Background Diabetic dyslipidemia poses significant health risks; this study assesses the efficacy of traditionally used Punica granatum and Beta vulgaris in lowering blood sugar and lipids, focusing on their influence on hepatic CYP7A1 expression, which is crucial for cholesterol regulation. Methods A type 2 diabetic-dyslipidemic rat model was established by injecting streptozotocin in neonates, followed by a diet higher in cholesterol and fat. The animals were allocated into five groups (n=6): Normal Control (NC), Diabetic-Dyslipidemic Control (DDC), Gliclazide (GT; 20 mg/kg), P. granatum extract (PG; 1.25 g/kg), and B. vulgaris extract (BV; 1.25 g/kg). Over 28 days, the investigation assessed body weight, fasting glucose, serum insulin, lipid profiles, and hepatic CYP7A1 mRNA expression. Phytochemical and antioxidant analyses were also performed. Results Both PG and BV extracts were rich in flavonoids and phenols. Significant metabolic improvements were observed in each group treated with plant extracts, relative to the DDC control group. These improvements included a marked decrease in fasting glucose (p<0.001), as well as suppressed lower levels of total cholesterol, triglycerides, and LDL, and higher HDL levels. A significant recovery of serum insulin and a reduction in body weight also accompanied these changes. Crucially, the diabetic state suppressed hepatic CYP7A1 expression, and treatment with both extracts upregulated its expression, providing a mechanism for the observed cholesterol reduction. Conclusion P. granatum and B. vulgaris extracts demonstrate potent antidiabetic and lipid-lowering capabilities by simultaneously improving insulin secretion and boosting cholesterol catabolism via hepatic CYP7A1 upregulation.
The medicinal plant Limonia acidissima (Rutaceae) has long been used to treat a variety of ailments; however, the bioactivity of its leaves remains poorly explored. This study evaluated the phytochemical screening, antioxidant potential, and in vitro anticancer activity of the Methanolic Leaf Extract (MLE). Preliminary screening revealed tannins, flavonoids, phenols, saponins, alkaloids, steroids, and glycosides, indicating therapeutic potential. Gas Chromatography-Mass Spectrometry (GC-MS) analysis identified fifty-five compounds, including fatty acids, phenolics, sterols, terpenoids, alkaloids, and vitamins, with oleic acid, stearic acid, squalene, stigmasterol derivatives, and tocopherol-related compounds predominating. Antioxidant activity assessed via 2,2-diphenyl-1picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC), and oxygen radical absorbance capacity (ORAC) assays. Assays showed strong free radical scavenging and reducing capacity, with IC50 of 150.27 & micro;g TE/g (DPPH), FRAP 173.00 & micro;g TE/g, TEAC 185.53 & micro;mol TE/g, and ORAC 125.41 & micro;mol TE/g. In vitro cytotoxicity in MCF-7 cells showed dose-dependent inhibition (76.78% at 400 & micro;g/mL; IC50 = 184.21 & micro;g/mL), with morphological changes confirming cytotoxicity, supporting the potential of L. acidissima leaves as a source of antioxidant and anticancer compounds. Further studies are warranted to isolate active constituents and elucidate their molecular mechanisms for therapeutic applications.
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of gene expression, playing essential roles in cancer initiation, progression, metastasis, and therapy resistance. Accumulating evidence indicates that lncRNAs interact closely with the Hippo signaling pathway, a key regulator of cell proliferation, apoptosis, and tissue homeostasis, whose dysregulation is frequently associated with tumor development. Recent studies have highlighted the potential of plant-derived phytochemicals to modulate lncRNA expression and influence Hippo pathway activity. Well-known compounds such as curcumin, resveratrol, quercetin, and berberine can regulate both oncogenic and tumor-suppressive lncRNAs, thereby affecting YAP/TAZ signaling and tumor progression. Despite promising preclinical findings, clinical translation remains limited due to poor bioavailability and stability of many phytochemicals. Nanotechnology-based delivery systems offer a promising solution by enhancing compound stability and targeted delivery. Collectively, these findings suggest that phytochemical-mediated modulation of the lncRNA-Hippo signaling axis could represent a novel and effective strategy for future cancer therapies.
Background: Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder influenced by both environmental and genetic factors. The transcription factor KLF11 regulates insulin gene expression and metabolic pathways, and the rs35927125 (Q62R) variant has been proposed as a functional candidate influencing T2DM susceptibility. However, findings across populations have been inconsistent, and no data exist for Kurdish Iranians. Objectives: To determine the frequency of the KLF11 rs35927125 (Q62R) variant in a Kurdish Iranian population and evaluate its association with T2DM and dyslipidemia. Methods: In this case-control study, 200 adults with T2DM and 200 age-, sex-, and BMI-matched controls were recruited. Clinical and biochemical measurements were obtained after a 10-12-h fast. Genotyping was performed using ARMS-PCR with Sanger validation. Associations between rs35927125 and T2DM or dyslipidemia were assessed using multivariable logistic regression adjusted for age, sex, BMI, and diabetes status. Bonferroni correction was applied. Results: Genotype frequencies were AA 88%, AG 10%, GG 2% in controls and AA 80%, AG 14%, GG 6% in cases. Controls were in Hardy-Weinberg equilibrium. No significant associations were observed between rs35927125 and T2DM under allelic, genotypic, dominant, or recessive models (all p > 0.0125). Similarly, no associations were detected with hypertriglyceridemia, hypercholesterolemia, low HDL-C, or high LDL-C. Wide confidence intervals, particularly for the GG genotype, reflected the low minor allele frequency (0.11) and limited statistical power. Conclusion: The rs35927125 (Q62R) variant in KLF11 was not associated with T2DM or dyslipidemia in this Kurdish Iranian cohort. However, the low frequency of the G allele and modest sample size limit the precision of effect estimates. Larger studies with greater representation of the minor allele are needed to clarify whether small or population-specific effects exist.
Background: Kidney transplantation is the best treatment option for patients with kidney failure. Despite the increased prevalence of transplantation, allograft rejection continues to cause morbidity and mortality among transplant recipients. Vitamin_D3 {25(OH)D} and renal function are still debated for long-term in renal transplant recipients. Aims: Evaluation of 25(OH)D level in pre- and post-kidney transplantation as a strong evidence of successful kidney transplantation after one year and its association with kidney function pre- and post-kidney transplantation. Methods: This study followed 85 patients (70 males and 15 females) aged 18-56 years pre- and post-kidney transplantation. 25(OH)D, blood urea nitrogen (BUN), creatinine clearance (CrCl), creatinine, and BUN/creatinine ratio were tested pre- and post-kidney transplant. The correlation between 25(OH)D with BUN, creatinine, CrCl, and BUN/creatinine ratio was analyzed. Multiple regression analysis controlled for confounders. A ROC curve analysis study of 25(OH)D assessed as a successful marker in kidney transplant recipients. Results: Post-transplant serum 25(OH)D level exhibited significantly higher compared with pre-transplant (P < 0.001). 25(OH)D strong positively correlated with BUN/creatinine ratio (r = 0.64, P < 0.001), CrCl (r = 0.692, P < 0.001) and strong negatively correlated with BUN (r = -0.69, P < 0.001), creatinine (r = -0.761, P < 0.001). Multiple regression analysis showed that CrCl and BUN/creatinine ratio were independently associated with 25(OH)D (p < 0.001). The area under the ROC curve analysis for 25(OH)D was 0.954 (95% CI: 0.894-1). Conclusion: Vitamin_D3 levels are strongly associated with kidney function, particularly graft function. Furthermore, the 25(OH)D level can be used as a good indicator of successful graft function.
Cerebral malaria is characterized by severe neurological deficits, lethal inflammation and oxidative stress. The current study sought to establish if co-administration of co-enzyme Q10 (CoQ10), a potent antioxidant, antiinflammatory and chloroquine (CQ) can improve treatment outcome in an experimental cerebral malaria (ECM). Mice were divided into five groups: control, PbA-infected, and PbA-infected treated with CoQ10, CoQ10 plus chloroquine, or chloroquine alone, using doses of 200 mg/kg for CoQ10 and 50 mg/kg for chloroquine. The study evaluated relative organ weights, neurological symptoms, blood-brain barrier integrity (BBB), hematological profile, creatinine, urea uric acid, albumin, nitrite levels, lipid peroxidation and brain pathology. Rapid murine coma and behavioral scale (RMCBS) data showed that combined CQ and CoQ10 treatment significantly improved neurological symptoms linked to ECM. This therapeutic regimen also prevented the disruption of the blood-brain barrier (BBB) during severe Plasmodium berghei ANKA (PbA) infection. Notably, it attenuated PbAinduced brain edema, leukopenia, microcytic hypochromic anemia, and thrombocytopenia, and restored the PbA-associated reduction trend in lung relative organ weight. The CQ/CoQ10 combination abrogated PbA-driven elevations in creatinine, urea, and uric acid, and was most effective in restoring depleted albumin and nitric oxide (NO) levels. Additionally, it reduced PbA-induced malondialdehyde (MDA) levels. Signs of brain injury, such as focal gliosis and perivascular cuffing, were also ameliorated. In conclusion, this regimen enhanced therapeutic efficacy, evidenced by improved RMCBS scores, preserved BBB integrity, and correction of hematological and biochemical abnormalities. CoQ10, used alongside CQ, shows promise as adjunct therapy, supporting evaluation in additional preclinical studies.
Novel acrylate derivatives (1-4) were synthesized by Knoevenagel condensation of thiophene-2-carbaldehyde with malononitrile, cyanoacetamide, ethyl cyanoacetate and isobutyl cyanoacetate in the presence of ammonium acetate (NH4OAc) using microwave irradiation under solvent-free conditions. The reactions were completed in 30 sec with excellent yield. All the synthesized compounds were characterized by FT-IR, and NMR (1H, 13C, DEPT-135) analyses. The biological assays revealed that analog 3 had the highest antibacterial activity against Salmonella typhi (7.5 +/- 0.33 mm), while analog 2 demonstrated the strongest antifungal effect against Aspergillus niger (90.33 +/- 0.23 mm) and Aspergillus flavous (89.55 +/- 0.33 mm). Some analogs exhibited no activity against Staphylococcus hominis and Shigella flexneri. Additionally, molecular docking studies indicated that analog 4 had the strongest interaction with the fungal receptor (PDB: 5V5Z), supporting the observed biological activities. The molecular dynamics simulation was performed against Lanosterol 14-alpha demethylase (LDM) (PDB ID: 5V5Z; organism: Candida albicans) to investigate the binding stability and interactions between the drug and targeted protein. The outcome of the antimicrobial activity and in-silico analysis assessment of the compounds demonstrated significant effectiveness, supporting their selection as potential antifungal drug candidates.
Background: Pulmonary endothelial barrier dysfunction is characterized by increased vascular permeability, lung edema, and impaired gas exchange. Synthetic somatostatin analogs (SSA), including Lanreotide (LAN), have demonstrated cytoprotective effects in experimental models of endothelial injury, but the corresponding mechanisms mediating those effects are still unclear. Objective: This study aimed to determine whether the unfolded protein response (UPR) sensor ATF6 is involved in the protective outcomes of LAN in lung endothelial cells. Methods: Human and bovine pulmonary endothelial cells were exposed to Ceapin-A7, an ATF6 inhibitor, prior to LAN exposure. Protein expression levels of BiP, Grp94, MLC2, Cofilin, STAT1, STAT3, and stress kinases were assessed. Reactive oxygen species (ROS) generation was also measured, as well as paracellular permeability using FITC-Dextran assay. Results: LAN enhanced protein expression of BiP and Grp94, decreased ROS production, suppressed STAT1, STAT3 and ERK1/2 phosphorylation, and improved barrier function. Those effects were counteracted by Ceapin-A7. Conclusions: Our findings suggest that ATF6 inhibition opposes the beneficial effects of LAN in endothelial cells.
Background: Colorectal cancer (CRC) incidence is rising in sub-Saharan Africa, coinciding with the high prevalence of immune-modulating infections such as HIV and helminths. The gut virome, a critical yet understudied component of the microbiome, may influence oncogenic processes through epigenetic and metabolic alterations. However, the interplay between gut viral communities, HIV-helminth co-infection, and CRC risk remains poorly characterized in African populations. This study aimed to investigate gut virome-associated epigenetic and metabolic signatures linked to CRC susceptibility among South African adults, with a focus on HIV and helminth co-infection dynamics. Methods: Untargeted shotgun metagenomic sequencing was performed on stool DNA samples from 62 adults stratified into five groups: uninfected controls (n = 10), HIV-only (n = 14), helminth-only (n = 15), HIVhelminth co-infected (n = 13), and CRC-confirmed patients (n = 10). Bioinformatic analyses were used to identify differentially abundant viral genes and to functionally annotate epigenetic and metabolic pathways associated with infection status and CRC occurrence. Results and discussion: Adenine-specific DNA methylase (COG2189) emerged as one of the most significantly enriched epigenetic markers across all infected and CRC groups, CRC (7.0 f 1.26, q = 2.98e-06), helminth-only (7.1 f 1.16, q = 1.30e-07), HIV-only (6.2 f 1.21, q = 1.28e-05), and co-infected 6.5 f 1.21, q = 6.11e-06), suggesting a shared viral epigenomic mechanism potentially contributing to tumorigenesis. Additionally, diverse metabolism-related genes were differentially abundant, particularly those linked to butyrate metabolism, oxidative stress response, and polyamine biosynthesis, metabolic pathways known to influence tumor initiation, immune evasion, and disease progression. These findings indicate that the gut virome may play an intermediary role in modulating host epigenetic and metabolic landscapes in infection-driven CRC risk. Conclusion: This study identifies novel gut virome-associated epigenetic and metabolic functional signatures that may serve as early, non-invasive biomarkers of CRC susceptibility in HIV-and helminth-endemic populations. Integrating such molecular indicators into cancer surveillance and prevention frameworks could enhance early detection strategies and precision cancer care in underrepresented, high-infection burden African regions.
Current commercial methods of detection of high-risk human papilloma virus (hrHPV) rely mostly on the polymerase chain reaction (PCR) that use either 14 specific primer pairs or a single consensus primer pair (e.g., GP5+/GP6+). However, PCR requires the use of a thermal cycler (PCR machine) and electricity and therefore is not suitable for a low-cost Point of Care Test (PoCT). Moreover, PCR primers are often not suitable for isothermal amplification since at lower temperature they may anneal non-specifically leading to background amplification. We have developed an isothermal point of care method for the rapid detection of hrHPV that works at a constant temperature (<42°C) using recombinase polymerase amplification (RPA). A novel consensus primer pair was designed able to amplify all 14 hrHPV types. To enable the detection of the amplified double-stranded RPA products, one primer was labelled with a 5′-phosphate, and the other primer was labelled at the 5′-end with 6-carboxyfluorescein (FAM). Then, the double-stranded labelled RPA product was digested with Lambda exonuclease, which preferentially digests 5′-phosphorylated DNA ends whereas the 5′-FAM ends are protected, generating single-stranded 5′-FAM-labelled RPA products. These products can be detected by paper-based lateral flow assays (LFA) using biotinylated detection probes that detect all 14 hrHPV types at the same time (universal consensus detection probe). Lateral flow assay conditions were developed that allow these probes to detect all 14 hrHPV types. Using this novel isothermal rapid hrHPV detection method, amplification of all 14 hrHPV types at constant temperature (currently set at 37°C) within short time (<1h) was achieved.
Due to the effectiveness and relatively lower toxicity at high dose levels, natural products have been practiced in different medicine systems since ancient times. It plays a vital role in prophylactics and therapeutics of many maladies and has been an accessible and affordable choice to modern medicines. For a possible treatment option for the current pandemic caused by SARS-CoV-2, various chemical components of Swertia chirayita Roxb. ex Fleming plant were explored by computational methods. The phytochemicals present in the plant, amaroswerin, amarogentin, mangiferin, oleanolic acid, syringaresinol, swertiamarin, and sweroside were proposed as the top candidates with probable inhibition capabilities determined in terms of docking scores/binding affinities against non-structural protein 13 (PDB ID: 5RMM) calculated from flexible receptor molecular docking. The values calculated were -17.2, -15.7, -14.9, -13.0, -13.6, -13.0, and -13.3 kcal/mol, respectively and were better than those calculated for some FDA approved drugs and a native ligand which showed values from -12.9 to -8.9 kcal/mol. From the 200 ns long molecular dynamics simulations of different protein-ligand adducts, it was found that oleanolic acid RMSD was less than 5 & Aring; and snapshots at multiple instances displayed that it nearly retained the docked position with moderately smooth nature of the curve. These geometrical results implied acceptable structural stability of the protein-ligand adduct. The binding free energy change of protein-oleanolic acid complex (-32.72 f 4.65 kcal/mol) was the best among the test cases. This thermodynamic parameter hinted at the spontaneous nature of the reaction and its frame-by-frame analysis complemented the geometrical results. The ADMET prediction revealed lipophilic nature and some toxicity end-points of the hit molecule, oleanolic acid. The results point towards the need for further extensive characterization of it by in vitro and in vivo methods in the development of anti COVID-19 drug from readily available plant with ethnobotanical values.
Background: Snakebite envenomation Snakebite envenomation is a major public health problem, affecting an estimated 1.8-2.7 million people annually, predominantly in low-and middle-income countries. Despite its classification as a neglected tropical disease by the World Health Organization, snakebite envenomation continues to cause substantial morbidity and mortality, driven in part by limited access to effective antivenoms, delays in treatment, and the lack of widely available rapid diagnostic tools. The marked biological complexity and geographic variability of snake venom composition further complicate clinical management, underscoring the need for innovative and context-appropriate approaches to improve both therapeutic effectiveness and diagnostic accuracy. This review examines recent advancements in regionally informed antivenom strategies and next-generation diagnostic technologies, emphasizing their necessity for achieving more precise, timely, and context-appropriate snakebite management. Methods: This review adopts a structured, critical narrative approach, synthesizing peer-reviewed literature and global health reports to evaluate recent innovations in antivenom development and snakebite diagnostics. Literature was identified using PubMed, Web of Science, and Scopus, with emphasis placed on studies published from 2010 onward, reflecting the period of rapid advances in venom omics, recombinant antivenoms, and diagnostic technologies. Searches were focused on terms directly relevant to the review's analytical scope, including antivenom development, venom proteomics, transcriptomics, and snakebite diagnostics. Rather than aiming for exhaustive coverage, studies were prioritized based on their relevance to therapeutic effectiveness, translational feasibility, scalability, and accessibility in snakebite-endemic settings. Findings were synthesized comparatively to identify key advances, persistent limitations, and barriers to clinical implementation. Findings: Recent advances in antivenom research include the development of recombinant antibody platforms, immunoinformatics-guided design strategies, synthetic biology approaches, and the characterization of endogenous venom resistance mechanisms, all of which have contributed to improved understanding of how specificity and immunogenicity might be optimized beyond conventional antivenoms. At the same time, progress in diagnostic research, particularly involving lateral flow-based immunoassays and multi-omic venom profiling, has highlighted potential pathways for improving venom or toxin identification and supporting more informed clinical decision making. However, translation of these scientific advances into routine clinical practice remains limited. Persistent challenges related to large-scale manufacturing, regulatory approval, affordability, and implementation within resource-constrained health systems continue to restrict the real-world impact of next-generation antivenoms and diagnostics in snakebite-endemic regions. Conclusion: Future progress in snakebite envenomation management will depend on coordinated advances across antivenom development, diagnostic innovation, and supportive global health policy frameworks. Region-informed antivenom strategies, enabled by venom profiling and supported by scalable and modular production models, together with appropriately validated rapid diagnostic tools, represent a plausible pathway toward improving treatment effectiveness and access. Nevertheless, achieving meaningful reductions in morbidity and mortality will require sustained interdisciplinary collaboration and explicit attention to translational, regulatory, and health system constraints, ensuring that scientific innovation is matched by practical feasibility and equitable implementation in high-burden settings.
Globally, lung cancer—more specifically, non-small cell lung cancer (NSCLC)—contributes significantly to the death toll from cancer. Recent advances in molecular research have identified key genetic mutations that drive tumor growth, including those in the EGFR, KRAS, ALK, and MET genes, accounting for around 80 % of lung cancers that are categorized as non-small cell lung cancer (NSCLC). The advent of targeted therapies such as Tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, have revolutionized cancer treatment by specifically inhibiting oncogenic pathway. However, despite this advancements, treatment outcomes remain suboptimal due to intrinsic heterogeneity of cancers and the development of resistance mechanisms. The cancer treatment landscape is constantly changing to address these challenges and improve patient outcomes. Customization of cancer therapies through pharmacogenomics is hindered by tumor adapatability and resistance, limited prognostic biomarkers and suboptimal monotherapies, necessitating innovative research in adoptive therapies biomarker development and combination therapies. Ongoing trails aims to enhance treatment endurance via the advancement of combination regimens incorporating multiple targeted therapies or synergistic combination immunotherapy with chemotherapy. Ongoing research is focused on optimizing CRISPR-Cas9 delivery system, improving specificity and minimizing half target effect. Emphasizes the crucial role of molecular mutations, the advantages and disadvantages of targeted medicines, and the prospects for enhancing the effectiveness of lung cancer treatment results are all highlighted in this Review.
Despite ongoing efforts, the current human reference genome lacks diversity. Consequently, research using this resource might miss disease-causing variants in individuals whose ancestry does not correspond to that of the standard reference. Most individuals from South Africa are admixed to some extent, with ancestral contributions from several continental populations. This study set out to create a population-specific reference genome for admixed South Africans with the same coordinate system as the widely used GRCh38 reference. This approach was tested in diagnosing a South African individual with Mendelian susceptibility to mycobacterial disease (MSMD) using a novel approach that replaced portions of the reference genome with corresponding, but more variable portions of the population-specific sequences. We implemented the algorithm in a tool we named PopPatch. Short sequencing reads from two individuals were used for a rudimentary genome assembly which was then aligned to GRCh38p13. To test the algorithm and the generated reference genome, whole genome sequencing data from a TB-susceptible individual was aligned to SA_PopPatch and GRCh38, with variant call sets compared. The GRCh38p13 reference yielded no discoveries, while the SA_PopPatch reference identified a homozygous, non-synonymous single nucleotide variant in exon 20 of the JAK1 gene. This project introduces a novel method for creating population-specific reference genomes that align with the standard reference, ensuring congruency with databases based on the most widely used reference genome, GRCh38, while minimizing additional costs.
Variant calling in complex genomic regions remains a critical challenge in cancer genomics, yet systematic evaluations of false positive rates in such regions are rarely reported. This investigative study examined somatic mutations in esophageal squamous cell carcinoma (ESCC) using Whole Genome Sequencing (WGS) data, that identified a high frequency of putative mutations in MUC3A, a gene with an inherently complex sequence architecture. Quantitative laboratory validation attempts failed to confirm any of these computationally predicted mutations, prompting systematic re-analysis. By assessing multiple variant calling algorithms and implementing a Panel of Normals (PON) filtering strategy, we demonstrate that standard bioinformatics pipelines generated extensive false positive calls in MUC3A, with false positive rates approaching 100 % for this gene. While previous studies have acknowledged limitations in variant calling for repetitive or homologous regions, our work provides evidence of complete analytical failure in the MUC3A gene, and establishes a reproducible framework for identifying such artefacts. These findings address a critical research gap by quantifying the magnitude of false discovery in complex genomic contexts and demonstrating that multi-tool consensus approaches combined with PON filtering are insufficient without accompanied experimental validation. We recommend mandatory quantitative confirmation for variants identified in sequence-complex genes and advocate for transparent reporting of validation rates in cancer genomic studies to prevent propagation of spurious findings in literature. This paper provides a cautionary warning to future research to take into consideration the limitations of alignment and variant calling tools and to employ a combination of tools to obtain robust and reliable results.
Background: Histone Deacetylase 3 (HDAC3) is an epigenetic enzyme that controls cell cycle progression, apoptosis, and gene expression. Overexpression of HDAC3 has been shown to be a potential contributing factor to the development and spread of breast cancer, and it has recently been identified as a promising target in breast cancer. As a result, repurposing currently approved drugs as novel HDAC3 inhibitors may reduce the laborintensive and time-consuming process of developing new molecules. Materials and methods: We sourced 4288 compounds from the ZINC15-approved drugs. We then employed both virtual and structure-based screening to identify and repurpose current drugs as selective inhibitors against the HDAC3 target protein. MD simulation was performed to assess the dynamic behavior and stability of the top ligand complexes for 100 ns. Results: This computational screening obtained the top five compounds with docking scores of-10.96,- 10.32,- 9.83,- 9.83, and-8.81 kcal/mol, respectively, in comparison with the reference ligand, BG45 (-4.18 kcal/ mol), suggesting they may be more potent HDAC3 inhibitors. The MD simulation study of the top hit ligandprotein complex (HDAC3-ZINC000095618609 complex) revealed stable conformational changes. The results of pharmacokinetic and drug-likeness properties of the top-performing compounds reveal their potential to be considered viable HDAC3 inhibitors. Conclusion: This study highlights the potential of drug repurposing as a cost-effective and faster approach to cancer treatment. here we have identified drugs have the potential to be repurposed as HDAC3 inhibitors; however, additional in vitro and in vivo studies are needed to confirm their efficacy.
Phytochemicals, have long been studied for various severe metabolic illnesses and degenerative diseases like heart disease and cancer because of their significant therapeutic effects. In animal cells, cholesterol serves a critical role being a component of cell membranes and essential for the normal functioning of precursor cells to some steroid hormones. Three-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) is converted into mevalonate by the HMG-CoA Reductase (HMGCR) enzyme to produce cholesterol. However, when cholesterol levels are high, it may result in atherosclerosis. Statins, also known as synthetic drugs which decrease cholesterol, are therefore designed to work by targeting this enzyme. For patients with dyslipidemia, the side effects of excessive statin therapy have proven alarming hence using natural plant-based inhibitors is a promising alternative. Computational approach helps to identified many drugs that can target HMG-CO A Reductase. In this study, using in-silico molecular docking via auto-dock, 20 medicinal plants with 120 phytochemicals, reported as having antihyperlipidemic activity through deep literature study, were screened as HMG-CoA reductase enzyme inhibitors. The virtual molecular docking results reveals that five bioactive compounds; Sominone, Guggulsterone, Phytosterol, Withanolide A and Basilol, had higher binding affinities towards the HMG-CO A Reductase having binding energies of -9.33, -8.99, -8.87, -8.58, and -8.48 kcal/mol, respectively. ADMET properties of selected compounds were analysed using swiss adme tool. Results showed that out of five compounds three follow Lipinski rule of five, having ADMET properties. The HMG-CoA reductase-ligand complex's stability was validated by RMSD, RMSF, Rg, H-bond results and principal component analysis. The resulting trajectories of converged period of MD were further exploited in MM-P/G/BSA calculations to derive accurate estimates of binding free energies. This leads one to the conclusion that five phytochemicals, Sominone, Guggulsterone, Phytosterol, Withanolide A and Basilol can serve as potential inhibitors in regulating HMGCR's function may assist the development of effective anti-hyperlipedemic drugs.
