Harish Darasaguppe Ramachandra

Hepatitis B virus (HBV) infection remains a major global health burden and often progresses to chronic liver inflammation, fibrosis, and hepatocellular carcinoma. Although current antiviral therapies effectively suppress viral replication, their ability to modulate HBV‐associated complications remains limited. This study investigates the HBV‐associated antiviral and host modulatory potential of methanolic extract of Allium cepa bulb (AC) using integrated in vitro and computational approaches. Cytotoxicity, reverse transcriptase inhibition, time‐ and dose‐dependent inhibition of HBsAg and HBeAg levels, inflammatory cytokines, and specific host gene expression linked to HBV infections were assessed using HBV‐expressing HepG2.2.15 cells. LC‐MS detected phytocompounds were evaluated for their interaction with TLR4 using molecular docking and dynamics simulations using the Schrödinger suite. AC treatment reduced HBsAg and HBeAg levels up to 61.0% and 75.37%, respectively. Co‐treatment with Tenofovir alafenamide enhanced the inhibition to 79.0% and 94.55% without compromising cell viability. Among LC‐MS‐identified phytocompounds, computational analysis revealed stable interactions with Quercetin 3,4'‐diglucoside exhibiting the highest affinity (−14.23 kcal/mol) and maintaining stability with TLR4 throughout a 100 ns simulation. Overall, AC attenuated HBV‐induced inflammation through predicted modulation of TLR4‐mediated pathways and reduction of HBV antigen secretion, supporting its potential as a complementary therapeutic candidate for the management of chronic HBV infection.

Snake venom Metalloproteinases (SVMPs) are Zn²⁺-dependent endopeptidases categorised under metzincin superfamily and are predominantly found in venom of the “Viperidae” family snakes. They are key mediators of venom-induced pathology with associated tissue damage including haemorrhage and oedema. SVMPs are classified as P-I, P-II, and P-III depending on the domains, each differing in structural complexity and organization. Further, the conserved HEXXHXXGXXH catalytic motif organizes a Zn²⁺ ion, essential for the breakdown of peptide bonds and proteins. Given the limitations of conventional antivenom therapy, increasing attention has been directed toward targeted approaches for SVMPs neutralization, including plant-derived phytocompounds, synthetic and repurposed small-molecule inhibitors, recombinant monoclonal antibodies, and camelid-derived nanobodies. Structure-based drug discovery, molecular docking, and mechanistic studies have facilitated the identification of compounds and biologics capable of interfering with SVMP catalytic activity, substrate recognition or functionally relevant epitopes. Emerging technologies such as CRISPR-engineered venom gland organoids and artificial intelligence/machine learning-assisted molecular screening further provide opportunities for functional target validation and rational therapeutic discovery. This review integrates these conventional and emerging strategies, highlighting the structural basis of SVMPs inhibition and their potential to support the development of precise, broad-spectrum, and next-generation therapeutic interventions against SVMP-mediated envenoming.

Olanzapine (OLZ), a commonly prescribed atypical antipsychotic, is strongly linked to cardiometabolic disorders (CMDs) such as obesity, insulin resistance, dyslipidemia, and cardiac dysfunction. Garcinia indica Choisy (kokum), a nutrient‐rich medicinal fruit with antioxidant, anti‐obesity, antidiabetic, and cardioprotective properties, has not yet been investigated for its potential to counter OLZ‐induced CMD(s). This study examined the protective effects and underlying mechanisms of G. indica hydroalcoholic extract (GIE) against OLZ‐induced cardiometabolic alterations using in vitro and computational approaches. GIE significantly reduced OLZ‐induced cytotoxicity in H9c2(2‐1) cardiomyocytes by lowering lactate dehydrogenase (LDH), creatine kinase‐MB (CK‐MB), and nitric oxide (NO) levels, while enhancing glucose utilization. Gene expression analysis showed downregulation of IL6, BAX, CASP3, and CAMK2B, alongside upregulation of BCL2, indicating anti‐inflammatory and anti‐apoptotic modulation. Network pharmacology and in silico analyses identified thirteen phytocompounds targeting 35 CMD‐related proteins, with gambogic acid‐ RAGE and amentoflavone‐ CALM1 interactions demonstrating the strongest binding affinities, supported by docking and molecular dynamics simulations. Overall, GIE exhibits multi‐target regulatory effects on oxidative, inflammatory, and metabolic pathways, suggesting its therapeutic potential in mitigating OLZ‐induced cardiometabolic disturbances. The current findings indicate promising mechanistic potential of GIE against OLZ‐ induced cardiometabolic alterations, warranting further validation through in vivo and clinical studies.

Background: Tenofovir, a nucleotide reverse transcriptase inhibitor (NRTI), is a first-line therapy for HBV and HIV and is administered as tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). However, long-term use of TDF is linked to renal and other organ toxicities, which is largely attributed to oxidative stress mediated by xanthine oxidase (XO), a key enzyme in purine metabolism. To address this, plants with documented nephroprotective and XO-inhibitory properties were investigated through computational, in vitro , and in vivo approaches. Methods: Bioactive compounds from nine medicinal plants were subjected to computational screening for XO inhibition, leading to the selection of Allium cepa and Vitex negundo as promising candidates. Fifteen extracts from different plant parts were prepared and assessed in vitro for XO inhibitory activity. The methanolic extract of A. cepa bulb (AC) and the hydroalcoholic extract of V. negundo root (VN) demonstrated the highest potency. These extracts were further evaluated for their antioxidant potential and tested against TDF-induced renal and hepatic toxicities in a 35-day rat model. Results: Both AC and VN significantly mitigated TDF-induced elevations in serum biomarker levels, including creatinine, BUN, AST, ALT, GGT, bilirubin, and alkaline phosphatase, while enhancing albumin levels. They also restored the levels of oxidative stress markers such as MDA, GSH, catalase, and SOD. Histopathological examination confirmed substantial structural recovery of liver and kidney tissues. Conclusion: Overall, this preclinical study demonstrates that A. cepa and V. negundo extracts effectively alleviate TDF-induced organ toxicities and oxidative damage, supporting their potential as adjunct therapies to enhance the safety of TDF treatment in HBV and HIV management.

Alzheimer's disease (AD), Parkinson's disease (PD), and other dementia related metabolic disorders are linked to neuroinflammation as a key pathogenic process. Pro-inflammatory cytokines, chemokines, reactive oxygen species, and inflammasome are excessively released when microglia and astrocytes are activated. Although small molecules modulating these inflammatory cascades have a great deal of therapeutic promise, poor bioavailability, quick systemic clearance, off-target toxicity, and, most importantly, limited penetration across blood-brain barrier (BBB) continue to hinder their successful translation into effective brain therapies. Recent advances in computational and experimental biology, pharmacology, chemistry, and nanotechnology are being integrated to address these issues. It is feasible to develop treatments that are safer, more effective, and more in line with the intricate biology of neurodegenerative disorders by combining these delivery methods with mechanistic and systems-level analysis.Liposomes, polymeric nanoparticles, solid lipid nanoparticles, and dendrimers as nanocarrier systems have become innovative methods to overcome delivery hurdles associated with BBB.These allow small molecules to be encapsulated, improving their bioavailability and protecting from early breakdown. Crucially, nanocarriers regulate drug release, limit systemic exposure, and maintain therapeutic concentrations in brain regions. BBB traversal and sitespecific drug accumulation have been enhanced by recent advancements in nanocarrier engineering, e.g., surface functionalization with targeting ligands, receptor-mediated transport methods, and stimuli-responsive release mechanisms. These methods enable nanocarriers to release their payload preferentially at injured areas in response to inflammatory milieu. Wang et al. (2025) highlighted nanocarriers as transformative platforms for AD therapy to overcome BBB constraints to target neuroinflammation driven by microglial/astrocyte activation, TNF-α/IL-1β/IL-6/ROS release, and Aβ/tau feedback loops. These facilitate ligand-mediated transcytosis, stimuli-responsive release, and increased bioavailability with low toxicity. It highlights translational issues, e.g., immunogenicity, clearance, and scalability, and suggests biodegradable PLGA, theranostics, and biomarkerdriven personalization (APOE4/CRP) combined with CRISPR/siRNA for precision targeting.To connect delivery innovation with therapeutic impact, experimental validation is still By identifying important biological targets, signaling hubs, and route linkages, network pharmacology emphasizes how effective neuroinflammatory therapies are inherently polypharmacological. Integrating research on neonate hypoxia-ischemia brain damage and AD, Zhang et al (2025) identified shared hubs and inflammatory pathways. This shows related signaling networks can be modulated to influence disease progression, connecting bioinformatics insights with possible therapeutic interventions. Molecular docking and molecular dynamics simulations provide information on binding stability, conformational flexibility, and contact energetics under physiological conditions, and enable atomistic investigation of drug-receptor and drug-nanocarrier interactions. If paired with experimental validation, these computational frameworks speed up rational drug design, decrease trial-anderror testing, and improve formulation optimization.Given the multifactorial nature of neuroinflammation, therapeutic strategies targeting single pathways yield limited and transient benefits. Therefore, network pharmacology and systems biology increasingly support multi-targeting strategies. Small molecules capable of simultaneously modulating several inflammatory and neuroprotective pathways may more accurately reflect complex biology of neurodegenerative diseases. Natural small molecules originating from traditional medicine are valuable, as many polypharmacological profiles aligned with neuroinflammation regulation. Drug repurposing strategies aim to identify existing small-molecule therapeutics with previously unrecognized antineuroinflammatory potential. Repurposing can minimize development timelines and accelerate clinical translation by leveraging established safety and pharmacokinetic profiles.In this research topic, Luo et al. (2025), in mouse models, showed marein confers neuroprotection in cerebral ischemia-reperfusion injury by reducing oxidative stress, regulating HMGB1-dependent pyroptosis, and inhibiting pro-inflammatory cytokines.Similarly, Zhang et al. (2025) demonstrated calycosin protecting cerebral ischemiareperfusion injury by inhibiting HMGB1-NLRP3-caspase-1-GSDMD-IL-1β/IL-18 pyroptosis signaling. Furthermore, Li et al. (2025) showed, in pseudo germ-free rats, that coadministration of Senkyunolide I with Chuanxiong enhances bioavailability and reduces neuroinflammatory responses, underscoring potential of combinatorial traditional compounds for neuroprotection. Wei et al. (2024) reported glycyrrhizin modulating pyroptosis pathways, providing both neuroprotective and anticonvulsant effects. In addition, Zheng et al. (2025) used integrated computational target identification, molecular docking, and dynamics to identify monoamine oxidase A as nimodipine's target, supporting its potential in neurodegenerative diseases and oxidative-stress modulation. Lee et al. (2025) further demonstrated FDA-approved FGFR inhibitor erdafitinib diminishes neuroinflammatory responses by suppressing NLRP3 inflammasome activation in vitro and in vivo. These studies illustrate how systems biology and network pharmacology, combined with multitargeting small molecules, traditional medicine-derived compounds, and drug repurposing approaches, may accelerate translational progress, maximize therapeutic benefit, and address neuroinflammation.To develop next-generation therapeutics, it is essential to identify and characterize novel molecular...

Background: Our previous studies identified the hydroalcoholic extract of defatted Theobroma cacao L. bean (CE) as a cancer-preventive and a protective agent against chemotherapeutic-induced toxicities, specifically doxorubicin-induced heart, liver, and kidney toxicities.Methods: An analytical method for phytochemical standardization was developed, and acute oral toxicity was studied in female Wistar rats following the OECD 423 guidelines. In brief, the CE was extracted using an 80:20 alcohol–water (% v/v) mixture through cold maceration, followed by spray drying to obtain powdered CE. Utilizing a Quality by Design (QbD) approach with Design Expert (DoE) software, we optimized CE tablets via direct compression. The central composite design (CCD) included five center points, with Avicel PH − 101 and croscarmellose sodium (CCS) as factors, and disintegration time, hardness, and % loss due to friability as measurements.Results: Among the 13 formulations, batch F-9 emerged as the optimized one within the design space, containing 35% Avicel PH − 101 and 5% CCS. The optimized formulation exhibited a disintegration time of 5.2 min, hardness of 4.2 kg/cm², and friability of 0.34%. Importantly, no toxic effects were found at 2,000 mg/kg in the acute oral toxicity study. CE contains vital bioactive polyphenols, including (−)-epigallocatechin-3-gallate (EGCG) and (+)-catechin (CTN). We developed a marker-based HP-TLC densitometric analysis using a mobile phase of 9:9:2 v/v [ethyl acetate: toluene: formic acid], which revealed CTN at Rf 0.49 and EGCG at Rf 0.23. This method was validated according to ICH requirements.Conclusion: In conclusion, the novel, validated HP-TLC method simultaneously detects EGCG and CTN in the cocoa extract. Tablets formulated by direct compression are safe as nutraceuticals and hold promise as supplements in palliative cancer therapy.