Osteoporosis (OP) remains a major global health burden, yet current pharmacological interventions are constrained by adverse effects, limited efficacy, and a bone-centric therapeutic paradigm that overlooks upstream pathogenic drivers. Emerging evidence positions the gut microbiota (GM) as a critical rheostat of bone homeostasis, operating through a gut–immune–bone axis that integrates microbial metabolism, intestinal barrier integrity, and systemic immune regulation. This review systematically examines the immunopathological mechanisms of OP, with particular emphasis on the GM-derived metabolites—short-chain fatty acids, secondary bile acids, tryptophan derivatives, lipopolysaccharide, and trimethylamine N-oxide—that orchestrate osteoclastogenic versus osteoprotective outcomes via key immune checkpoints including the Th17/Treg, macrophage phenotypic polarization, and regulatory B cell axes. We further delineate the subtype-specific heterogeneity of this axis across postmenopausal, senile, glucocorticoid-induced, and diabetic osteoporosis, highlighting distinct microbial and immune signatures that mandate stratified therapeutic approaches. Importantly, we evaluate the translational potential of GM-targeted interventions—probiotics, prebiotics, fecal microbiota transplantation, and dietary modulation—as adjunctive or standalone strategies, and discuss their synergistic interplay with conventional anti-osteoporotic agents. By reframing OP as a systems-level disorder of the gut–immune–bone circuitry, this review establishes a mechanistic groundwork for precision medicine, identifies novel druggable targets, and charts a course toward safer, more durable, and disease-modifying anti-osteoporotic therapies.
ObjectiveThis study aimed to characterize the post-marketing safety profile and potential adverse event signals of resmetirom using the FAERS and VigiAccess databases.MethodsFAERS reports from the quarter of initial United States approval through 2026Q1 were analyzed. After deduplication, DEMO, DRUG, REAC, THER, and OUTC tables were integrated, and reports listing resmetirom as the primary suspect drug were included. Disproportionality analysis used four methods: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS), with IC and EBGM as the respective Bayesian signal metrics. PTs meeting all four predefined criteria were defined as robust signals. Additional analyses assessed SOC/PT profiles, label expectedness, seriousness and outcomes, time-to-onset (TTO), Weibull patterns, and cross-database consistency with VigiAccess.ResultsWe identified 1,409 resmetirom-related FAERS reports and 1,417 VigiAccess reports. Sixty-two robust PT signals across nine SOCs were detected, mainly involving gastrointestinal disorders, investigations, hepatobiliary disorders, and skin and subcutaneous tissue disorders. Prominent signals included diarrhoea, nausea, pruritus, alanine aminotransferase increased, aspartate aminotransferase increased, abdominal pain upper, dizziness, vomiting, weight decreased, and hepatic cirrhosis. Among FAERS reports, 419 (29.7%) were serious and 65 (4.6%) reported death. Sixteen robust PTs were not listed as corresponding adverse reactions in either the current United States. Prescribing Information or European SmPC. Complete temporal information was available for 170 reports (12.1%); median TTO was 26 days (IQR, 5–66), and the Weibull shape parameter was 0.72 (95% CI, 0.64–0.80), indicating an early-failure pattern. SOC-stratified analyses showed heterogeneous onset patterns. FAERS and VigiAccess showed high descriptive concordance in SOC- and PT-level reporting patterns (Spearman ρ = 0.998).ConclusionResmetirom-related reports were mainly gastrointestinal, laboratory, hepatobiliary, and skin-related. Hepatobiliary signals warrant particular attention, while cross-database concordance provides supportive, non-causal pharmacovigilance evidence.
BackgroundThe emergence of cephalosporin-resistant Neisseria gonorrhoeae strains, encoding altered Penicillin-Binding Protein 2 (PBP2), has become a major global public health concern. The increasing prevalence of antimicrobial resistance necessitates the development of novel antimicrobial agents. In the present study, phytocompounds derived from the haustorium of Borassus flabellifer L. were investigated as potential inhibitors of PBP2 using an integrated in silico approach.MethodologyPhytochemical profiling of the methanol, ethyl acetate and hexane extracts of white spongy palmyra haustorium was performed using GC–MS and the identified compounds were subsequently evaluated for molecular docking, ADMET analysis and molecular dynamics simulation.ResultsA total of 69 compounds were identified and subjected to molecular docking against the transpeptidase domain of PBP2. The docking analysis revealed predicted binding affinities, ranging from −4.5 to −9.7 kcal/mol. The top ten compounds were subsequently evaluated for their ADMET and drug-likeness properties. Among these, 5-(4-nitrophenyl)-1,3,4-oxadiazol-2(5H)-one and 1,2,4-triazol-3-amine, 5-(1,3,5-trimethyl-4-pyrazolyl)amino, demonstrated comparatively favourable pharmacokinetic properties and balanced predicted ADMET profile. Furthermore, the stability of the complexes was assessed for a time period of 100 ns using molecular dynamics simulation. RMSD, RMSF, Rg, SASA, and hydrogen bonds were examined to evaluate protein-ligand interactions throughout the time frame. Principal component analysis and free energy landscape studies further supported ligand-induced stabilization of the PBP2 structure. MM-PBSA revealed favourable interaction energies of −19.11 ± 2.29 kJ/mol and −11.16 ± 2.34 kJ/mol for the two selected compounds, respectively. Among them, 5-(4-nitrophenyl)-1,3,4-oxadiazol-2(5H)-one demonstrated comparatively greater binding stability and thermodynamic favourability.ConclusionThese findings suggest that 5-(4-nitrophenyl)-1,3,4-oxadiazol-2(5H)-one could serve as a promising lead molecule for the development of new therapeutics against drug-resistant gonococcal infections and necessitate further experimental validation.
IntroductionBreast cancer remains the most frequently diagnosed malignancy and the leading cause of cancer death among women worldwide as of 2026. While conventional interventions face challenges like drug resistance and systemic toxicity, the integration of green nanotechnology with ethnopharmacology offers a biocompatible, sustainable alternative. This review assesses the mechanistic pathways and therapeutic potential of phytogenic zinc oxide nanoparticles (ZnO NPs) synthesized using bioactive secondary metabolites.MethodsThis review combines findings from nine recent studies exploring biogenic ZnO NPs derived from diverse biological sources, including Rhus coriaria L. (Anacardiaceae), Withania somnifera (L.) Dunal (Solanaceae), Zingiber officinale Roscoe (Zingiberaceae). We critically analysed the characterization parameters, synthesis methods and pharmacological efficacy across 3D architectural spheroids, 2D monolayer cultures, and select in vivo models.ResultsThe collective data demonstrate that biogenic ZnO-NPs induce potent apoptosis through BAX upregulation, ROS-mediated mitochondrial dysfunction and specific cell cycle arrest. Notable benchmarks include tumour suppression comparable to Tamoxifen in in vivo models using melon-derived extracts and an IC50 of 14.7 μg/mL in 3D MCF-7 spheroids for ginger-mediated NPs.DiscussionIn spite of the promising results, a critical methodological tension exists between limited preclinical validation and innovative synthesis. The pervasive reliance on 2D models often fails to duplicate the dense architectural barriers of solid tumours. Future research must prioritize a realistic translational pathway, shifting from basic in vitro models to rigorous in vivo biodistribution profiling, detailed metabolic tracking, and long-term toxicological assessments against normal mammary epithelial controls (e.g., MCF-10A) to actually establish, rather than merely hypothesize, a definitive, selective therapeutic index and ensure baseline physiological safety.
Osteoarthritis (OA) lacks approved disease-modifying pharmacotherapy. Chondrocyte ferroptosis—iron-dependent phospholipid peroxidation caused by disrupted iron handling, lipid metabolism, and antioxidant defense—has been implicated in cartilage degeneration and is pharmacologically suppressible in experimental models. Natural products can modulate multiple ferroptosis-related nodes, including the Nrf2/SLC7A11/GPX4 axis, ACSL4-dependent lipid peroxidation, iron homeostasis, and mitochondrial redox balance. Their translation, however, is limited by poor solubility, instability, rapid clearance, uncertain dose–exposure relationships, and restricted cartilage penetration. This review integrates the pharmacological basis of chondrocyte ferroptosis, evidence for anti-ferroptotic natural products, and nanodelivery strategies that improve joint retention, cartilage targeting, chondrocyte uptake, and controlled release. We distinguish direct ferroptosis evidence from adjacent antioxidant or chondroprotective findings and evaluate polymeric, lipid-based, hydrogel, biomimetic, inorganic, and hybrid platforms as pharmacological optimization tools. Current integrated systems show encouraging structure-preserving effects in experimental OA, but evidence remains predominantly preclinical. Translation will require standardized compounds, ferroptosis-specific target-engagement assays, pharmacokinetic and dose–response studies, carrier-specific safety testing, clinically relevant models, and biomarker-guided patient selection. Rationally matching natural-product pharmacology with joint-specific delivery may enable mechanism-based OA therapies.
