BackgroundEmerging evidence highlights the anti-tumor properties of Glucagon-like peptide-1 receptor agonists (GLP-1RAs). However, their synergistic potential with standard chemotherapy remains largely unexplored.MethodsData from Genome-wide association study (GWAS) were used to select single-nucleotide polymorphisms (SNPs) strongly associated with lipid-lowering drug targets as instrumental variables. Causal effects were assessed primarily using the inverse variance weighted (IVW) method, supported by comprehensive sensitivity analyses to control for pleiotropy and heterogeneity. These Mendelian randomization (MR) findings were further validated through in vitro functional assays (cell viability, apoptosis, and Western blot) and an in vivo tumor-bearing mouse model.ResultsGlucagon-like peptide-1 receptor (GLP-1R) activity showed a significantly positive causal relationship with dihydrofolate reductase (DHFR; β = 0.323, P = 6.02 × 10−17) and apoptosis regulator Bcl-2 (β = 0.259, P = 2.1 × 10−11) but a negative relationship with ribonucleoside-diphosphate reductase large subunit (RRM1; β = −0.12, P = 2.32 × 10−3). Functional experiments validated these genetic findings. GLP-1RA significantly enhanced the antitumoral efficacy of gemcitabine both in vitro and in vivo by repressing RRM1. Conversely, GLP-1RA attenuated the anti-tumor effects of methotrexate and paclitaxel by upregulating DHFR and Bcl-2, respectively. Notably, GLP-1RA combination therapy achieved these modulatory effects without exacerbating chemotherapy-associated systemic toxicity.ConclusionGLP1-RAs can influence the efficacy of chemotherapeutic drugs such as methotrexate, paclitaxel, and gemcitabine.
This review critically evaluates the antifibrotic potential of silymarin by integrating its phytochemical composition, formulation-dependent exposure, molecular pharmacology, cross-organ preclinical evidence, and clinical translation, while distinguishing multicomponent silymarin extracts from purified silybin/silibinin and delivery-enhanced preparations. A structured, non-systematic evidence-mapping search of PubMed/MEDLINE, Web of Science, and Scopus covered English-language literature through December 2025. A targeted update of PubMed/MEDLINE and publisher records was performed through 9 August 2026, focusing on fibrosis, pharmacokinetics, formulation, drug delivery, ferroptosis, succinate metabolism, ANXA6, and related mechanisms. Preclinical studies indicate that silymarin-related interventions can modulate TGF-β/Smad signaling, oxidative and inflammatory pathways, fibroblast activation, myofibroblast differentiation, and extracellular-matrix turnover. Recent work has added hepatocyte succinate handling, FTH1-related ferroptosis, and ANXA6-associated stress signaling. Antifibrotic activity has been reported in liver, kidney, lung, peritoneal, and skin models, whereas human evidence remains limited and heterogeneous. Product composition, oral exposure, formulation, and endpoint selection may contribute to discordant clinical findings. Silymarin has biologically plausible multitarget antifibrotic activity, but current evidence does not establish it as an antifibrotic therapy. Future studies should use chemically defined preparations, exposure-informed dosing, validated target engagement, and fibrosis-centered outcomes.
Ethnopharmacological relevanceChinese herbal medicine (CHM) is used for recurrent or chronic urinary symptoms within the traditional category of dysuria, often through stage-specific treatment during symptomatic and remission phases. Whether defined CHM preparations prevent recurrent bacterial cystitis or modify recurrence biology remains uncertain. The aim of this study is to critically evaluate formulation-specific clinical evidence for CHM in women with recurrent urinary tract infection (rUTI) and determine whether reported benefits are connected to recurrence biology.Materials and methodsStructured searches of PubMed, China National Knowledge Infrastructure, and Wanfang Data were closed on 13 July 2026. After within-batch screening and cross-source reconciliation, 103 reports were linked into 96 study or unresolved-report clusters. Clusters were classified by directness, and clinical confidence was appraised using allocation, participant flow, recurrence ascertainment, denominator integrity, comparator, intervention identity, safety reporting, internal consistency, and report independence.ResultsTen core clusters directly addressed prospective recurrence or suppressive treatment, but every comparative estimate was of very low confidence. Reported signals were formulation-specific and were limited by attrition, responder-conditioned denominators, active comparators, co-interventions, poorly defined recurrence, internal numerical inconsistencies, or report linkage. Botanical identity and study-batch chemistry were usually inadequate. Experimental studies supported anti-adhesion, virulence-modulating, anti-inflammatory, immune, and urothelial plausibility, including chemically characterized Persicaria capitata extract and more specific Caveolin-1 evidence for purified cynaroside, but predominantly used acute or pretreatment models. No microbiome or biomarker study evaluated clinical mediation.ConclusionCurrent evidence is inconclusive rather than uniformly negative and supports cautious hypothesis generation for specific preparations, not a class-wide efficacy or safety claim. No clinical study demonstrates that CHM reduces recurrence by clearing persistent uropathogens, interrupting gut–bladder or vaginal transmission, restoring microbial ecology, or repairing the urothelial barrier. Reproducible products, intention-to-treat recurrence trials, longitudinal strain-resolved sampling, and prespecified mediation analyses are required.
Molecular hydrogen (H2) has emerged as a promising bioactive gas with well-documented antioxidant, anti-inflammatory, and cytoprotective properties, and its therapeutic potential for a range of human diseases has been increasingly recognized. Accumulating evidence suggests that the gut microbiota (GM) may contribute to some of the biological effects of H2. The GM serves as both a key site for endogenous H2 production and consumption, and a potential site of interaction with exogenous H2 supplementation, with possible implications for intestinal microecological homeostasis. This narrative review critically summarizes current evidence on the bidirectional relationship between H2 and the GM, focusing on microbial H2 production and consumption, the potential role of H2 in maintaining gut microbial homeostasis, and the impact of exogenous H2 supplementation on intestinal microecology. The potential therapeutic relevance of H2-associated GM modulation is further discussed in metabolic diseases, gastrointestinal disorders, and neurodegenerative diseases. Proposed mechanisms include regulation of microbial composition, reinforcement of intestinal barrier integrity, suppression of inflammation and oxidative stress, modulation of microbial metabolites, and gut-organ axis signaling. Collectively, current evidence supports that H2 may influence the GM ecosystem. However, most supporting data remains preclinical, and whether GM alterations causally mediate the biological or therapeutic effects of H2 remains to be established. Elucidating the reciprocal interaction between H2 and the GM may provide new mechanistic insight into H2-based interventions and facilitate the development of microbiota-targeted therapeutic strategies for human diseases.
Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide. Despite major pharmacological advances, a substantial gap persists between guideline recommendations and routine clinical practice, particularly after exacerbations. This narrative review summarizes current evidence supporting personalized pharmacological escalation in COPD, focusing on single-inhaler triple therapy (SITT) and the emergence of biologic therapy. SITT, combining an inhaled corticosteroid, a long-acting β2-agonist and a long-acting muscarinic antagonist, is now the preferred inhaled strategy for patients requiring ICS-containing triple therapy. Real-world studies indicate that, compared with multiple-inhaler triple therapy, SITT is associated with better adherence and persistence, lower exacerbation rates and improved clinical outcomes, although observational findings require cautious causal interpretation. In parallel, COPD has entered the era of targeted biologic therapy. Dupilumab was the first biologic approved for COPD, following the BOREAS and NOTUS trials in patients with chronic bronchitis, blood eosinophils ≥300 cells/µL and persistent exacerbations despite triple therapy. Mepolizumab has more recently provided robust phase 3 evidence in eosinophilic COPD through the MATINEE trial. Early real-world dupilumab studies further suggest potential effectiveness in selected patients under-represented in pivotal trials, including those with advanced age, severe airflow limitation, oxygen dependence or high mucus burden. Beyond canonical type 2 pathways, IL-33 inhibition with tozorakimab may further broaden targeted treatment to COPD phenotypes without a clear eosinophilic signature. Integrating these advances within a treatable-traits framework may help optimize patient selection, close post-exacerbation therapeutic gaps, and align pharmacological escalation with comorbidity management, adherence, inhaler technique and rehabilitation needs.
