Microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) cancers are enriched for dependence on Werner syndrome RecQ helicase (WRN), a synthetic-lethal vulnerability mechanistically linked to expanded TA-dinucleotide repeats, non-B DNA structures, and replication-associated genome instability. However, WRN dependence is not universal among dMMR/MSI-H tumors, indicating that MSI status is an enrichment biomarker rather than a complete predictor of biological dependency. In this review, we synthesize recent advances in WRN structural and molecular pharmacology, with particular emphasis on colorectal cancer, where the strongest functional and pharmacological evidence currently exists. We distinguish four translational biomarker layers: pretreatment predictors of WRN dependency, target-engagement and DNA-damage pharmacodynamic markers, early treatment-response biomarkers, and acquired-resistance markers. We further examine reversible and covalent WRN inhibitors, mechanisms of primary and therapy-emergent resistance, immune and replication-stress-based combinations, and the expanding early-phase clinical landscape. Rather than proposing quantitative WRN dependency as a new biological concept, we present an evidence-graded pharmacological framework that links established substrate biology with drug exposure, target engagement, downstream DNA damage, treatment response, and resistance evolution. This framework may guide prospective biomarker development in MSI-H/dMMR colorectal cancer while identifying the evidence still required for broader application across other gastrointestinal malignancies.
Bei-bei Shao, Tao Feng, Ji-cheng Jiang, Wen-lu Xing, Ming Ni, Lu-lu Li, Chao Liu, Shu-ping Meng, Yong-cheng Ma, Ai-feng Wang
Patients undergoing coronary artery bypass grafting (CABG) combined with valve surgery represent a high-risk surgical population with substantial perioperative hemodynamic disturbances and highly variable organ function, leading to high variability in vancomycin pharmacokinetics. Conventional vancomycin dosing solely on renal function frequently fails to achieve target trough concentrations in this complex subgroup. This study aimed to identify independent correlates c of vancomycin steady-state trough concentrations (C ss-min ), and to report observational findings for intra-aortic balloon pump (IABP) support, to inform individualized therapeutic drug monitoring. A single-center retrospective observational study enrolled adult patients undergoing combined CABG and valve surgery from January 2018 to October 2024. Clinical data and vancomycin TDM records were extracted from electronic medical records. Vancomycin C ss-min was detected by enzyme-multiplied immunoassay technique. Generalized Estimating Equations (GEE) accounting for within-patient repeated TDM measurements were used to identify clinical correlates of C ss-min . IABP support was pre-specified and force-entered into the multivariable model based on clinical observations and pathophysiological reasoning, independent of univariate screening results. We performed a sensitivity analysis for patients with at least one TDM within postoperative day 7, prespecified interaction tests for effect modification, and binary logistic-GEE for the supratherapeutic endpoint (C ss-min > 20 mg/L). A two-tailed P < 0.05 was set as statistical significance. A total of 283 eligible patients with 473 valid C ss-min measurements were included. Multivariate GEE demonstrated that categorical vancomycin dosing regimen, age, ventilator dependence ≥96 h, continuous renal replacement therapy (CRRT), IABP support, serum creatinine (Scr), and serum urea nitrogen (SUN) were positively associated with higher geometric-mean C ss-min . Associations remained largely consistent in the sensitivity-analysis subgroup of patients with at least one early-phase TDM within postoperative day 7. A significant CRRT-by-postoperative-time interaction was detected, indicating that the influence of CRRT on vancomycin exposure varied across different postoperative phases. Of note, the association signal linking IABP to supratherapeutic trough concentrations (C ss-min >20 mg/L) was modest and requires cautious interpretation. Multiple clinical factors jointly affect vancomycin steady-state trough concentrations in patients undergoing combined CABG and valve surgery, including dosing regimen, age, renal biomarkers, and critical-care supportive interventions such as IABP, CRRT and prolonged mechanical ventilation. IABP support represents an intriguing observational signal; this finding remains hypothesis-generating and requires prospective external validation before it can guide formal dose-adjustment strategies. Individualized vancomycin management for this population should comprehensively integrate hemodynamic support measures and laboratory indices rather than depend merely on renal-function markers. This study focuses on clinically accessible trough concentration monitoring rather than constructing complex pharmacokinetic models, which is more in line with real-world clinical practice.
Coptis chinensis Franch. (Huanglian), a traditional Chinese medicinal herb used for “heat” and “dampness” syndromes, is clinically associated with metabolic disorders such as NAFLD. Berberine (BBR), its major bioactive alkaloid, has shown metabolic benefits, though its mechanistic basis in NAFLD remains unclear. To identify candidate pathways underlying the effects of BBR in NAFLD, a computational target prediction approach was employed, followed by in vivo experimental validation in a zebrafish model. A thioacetamide (TAA)-induced liver injury zebrafish model was established. Hepatic lipid accumulation and histopathology were assessed by Oil Red O staining, H&E staining, and qPCR. A computational target prediction approach was employed to identify potential BBR-NAFLD overlapping targets, followed by pathway enrichment analysis and molecular docking simulations to prioritize candidate pathways. Bile acid profiles were analyzed using UHPLC-MS/MS metabolomics. The predicted PPARγ pathway was experimentally validated using the specific antagonist GW9662 and the agonist rosiglitazone. BBR significantly reduced hepatic steatosis and restored liver morphology. A total of 104 overlapping targets were identified, with PPAR signaling emerging as a key pathway. BBR showed stable binding to PPARγ (−7.92 kcal/mol). In vivo, BBR restored the expression of pparg, rxra, cyp7a1, cyp27a1, and cyp8b1, all of which were suppressed by TAA; these effects were reversed by GW9662, confirming PPARγ dependence. Metabolomics revealed reduced levels of 6-ketoLCA and UDCA-3S, which were partially reversed by PPARγ inhibition. BBR alleviates TAA-induced liver injury by regulating PPARγ and bile acid homeostasis, integrating systems pharmacology and experimental validation to support the ethnopharmacological use of C. chinensis in metabolic liver disease.
Emilie Huon, Justine Rayssac, Marie-Charlotte Lamau, Carole Abo, Gauthier Dietrich, Ylann Abrahami, Jordan Kouby, Julien Adam, Nicolas R. Chevalier
Uterine smooth muscle dysfunction is a common factor in many gynecological conditions, such as endometriosis, adenomyosis, dysmenorrhea, infertility, and labor dystocia. Here, we present a novel high-throughput, optical, low-cost, 96-well plate-based method for measuring ex-vivo uterine contractility. We validate this new method on non-pregnant human myometrial samples obtained from hysterectomies by systematically comparing contraction frequency, amplitude, and duration with the standard isometric force transducer approach. We illustrate the potential of this method by screening 8 different compounds, including hormones and pharmacological agents. In particular, we found that antagonists of T-type calcium channels (Z944) and chloride channels (benzbromarone) both decreased contractility in the non-pregnant human uterus. This method will accelerate the pharmacological development of myometrium-specific relaxing agents and provide a powerful tool to investigate the dysregulation of myogenic contractility in gynecological pathologies.
Jian Kang, Heng Yang, Yan Wang, Xin Zhang, Chunyang Zhu, Yanhong Zhou, Yanqin Li
Polystyrene nanoplastics (PS-NPs) are emerging environmental contaminants that may impair intestinal barrier integrity, but the involvement of macrophage inflammatory responses remains incompletely understood. Quercetin is a natural flavonoid with well-established anti-inflammatory and immunomodulatory properties. This study investigated the role of macrophage inflammatory responses in PS-NP-induced intestinal injury and evaluated the protective effects of quercetin. Male ICR mice were orally exposed to PS-NPs for 4 consecutive weeks, and the effects of quercetin intervention on colonic injury, inflammatory responses, tight junction-associated proteins, and macrophage polarization markers were evaluated. RAW 264.7 macrophages were used to further examine PS-NP-induced inflammatory responses and the effects of quercetin in vitro . An indirect Transwell co-culture system of RAW 264.7 macrophages and MODE-K intestinal epithelial cells was established to assess macrophage-mediated epithelial barrier alterations. NF-κB and STAT1 signaling activation was also examined. PS-NP exposure induced dose-dependent colonic histopathological injury, increased the expression of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6, and reduced the expression of the tight junction proteins ZO-1 and occludin. PS-NPs were also associated with a shift toward a pro-inflammatory macrophage phenotype, characterized by increased CD86 and decreased CD206 expression. Consistently, PS-NPs promoted inflammatory responses in RAW 264.7 macrophages and increased NF-κB p65 and STAT1 phosphorylation. In the Transwell co-culture system, MODE-K cells co-cultured with PS-NP-stimulated macrophages exhibited reduced tight junction-associated protein expression and disrupted junctional integrity. Quercetin treatment attenuated PS-NP-induced colonic injury and inflammatory responses, partially restored ZO-1 and occludin expression, modulated macrophage polarization-associated markers, and reduced NF-κB and STAT1 activation. These findings indicate that 50 nm PS-NP exposure induces intestinal inflammatory responses and barrier-associated injury accompanied by pro-inflammatory macrophage activation and altered NF-κB/STAT1 signaling. The co-culture findings further support the involvement of macrophage-derived inflammatory responses in epithelial barrier impairment. Quercetin attenuates PS-NP-induced intestinal injury, potentially in part through modulation of macrophage inflammatory responses accompanied by reduced NF-κB and STAT1 activation.
