFs thickness was confirmed by TEM analysis and found to be ~20-30 nm. The optical, photoelectric, and field emission (FE) characteristics are thoroughly explored which shows significant enhancement due to the formation of heterojunction between the gold-coated silicon substrate and CdSSe-FFs. The UV-visible absorption spectra of CdSSe-FFs show enhanced absorption at 700 nm, corresponding to the energy band gap (Eg) of 1.77 eV. The CdSSe-FFs exhibited field emission and photosensitive field emission (PSFE) characteristics. In FE study CdSSe-FFs shows an increase in current density of 387.2 µ A cm-2 in an applied field of 4.1 V m-1 which is 4.08 fold as compared to without light illumination (95.1 µ A cm-2). Furthermore, it shows excellent emission current stability at the preset value of 1.5 µA over 3 h with a deviation of the current density of less than 5% respectively. RESEARCH HIGHLIGHTS: Novel CdSSe flake flowers were grown on Au-coated Si substrate by a cost-effective chemical bath deposition route. The growth mechanism of CdSSe flake flowers is studied in detail. Field emission and Photoluminescence study of CdSSe flake flowers is characterized. CdSSe flake flowers with nanoflakes sharp edges exhibited enhanced field emission properties.

Effect of non-surgical periodontal therapy on salivary and gingival crevicular fluid concentration of visfatin in periodontal health and disease.

Background and objective: Visfatin, a pleotropic mediator mostly produced by visceral fat, is crucial in controlling the immunological and defensive systems. It serves the roles of a cytokine, an enzyme involved in energy metabolism, and a growth factor. The objective of the present study was to assess the impact of non-surgical periodontal therapy (scaling and root planing) on visfatin concentrations in saliva and gingival crevicular fluid in individuals with Periodontitis (stage-II grade-A). Materials and methods: 54 individuals were divided into Group A (Periodontally Healthy) and Group B1(Periodontitis baseline) based on periodontal parameters including plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment level (CAL), and radiographic parameters. After NSPT (SRP), Group B1 patients were recalled after 4 weeks, constituting Group B2 (post NSPT group B1). At baseline and 4 weeks after non-surgical periodontal therapy (SRP), all clinical parameters, salivary and GCF samples were recorded. An ELISA kit was used to measure the levels of visfatin. Using the paired t-test, unpaired t-test, and Pearson's correlation coefficient, data were analysed using SPSS 15. Results: After non-surgical periodontal treatment (SRP), the mean salivary and gingival crevicular fluid concentration of visfatin considerably decreased to a level comparable to periodontal health. In all groups, GCF visfatin concentration was higher than salivary concentration of visfatin. In periodontitis patients, visfatin concentration in GCF was 1.5 times higher than in saliva. Conclusion: The results of this investigation suggest a direct correlation between salivary and gingival crevicular fluid visfatin concentration and periodontal tissue inflammation and disease activity.

Unveiling the Detrimental Effect of Glipizide on Structure and Function of Catalase: Spectroscopic, Thermodynamics and Simulation Studies.

Free radicals, products of oxidative processes, induce cellular damage linked to diseases like Parkinson's and diabetes due to increased reactive oxygen species (ROS) levels. Catalase, crucial for scavenging ROS, emerges as a therapeutic agent against ailments including atherosclerosis and tumor progression. Its primary function involves breaking down hydrogen peroxide into water and oxygen. Research on catalase-drug interactions reveals structural changes under specific conditions, affecting its activity and cellular antioxidant balance, highlighting its pivotal role in defending against oxidative stress-related diseases. Hence, targeting catalase is considered an effective strategy for controlling ROS-induced cellular damage. This study investigates the interaction between bovine liver catalase and glipizide using spectroscopic and computational methods. It also explores glipizide's effect on catalase activity. More than 20% inhibition of catalase enzymatic activity was recorded in the presence of 50 µM glipizide. To investigate the inhibition of catalase activity by glipizide, we performed a series of binding studies. Glipizide was found to form a complex with catalase with moderate affinity and binding constant in the range of 3.822 to 5.063 × 104 M-1. The binding was spontaneous and entropically favourable. The α-helical content of catalase increased from 24.04 to 29.53% upon glipizide complexation. Glipizide binding does not alter the local environment surrounding the tyrosine residues while a notable decrease in polarity around the tryptophan residues of catalase was recorded. Glipizide interacted with numerous active site residues of catalase including His361, Tyr357, Ala332, Asn147, Arg71, and Thr360. Molecular simulations revealed that the catalase-glipizide complex remained relatively stable in an aqueous environment. The binding of glipizide had a negligible effect on the secondary structure of catalase, and hydrogen bonds persisted consistently throughout the trajectory. These results could aid in the development of glipizide as a potent catalase inhibitor, potentially reducing the impact of reactive oxygen species (ROS) in the human body.

MolDy: molecular dynamics simulation made easy.

MOTIVATION: Molecular dynamics (MD) is a computational experiment that is crucial for understanding the structure of biological macro and micro molecules, their folding, and the inter-molecular interactions. Accurate knowledge of these structural features is the cornerstone in drug development and elucidating macromolecules functions. The open-source GROMACS biomolecular MD simulation program is recognized as a reliable and frequently used simulation program for its precision. However, the user requires expertise, and scripting skills to carrying out MD simulations. RESULTS: We have developed an end-to-end interactive MD simulation application, MolDy for Gromacs. This front-end application provides a customizable user interface integrated with the Python and Perl-based logical backend connecting the Linux shell and Gromacs software. The tool performs analysis and provides the user with simulation trajectories and graphical representations of relevant biophysical parameters. The advantages of MolDy are (i) user-friendly, does not requiring the researcher to have prior knowledge of Linux; (ii) easy installation by a single command; (iii) freely available for academic research; (iv) can run with minimum configuration of operating systems; (v) has valid default prefilled parameters for beginners, and at the same time provides scope for modifications for expert users. AVAILABILITY AND IMPLEMENTATION: MolDy is available freely as compressed source code files with user manual for installation and operation on GitHub: https://github.com/AIBResearchMolDy/Moldyv01.git and on https://aibresearch.com/innovations.

Black Seed Oil-Based Curcumin Nanoformulations Ameliorated Cuprizone-Induced Demyelination in the Mouse Hippocampus.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by the demyelination of nerves, axonal damage, and neuroinflammation. Cognition impairment, pain, and loss of mobility are some of the usual complications of MS. It has been postulated that the overproduction of proinflammatory cytokines and reactive oxygen species (ROS) are the main factors that contribute to MS pathology. Among various animal models, the cuprizone model is the most widely used model for investigating MS-related pathology. We assessed the effects of cuprizone along with the protective effects of some black seed oil-based nanoformulations of curcumin with and without piperine, in mice hippocampus in terms of the changes in antioxidant enzymes, transcription factors, and cytokines during demyelination and remyelination processes. The results of behavioral studies point toward impairment in working memory following the feeding of cuprizone for 5 weeks. However, in treatment groups, mice seemed to prevent the toxic effects of cuprizone. Nanoformulations used in this study were found to be highly effective in lowering the amount of ROS as indicated by the levels of antioxidant enzymes like catalase, superoxide dismutase, glutathione, and glutathione peroxidase. Moreover, nanoformulations CCF and CCPF were observed resisting the toxic effects of cuprizone. We observed greater expression of NFκB-p65 in the CPZ group than in the control group. CCF nanoformulation had a better inhibitory effect on NFκB-p65 than other formulations. Histological examination of the hippocampus was also conducted. Nanoformulations used here were found effective in reversing MS-related pathophysiology and hence have the potential to be applied as adjuvant therapy for MS treatment.

Withaferin A alleviates inflammation in animal models of arthritis by inhibiting the NF-κB pathway and cytokine release.

Withaferin A, a steroid lactone from Withania somnifera, exhibits anti-inflammatory, immunomodulatory, and antioxidant properties. This study investigated the effects of withaferin A on collagen-induced arthritis (CIA) rats, focusing on NF-κB p65 regulation and cytokine release. Withaferin A (50 mg/kg b.wt., orally) or methotrexate (0.25 mg/kg b.wt., i.p., as a reference drug) was given to CIA rats daily for 20 days postarthritis induction. Joints were removed from nonarthritic and arthritic rats to assess the levels of NO, MPO, interleukin (IL)-1ß, IL-6, IL-10, TNF-α, COX-2, and NF-κB via ELISA. Furthermore, the mRNA expression of IL-1ß, IL-10, TNF-α, COX-2, iNOS, and NF-κB was also assessed through qPCR. Treatment with withaferin A significantly inhibited the levels of inflammatory cytokines and the transcription factor NF-κB; suppressed the expression of IL-1ß, IL-10, TNF-α, COX-2, iNOS, and NF-κB in the joint tissue of CIA rats; and reduced cartilage and bone destruction, as shown by H&E staining. To confirm the results obtained from biochemical and molecular studies and to determine the molecular target of withaferin A, we performed a molecular simulation of the potential targets of withaferin A, which identified the NF-κB pathway as its target. These results suggested that withaferin A effectively attenuated rheumatoid arthritis progression by inhibiting the activation of the NF-κB pathway and the downstream secretion of inflammatory cytokines.

Quest for Anti-SARS-CoV-2 antiviral therapeutics: in-silico and in-vitro analysis of edible mushroom- Cordyceps militaris.

BACKGROUND: The emergence and evolution of SARS-CoV-2 resulted a severe threat to public health globally. Due to the lack of an effective vaccine with durable immunity, the disease transited into the endemic phase, necessitating potent antiviral therapy including a scientific basis for current traditional herbal medicine. OBJECTIVE: This study aimed to conduct a pharmacoinformatic analysis of selected chemical ingredients and in-vitro evaluation of Cordyceps militaris extract against SARS-CoV-2. MATERIALS AND METHODS: C. militaris, the widely used fungus in conventional herbal medicine, was subjected to computational investigation using molecular docking, molecular dynamic simulation and network pharmacology analysis followed by the in-vitro assay for evaluating its anti-SARS-CoV-2 potential. RESULTS: The molecular docking analysis of C. militaris revealed the Cordycepin's highest affinity (-9.71 kcal/mol) than other molecules, i.e., Cicadapeptin-I, Cicadapeptin-II, Cordycerebroside-B, and N-Acetyl galactosamine to the receptor binding domain of the SARS-CoV-2 spike protein. C. militaris aqueous extract could reduce the SARS-CoV-2 viral copy numbers by 50.24% using crude extract at 100 µg/mL concentration. CONCLUSION: These findings suggest that C. militaris has promising anti-SARS-CoV-2 activity and may be explored as traditional medicine for managing the COVID-19 surge in the endemic phase.

Coupling hydrothermal liquefaction and anaerobic digestion for waste biomass valorization: A review in context of circular economy.

In light of the substantial global production of biomass waste, effective waste management and energy recovery solutions are of paramount importance. Hydrothermal liquefaction (HTL) and anaerobic digestion (AD) have emerged as innovative techniques for converting biomass waste into valuable resources. Their integration creates a synergistic framework that mitigates inherent limitations, leading to improved efficiency, enhanced product quality, and the comprehensive utilization of biomass. This review paper investigates the integration of HTL and AD, highlighting its significance and potential benefits as well as the optimal sequencing (HTL followed by AD and AD followed by HTL). The review encompasses experimental procedures, factors influencing both sequencing options, energy recovery characterizations, final product outcomes, as well as toxicological assessments and discussions on reduction. Additionally, it delves into the transition towards a circular bioeconomy and discusses the challenges and opportunities intrinsic to these processes. The findings presented in this review offer valuable insights to shape future research in this evolving field.

Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4+ regulatory T cells by regulating IL2RA.

Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.

Detection of water pollutants using super-hydrophobic porous silicon-based SERS substrates.

Super hydrophobic porous silicon surface is prepared using a wet chemical synthesis route. Scanning electron microscopic investigation confirms a correlation between pore size and reaction time. SERS substrates are prepared by silver nanoparticle deposition on porous silicon surface. They exhibit excellent characteristics in terms of sensitivity, reproducibility, stability, and uniformity. They could detect rhodamine 6G in femtomolar range with SERS enhancement factor of ~ 6.1 × 1012, which is best ever reported for these substrates. Molecule-specific sensing of water pollutants such as methylene blue, glyphosate, and chlorpyrifos, is demonstrated for concentrations well below their permissible limits along with excellent enhancement factors. Porous silicon substrate functionalized with Ag nanoparticles demonstrates to be a promising candidate for low-cost, long-life, reliable sensors for environmental conservation applications.

Attenuated adiponectin, omentin, increased interleukin-6 and tumor necrosis factor-alpha levels with altered cognition and depression in non-Hodgkin lymphoma patients: A case-control study.

BACKGROUND AND PURPOSE: Immune dysfunction is one of the risk factors which plays an important role in the development of non-Hodgkin lymphoma (NHL), and inflammation may be involved in its etiology. Minimal data is available on the effect of cytokine levels on neurobehavioral function in lymphoma before the initiation of chemotherapy. Therefore, we aimed to explore the risk of NHL by assessment of cytokine and adipokine levels and their correlation with neurobehavioral changes. METHODS: This case-control study enrolled 62 subjects (age-sex matched: 31 cases and 31 controls). Neurobehavioral assessment was done using Montreal Cognitive Assessment questionnaire (MoCA) and Patient Health Questionnaire (PHQ-9). EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) was used to assess quality of life. Questionnaire assessment and sample collection were done after the patient enrolment and before first cycle of chemotherapy. RESULTS: Mean age of NHL patients and healthy controls was 51.9 ± 11.8 and 50 ± 10.9 years, respectively. NHL patients showed significantly higher levels of IL-6 (0.77 ± 0.11) and TNF- α (1.47 ± 1.31) than controls (0.55 ± 0.4 and 0.66 ± 0.89, respectively) with p-value<0.005. Also, NHL patients showed significantly lower levels of adiponectin (0.31 ± 0.24) and omentin (0.46 ± 0.1) than controls (0.42 ± 0.13 and 0.53 ± 0.11, respectively) with p-value<0.005. Lower MoCA and EORTC QLQ C-30 scores and higher PHQ-9 scores were observed in NHL patients in comparison to healthy control. CONCLUSION: Our results showed that adiponectin, omentin IL-6 and TNF-α may be used as pre-diagnostic markers of NHL risk. Neurobehavioral changes observed in NHL patients may alter the quality of life.

A proximal enhancer regulates RORA expression during early human Th17 cell differentiation.

Gene regulatory elements, such as enhancers, greatly influence cell identity by tuning the transcriptional activity of specific cell types. Dynamics of enhancer landscape during early human Th17 cell differentiation remains incompletely understood. Leveraging ATAC-seq-based profiling of chromatin accessibility and comprehensive analysis of key histone marks, we identified a repertoire of enhancers that potentially exert control over the fate specification of Th17 cells. We found 23 SNPs associated with autoimmune diseases within Th17-enhancers that precisely overlapped with the binding sites of transcription factors actively engaged in T-cell functions. Among the Th17-specific enhancers, we identified an enhancer in the intron of RORA and demonstrated that this enhancer positively regulates RORA transcription. Moreover, CRISPR-Cas9-mediated deletion of a transcription factor binding site-rich region within the identified RORA enhancer confirmed its role in regulating RORA transcription. These findings provide insights into the potential mechanism by which the RORA enhancer orchestrates Th17 differentiation.

Phytoconstituents of Nymphaea rubra flowers and their anti-diabetic metabolic targets.

Nymphaea rubra (N. rubra) flowers are prevalent in subtropical regions for both dietary and traditional medicinal purposes, attributing to their beneficial properties in supporting overall health. This study first time provides descriptions of the antidiabetic and dyslipidemic properties employing STZ induced high fat diet fed diabetic rats and inhibition of α-amylase enzyme activity first by in vitro analyses, followed by a confirmatory in silico study to create a stronger biochemical rationale. Furthermore, in 3 T3-L1 cells, this extract promoted the suppression of adipogenesis. GC-MS investigation of the ethyl acetate fraction of ethanolic extract of N. rubra flowers revealed the presence of marker compounds of N. rubra, Nuciferine, and Apomorphine, which were the focus of molecular docking studies. The acquired concentrations of Nuciferine (22.39%) and 10, 11-dimethoxy-Apomorphine (1.47%) were detected. Together with other alkaloids identified by GC-MS analysis from this extract, mechanistically suggested that it might be caused by the synergistic impact of these bioactive chemicals. Molecular docking has been done to check the binding affinities of various isolated phytochemicals with HPAA, the dose-response effect of 100 mg/kg and 250 mg/kg of flower extract after 30 days showed a significant effect on body weight, food, water intake, serum insulin, FBG, OGTT, lipid profile, glycated haemoglobin, liver and kidney function test. Kidney histopathology results show a significant effect. These findings offer a strong foundation for the potential application of the ethyl acetate fraction of ethanolic extract from Nymphaea rubra flowers and its bioactive constituent in an in vivo system for the treatment and control of diabetes and its associated condition dyslipidemia.

Understanding the interactions between repurposed drugs sertindole and temoporfin with receptor for advanced glycation endproducts: Therapeutic implications in cancer and metabolic diseases.

CONTEXT: In the pursuit of novel therapeutic possibilities, repurposing existing drugs has gained prominence as an efficient strategy. The findings from our study highlight the potential of repurposed drugs as promising candidates against receptor for advanced glycation endproducts (RAGE) that offer therapeutic implications in cancer, neurodegenerative conditions and metabolic syndromes. Through careful analyses of binding affinities and interaction patterns, we identified a few promising candidates, ultimately focusing on sertindole and temoporfin. These candidates exhibited exceptional binding affinities, efficacy, and specificity within the RAGE binding pocket. Notably, they displayed a pronounced propensity to interact with the active site of RAGE. Our investigation further revealed that sertindole and temoporfin possess desirable pharmacological properties that highlighted them as attractive candidates for targeted drug development. Overall, our integrated computational approach provides a comprehensive understanding of the interactions between repurposed drugs, sertindole and temoporfin and RAGE that pave the way for future experimental validation and drug development endeavors. METHODS: We present an integrated approach utilizing molecular docking and extensive molecular dynamics (MD) simulations to evaluate the potential of FDA-approved drugs, sourced from DrugBank, against RAGE. To gain deeper insights into the binding mechanisms of the elucidated candidate repurposed drugs, sertindole and temoporfin with RAGE, we conducted extensive all-atom MD simulations, spanning 500 nanoseconds (ns). These simulations elucidated the conformational dynamics and stability of the RAGE-sertindole and RAGE-temoporfin complexes.