Frontiers in Pharmacology最新文献

Background: The overexpression of the NorA efflux pump is known to be an important factor in the antimicrobial resistance mechanism of Staphylococcus aureus. Therefore, NorA inhibition can help disarm this pathogen and tackle antimicrobial resistance. In this study, we aim to unravel the molecular properties of prenylated (iso)flavonoids from Fabaceae as potential NorA inhibitors and to propose leading compounds for future research.

Methods: A collection of 37 prenylated isoflavonoids and flavonoids (obtained by purification, chemically synthesized, or commercially purchased), collectively referred to as (iso)flavonoids, was evaluated for its activity against norA-overexpressing Staphylococcus aureus using the checkerboard assay with ciprofloxacin (NorA substrate) and erythromycin (primarily non-NorA substrate), in combination with ethidium accumulation assays. Moreover, a norA-knockout Staphylococcus aureus strain was used to corroborate the specificity of the observed effects. Subsequently, in silico binary QSAR and pharmacophore models were developed to elucidate the key molecular properties for potential NorA inhibition.

Results: Seven prenylated (iso)flavonoids, namely, 8-prenylnaringenin, 6-C,7-O-diprenylnaringenin, glabrene, neobavaisoflavone, wighteone, licoisoflavone A, and glycyrrhisoflavone, potentiated ciprofloxacin up to 8-fold in norA-overexpressing and up to 2-fold in norA-knockout strains at 10 μM, without any membrane permeabilization effects. Moreover, prenylated (iso)flavonoids potentiated erythromycin in norA-overexpressing Staphylococcus aureus only up to 2-fold. Binary QSAR models were generated using datasets from the checkerboard and ethidium accumulation assays with a total prediction accuracy of up to 90% for active and 88% for inactive compounds. Based on QSAR models, the polar surface area, the balance of hydrophobicity and hydrophilicity, and the overall hydrophobicity were correlated with antibiotic potentiation and efflux inhibition of prenylated (iso)flavonoids. Moreover, in our study, we revealed that fractional negative polar surface area and formal (negative) charges are key properties that differentiate prenylated (iso)flavonoids with antimicrobial activity from those that act as potential NorA inhibitors. A pharmacophore model provided the basis for further optimization of prenylated (iso)flavonoids, mainly neobavaisoflavone and wighteone, as potential NorA inhibitors.

Conclusion: In our study, we provide, for the first time, predictive QSAR models of prenylated (iso)flavonoids as potential NorA inhibitors and propose two potential leads based on this family of plant-derived compounds. Future research on the specificity and validation of prenylated (iso)flavonoids as NorA inhibitors is required.

Chronic kidney disease (CKD) presents a significant global health concern due to its progressive impact on kidney function, and associated complications. This narrative review highlights the role of traditional system of medicine and comprehensive approach to managing chronic kidney disease (CKD) including their molecular mechanisms and therapeutic roles. The interdependence of physical, mental, and spiritual wellbeing is acknowledged by AYUSH, and other indigenous traditions, which emphasize on botanical drugs with proven nephroprotective qualities in addition to dietary changes, lifestyle adjustments, and mind-body therapies. For instance, traditional botanical drugs have shown nephroprotective effects in both preclinical and clinical trials. Yoga activities promote overall wellbeing, which is particularly beneficial for individuals with chronic kidney disease. Our aim is to explore and integrate traditional medicine with modern nephrology practices for enhancing CKD management. However, the review presents the brief importance of this integration and challenges such as the need for robust clinical trials to substantiate safety and efficacy. It also discusses the legal and quality control concerns related to botanical drugs. Overcoming these hurdles is paramount for the successful assimilation of traditional medicine systems with modern healthcare practices. The review also contains the synergistic blend of contemporary nephrology with ancient healing systems like AYUSH offering a compelling approach to CKD treatment and nephroprotection.

The term tumour microenvironment (TME) encompasses the coexistence of microorganisms and different cellular elements including endothelial cells, macrophages, cancer-associated fibroblasts and a complex network of microvessels. Integration of tumour immunity and intratumoural microbiome into anti-cancer strategies represents a promising frontier in precision oncology (for instance in case of solid cancers, such as pancreatic or colorectal tumours). Characterization of the intratumoural microbial signature has emerged as a critical step in drug discovery, influencing therapeutic efficacy as well as resistance. There are several approaches, such as elimination of pathogenic microorganisms within the TME, modulation of specific microbial-immune axes, including interactions among microbial species that may enhance or suppress tumour progression, and exploitation of bacterial strains engineered to express pro-drug-converting enzymes for localized tumour therapy via intratumoural injection. Furthermore, tumour organoid-immune co-culture models, particularly when combined with 3D bioprinting technologies, offer robust experimental platforms for dissecting tumour-microbiome-immune crosstalk. The reciprocal communication between the immune system and the tumour-associated microbiome/metabolome highlights novel opportunities for therapeutic innovation in oncology and immuno-oncology.

Introduction: Cannabis sativa L. roots are traditionally used to manage gastrointestinal (GI) disorders; however, experimental pharmacological evidence supporting these uses remains limited. This study investigated the chemical profile, safety, and GI-related pharmacological effects of an ethanolic extract of C. sativa roots (CEECs).

Methods: Chemical characterization was performed by spectrophotometric determination of total triterpenes and HPLC profiling. Safety and pharmacological effects were assessed through acute oral toxicity testing, antibacterial assays, and in vivo murine models of gastric emptying, diarrhea, and ethanol-induced gastric ulcer.

Results: CEECs showed a total triterpene content of 67.64 ± 5.39 μg LE·mg^-1, and HPLC analysis detected p-coumaric acid and N-trans-feruloyltyramine. In vivo, CEECs significantly delayed gastric emptying at 50 mg·kg^-1 (P = 0.0033) and reduced fecal output in the castor oil-induced diarrhea model at 50 (P < 0.001) and 100 mg·kg^-1 (P = 0.0233), with no effect in the magnesium sulfate-induced model. CEECs also significantly reduced ethanol-induced gastric mucosal injury at 50 mg·kg^-1 (P = 0.0484) and 100 mg·kg^-1 (P = 0.0164). No signs of acute toxicity were observed at 2000 mg·kg^-1. Antibacterial activity against Staphylococcus aureus strains was weak under the tested conditions.

Discussion: These findings provide experimental support for the traditional use of C. sativa roots in GI disorders and indicate their potential as a non-psychoactive source of bioactive constituents.

Scorpions, having inhabited the Earth long before the emergence of humans, represent an ancient lineage of arthropods. While often regarded with fear due to their potential to induce severe pain or fatal envenomation, scorpion venoms constitute complex cocktails of bioactive molecules known as toxins. Notably, these toxic components have been repurposed in medical research as valuable sources for therapeutic development. In traditional Chinese medicine (TCM), the venom of Buthus martensii Karsch (BmK), commonly referred to as the Chinese scorpion, has been historically employed in the treatment of various neurological disorders, including epilepsy, stroke, glioma, and pain. The principal bioactive constituents of BmK venom are polypeptides that selectively target membrane ion channels. Among these, defensins and short-chain toxins (28-40 amino acids in length) have been identified as key modulators of potassium channels, TRP channels, and chloride channels. These short-chain peptides exhibit several distinct pharmacological advantages, including efficient tissue penetration due to their low molecular mass, remarkable target specificity for particular ion channel isoforms or states, inherently low immunogenicity, and considerable structural versatility that facilitates engineering (e.g., fusion strategies, point mutations) to optimize pharmacokinetics and pharmacodynamics. As such, they represent promising molecular scaffolds for drug design aimed at addressing unmet clinical needs in neurology. We summarize the most advanced drug candidates derived from BmK defensins and short-chain toxins, which exhibit activity against Kv1.3, BK, TRPV1, and other channels implicated in epilepsy, neuroinflammation, glioma, and pain. Structural and functional insights into these peptides reveal mechanisms underlying their target specificity and pharmacological advantages, such as blood-brain barrier penetration and low immunogenicity. This review underscores the originality of BmK peptides as molecular tools and lead compounds for next-generation neurology therapeutics, providing a focused resource for researchers in ion channel pharmacology and peptide-based drug design.

Ovarian cancer remains a lethal disease marked by profound therapeutic resistance, largely orchestrated by a complex tumor microenvironment (TME) governed by metabolism-immune crosstalk. This review focuses on the spatiotemporal dynamics of the metabolism-immune axis in ovarian cancer progression and resistance, with particular emphasis on how cutting-edge spatial multi-omics technologies reveal previously unrecognized layers of intratumoral heterogeneity and geographic organization that cannot be captured by bulk analyses. Using tools such as MALDI-MSI, GeoMx DSP, and CODEX, these approaches enable high-resolution, spatially resolved mapping of metabolite gradients (e.g., lactate, lipids, kynurenine), immune cell niches, and immunometabolic checkpoints within distinct tumor regions. Such spatial profiling uncovers how metabolic reprogramming-dysregulated glycolysis, lipid metabolism, and glutaminolysis-drives localized immunosuppression and chemoresistance through compartment-specific interactions among tumor cells, cancer-associated fibroblasts (CAFs), adipocytes, and immune populations. These geographically defined insights reshape our understanding of therapeutic failure and highlight precise, location-aware vulnerabilities. Accordingly, we propose spatially informed therapeutic strategies, including regional glycolysis inhibition, glutaminase blockade, lipid pathway interference, and their rational combination with immune checkpoint inhibitors (ICIs), to disrupt pathogenic metabolic-immune circuits and improve immunotherapy outcomes. Looking ahead, advances in vivo spatial imaging, gut microbiota modulation, and AI-powered integrative multi-omics frameworks promise truly personalized treatment of ovarian cancer.

Objectives: Drug-induced liver injury (DILI) is a recognized adverse drug event. Although most cases present with acute hepatic damage, evidence indicates that a proportion progress to persistent liver injury. The absence of a standardized definition for chronic DILI has contributed to significant discrepancies in reported incidence rates across clinical studies. This meta-analysis aims to determine the pooled incidence of chronic DILI, providing robust epidemiological evidence.

Methods: This meta-analysis was conducted in accordance with the PRISMA and MOOSE guidelines. A systematic search was conducted in PubMed, Web of Science, Embase and Cochrane Library databases from their respective inception dates to 11 July 2025. The quality of cohort studies was assessed using the NOS. A random-effects model was used to calculate the pooled incidence of chronic DILI, expressed as corresponding 95% confidence intervals (CIs). Subgroup analyses were performed to explore potential sources of heterogeneity. Publication bias was assessed and sensitivity analyses were conducted. All statistical tests were two-tailed, and a P value <0.05 was considered statistically significant.

Results: A total of 24 studies were included in the final analysis. The pooled incidence of chronic DILI (based on a duration of liver injury lasting more than 6 months without distinguishing the suspected drugs) was 14.09% (95% CI: 10.35%-18.29%; I ² = 80.76%). Four studies that reported the incidence of chronic DILI based on a 12-month follow-up (without distinguishing causative drugs) showed a pooled incidence of 7.95% (95% CI: 5.16%-11.24%; I ² = 54.8%). The pooled incidence of chronic DILI attributed to antimicrobial drugs (6-month follow-up) was 14.56% (95% CI: 10.86%-18.65%; I ² = 0%).

Conclusion: Chronic DILI accounts for a clinically certain proportion of DILI cases. Greater emphasis should be placed on the long-term management and follow-up of patients with DILI to mitigate the risk of chronic progression.

Systematic review registration: https://inplasy.com, identifier INPLASY202580021.

Background: Sintilimab is an effective PD-1 immune checkpoint inhibitor (ICI) for advanced non-small cell lung cancer (NSCLC). However, it can cause severe immune-related adverse events (irAEs) such as toxic epidermal necrolysis (TEN), a rare hypersensitivity reaction with significant mortality. Reports of Sintilimab-induced TEN are exceedingly rare, making its recognition and management crucial.

Case summary: A 60-year-old female with advanced NSCLC developed TEN 3 days after her second dose of Sintilimab. The condition progressed rapidly, with epidermal detachment affecting 85% of her body surface area (BSA). Immediate interventions, including high-dose corticosteroids, intravenous immunoglobulin, meticulous wound care, and infection control, led to gradual recovery. After 39 days of intensive care, the patient was discharged with complete healing of skin lesions and no significant complications.

Conclusion: This report highlights the potential for Sintilimab to induce life-threatening TEN, emphasizing the need for vigilant monitoring and prompt intervention during ICIs therapy.