Frontiers in Pharmacology最新文献

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.].

Objective: To systematically identify medications potentially causing male infertility or sperm abnormalities and provide risk alerts for clinical practice.

Methods: A pharmacovigilance study was conducted using the FAERS database (Q1 2004-Q2 2025) and EudraVigilance (EV) database (January 2002-October 2025). Adverse events related to male reproductive toxicity were screened using the MedDRA dictionary. Drug safety signals were detected using ROR, PRR, IC, and EBGM, with reliability enhanced through cross-database validation and dechallenge/rechallenge analyses.

Results: The study included 1,955 FAERS cases and 1,384 from EV, with a median patient age of 35 years and 37% being reproductive-age males (18-44 years). The median time to event onset was 132 days, consistent with the spermatogenic cycle. Cross-validation identified 19 high-risk drugs, including hormonal agents (finasteride, dutasteride, testosterone), antineoplastic drugs (bleomycin, vinblastine, hydroxycarbamide), and antidepressants (citalopram, paroxetine). Finasteride satisfied both dechallenge and rechallenge criteria, providing strong evidence for causality. Signals concentrated in three major categories: genitourinary and sex hormones, dermatological preparations, and antineoplastic agents. Stratified analysis showed that both consumer and healthcare professional reports identified 13 high-risk drugs, with high consistency for major drugs (finasteride, testosterone), confirming result robustness.

Conclusion: This pharmacovigilance study identified 19 high-risk drugs for male infertility across hormonal agents, antineoplastic drugs, and antidepressants. These findings underscore pre-prescription, risk-stratified fertility counseling for reproductive-age males, prioritizing sperm cryopreservation before chemotherapy and considering it selectively for 5α-reductase inhibitors, testosterone, or antidepressants.

Coptis chinensis (Huanglian), a key component in numerous classical Chinese herbal formulas, is traditionally applied for treating metabolic diseases based on its activity including clear heat, dry dampness, purge fire, and detoxify. Berberine (BBR), one key active component from Coptis chinensis, was contained in numerous classical Chinese herbal formulas for improving insulin resistance and regulating blood glucose levels, making them applicable for diabetes mellitus (DM) treatment. Clinical trials confirm that BBR monotherapy reduces glycated hemoglobin (HbA1c) by 1.5% in T2DM patients comparable to metformin. This review aims to explore its applications and current research progress in DM therapy. This article systematically reviews the modern separation, extraction, and purification techniques for BBR, its molecular pharmacological mechanisms, and advances in novel delivery technologies for diabetes treatment. This review synthesizes evidence that BBR exerts its anti-diabetic effects through multi-tiered mechanisms converging on the amelioration of insulin resistance and systemic inflammation. The findings provide a theoretical foundation for optimizing BBR's clinical application and promote the transformation of traditional Chinese medicine from empirical usage to a scientific and standardized therapeutic paradigm. By integrating BBR's multi-target pharmacology with cutting-edge delivery technologies, this review provides a transformative perspective, positioning BBR not merely as a natural product but as a scaffold for the rational development of next-generation, multi-target diabetes therapeutics.

Uveal melanoma (UM) represents the most common primary intraocular malignancy in adults and remains a formidable clinical challenge due to its high metastatic potential and characteristically limited response to conventional systemic therapies. While the combination of radiotherapy and immunotherapy has emerged as a promising multimodal strategy for managing this complex malignancy, its efficacy is significantly constrained by profound individual variations in tumor biology, immune microenvironment composition, and dynamic treatment response patterns. In recent years, artificial intelligence (AI) has fundamentally transformed the landscape of precision oncology by enabling sophisticated image analysis, robust data-driven prediction, and seamless integration of heterogeneous multi-omics information. Within the specific context of uveal melanoma, AI-driven computational models have demonstrated significant potential to accurately predict therapeutic outcomes, quantitatively characterize the tumor immune microenvironment, and optimize radiotherapeutic strategies on a personalized basis. This comprehensive review critically examines and synthesizes recent progress in AI applications for immunoradiotherapy in uveal melanoma, systematically exploring their transformative potential to refine diagnostic accuracy, enhance treatment precision, and ultimately improve long-term patient outcomes through intelligent, data-driven personalized medicine approaches that bridge multiple disciplinary boundaries.

Background: Novel Psychoactive Substances (NPS) emerged in the early 2000s as chemically designed alternatives to circumvent laws which internationally control drugs. There is limited evidence that NPS are produced in the UK, whereas China has long been recognised as a primary source of NPS. This study aimed to evaluate the relative impact of UK, Chinese, and UN legislative controls on the availability of NPS in the UK, as evidenced by post-mortem detections of NPS in deaths.

Methods: Deaths reported to the National Programme on Substance Use Mortality (NPSUM) which occurred 2007-2022 were extracted for analysis. Drugs from the three major substance classes-opioids, stimulants and cannabinoids-which were detected in these deaths were categorised according to their control status as either classical substances (i.e., those under international control prior to 2007), NPS controlled in China, or other NPS.

Findings: Across all three drug classes, detections of classical substances dominated throughout the study period. Detections of NPS opioids-primarily fentanyl analogues-peaked in 2017, NPS stimulants-notably cathinones-in 2015, and synthetic cannabinoid receptor agonists in 2018 and 2021. Whilst UK legislative controls (the Misuse of Drugs Act 1971, Temporary Class Drug Orders, the Psychoactive Substances Act 2016) were generally implemented first, reductions in NPS detections were more closely associated with the introduction of Chinese legislations - in particular the 2021 Chinese generic ban on synthetic cannabinoids which resulted in an almost complete disappearance of these compounds in UK deaths in 2022.

Conclusion: The findings of this study indicate that the most effective way to reduce NPS availability in the UK is via legislation in producer countries, as evidenced by substantial declines in their detections in deaths following their control in China. This reliance on international controls places the UK in a vulnerable position, as its domestic drug landscape is being shaped largely by the pace and scope of independent international legislations. To achieve and maximise effectiveness, UK drug policy needs to integrate harm reduction measures alongside the introduction of legislative controls, whilst also encouraging international efforts to bring in global control of problem materials.

[This retracts the article DOI: 10.3389/fphar.2024.1345645.].