Frontiers in Pharmacology最新文献

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.

Background: Stir-fried atractylodis macrocephalae rhizoma (AMR) with aurantii fructus (AF) (SFALCA), a classical prescription of traditional Chinese medicine (TCM), has been widely used for promoting gastrointestinal health for centuries, with multiple pharmacological properties such as anti-tumor, anti-inflammatory, anti-aging, antioxidant, and antibacterial effects. Inflammatory bowel disease (IBD) is an immune-mediated chronic gastrointestinal inflammatory disorder that causes long-term distress to patients. Despite its widespread use, the specific effects of SFALCA on intestinal barrier function and underlying mechanisms remain unclear. Furthermore, interspecies discrepancies in animal studies and the physiological constraints of existing in vitro models synergistically limit the translational potential of current findings on this botanical combination.

Methods: To investigate the active components, mechanisms of SFALCA in treating IBD and assesses its safety. We designed an innovative organ-on-a-chip system to simulate the human intestinal and liver environment. By stimulating with LPS/PMA, we established an in vitro IBD model and intervened with SFALCA and its extracts. Immunofluorescence staining was used to evaluate the success of the model. TEER measurements were employed to assess the integrity of tight junctions. Alcian Blue staining characterizes the expression of acidic mucins in HT-29 cells. The levels of inflammatory cytokines and the human albumin were measured using ELISA kits. The cytotoxicity of TCM to liver was evaluated by CellTiter-Glo® 3D test according to the manufacturer's instructions. Flow cytometric analysis was used to detect the polarization of macrophages in intestinal inflammation model after drug treatment. RNA-seq analysis was used to identify key targets and pathways.

Results: The results showed that SFALCA and its extracts significantly increased transepithelial electrical resistance (TEER) and Zonula occludens-1 (ZO-1) expression, while inhibiting LPS/PMA-induced IL-6 levels and the proportion of M1 macrophages. Further analysis revealed that the main active components of SFALCA, Atractylenolide I and Naringin, exert anti-inflammatory effects by inhibiting the Interleukin-17C (IL-17C) mediated positive feedback loop. Additionally, organ-on-a-chip technology confirmed that SFALCA showed no significant toxicity to the liver.

Conclusion: In conclusion, this study elucidates the active components and mechanisms of SFALCA in treating IBD and assesses its safety, providing a reliable in vitro platform for future therapeutic strategies.

Endometriosis (EMs) is a gynecological inflammatory disease that depends on estrogen. Its chief symptoms include dysmenorrhea, chronic pelvic pain, reduced fertility, and pelvic masses. Although various hormonal therapies and surgical treatments are available, their long-term effectiveness is limited, recurrence rates are high, and side effects are significant. Programmed cell death (PCD) is a genetically regulated mechanism of cell clearance that includes apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. Numerous studies showed that dysregulation of PCD is strongly associated with the development of EMs, suggesting that targeting key molecular mechanisms of PCD could be a promising therapeutic strategy. Natural products, known for their multitarget activity and low toxicity, show unique advantages in modulating PCD in EMs. This review elucidates the regulatory mechanisms of various PCD pathways in EMs and their interactions with key signaling cascades, including PI3K/Akt/mTOR, MAPK, NF-κB, and Bcl-2. Furthermore, it explores how natural products modulate these PCD mechanisms and related pathways, providing insights into their therapeutic potential at the molecular level. We used "endometriosis," "programmed cell death," "natural products", and "signaling pathway" as keywords to systematically search the PubMed, Web of Science, and CNKI databases for relevant literature published in the past 10 years. A total of 55 studies were included, highlighting recent advances in regulating EMs progression through PCD modulation by natural products. The goal of this review is to provide a theoretical foundation for improving current treatments for EMs and to offer practical recommendations for future research.

The Signal Amplification, Binding affinity, and Receptor-activation Efficacy (SABRE) model is the most recent general and quantitative model of receptor function. A specific extension of the SABRE model enables the determination of K_d (the equilibrium dissociation constant of the agonist-receptor complex) and q (the fraction of receptors remaining operable after pretreatment with an irreversible receptor antagonist) from exclusively functional data. In the present investigation, we reevaluated the concentration-effect (E/c) data of our related recent study on the SABRE model to assess the properties of our newly developed multiline model, inspired by professional criticism of our previous study in question. We have found this multiline model, constructed within the framework of the SABRE model, to be capable of providing reliable results via one global fitting (i.e., with a single unified fit), even for our somewhat challenging data (containing some uncertainty). The multiline model that proved to be the most suitable for the current data was a relatively complex, six-model global fitting. These results further emphasize the significance of finding the best way to fit the equations of the SABRE model to the functional data to be evaluated.

Background: Curcumin is a biologically active substance present in turmeric. It has recently been suggested for its protective potential against a wide variety of chemical-induced toxicities.

Purpose: This systematic review aims to summarize current evidence on the protective effects of curcumin against chemical-induced toxicity, with particular emphasis on its impact on the male reproductive system.

Methods: A literature search was conducted using the major databases PubMed®, Scopus®, Web of Science®, and ScienceDirect®, up to December 2024. This review encompassed studies assessing curcumin's protective role against chemical toxicity, both in vitro and in vivo. Extracted data included the type of chemical agent, dosage, curcumin formulation, and reported toxicity outcomes.

Results and discussion: A total of 31 studies were included in the present review based on the established inclusion criteria. The toxicants studied contained heavy metals (lead and cadmium), pesticides (e.g., Malathion), and industrial solvents (notably titanium dioxide nanoparticles). Curcumin has demonstrated significant protective effects through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, and modulation of detoxification enzymes. Interestingly, curcumin supplementation was associated with reduced oxidative stress markers and improved histopathological findings across various animal models. The effective dose varied widely across studies, with most showing positive effects at doses between 50 mg/kg and 200 mg/kg.

Conclusion: The results of this systematic review suggest that curcumin holds promise for preventing various chemical-induced toxicities. Its diversified mechanisms of action show promise as a therapeutic agent for the relief of chemical toxicity. Nonetheless, additional studies are required to determine the most effective dosing strategies, examine bioavailability, and assess the safety of long-term use.

[This retracts the article DOI: 10.3389/fphar.2024.1343936.].