Frontiers in Pharmacology最新文献

Irritable bowel syndrome (IBS) is a complex and multifaceted disorder of the gut-brain interaction. Recent evidence suggests that γ-aminobutyric acid (GABA) may be involved in the development of IBS symptoms. Indeed, the GABAergic system exerts many gastrointestinal functions, such as modulation of visceral pain, intestinal motility, intestinal barrier integrity and immune response. GABA receptors and transporters are present and may influence intestinal functions at multiple levels: in the central nervous system, in the enteric nervous system and at the gut epithelial level. Furthermore, the gut microbiota is capable of producing GABA. This may also suggest a direct link between. intestinal microbiota composition and GABAergic tone within the microbiota gut-brain axis. Confirming the involvement of GABAergic dysregulation in IBS, altered GABA signaling and reduced GABA levels have been observed in this disease, especially in diarrhea-predominant subtypes. This review explores the possible roles of GABAergic dysregulation in IBS pathogenesis across multiple levels: in the central nervous system circuits, at the intestinal level, and in the microbiota-gut-brain axis interactions. Moreover, preclinical and limited clinical data regarding possible therapeutic approaches targeting the GABAergic system in IBS are discussed in the review. These include GABA receptor modulators, dietary supplements, probiotics producers of GABA and novel combinations such as GABA-Melissa officinalis. However, despite promising results, current evidence on these approaches is limited and mainly based on animal models. Therefore, randomized clinical trials are needed to establish the efficacy of GABA-based products in IBS management.

The global prevalence of type 2 diabetes mellitus (T2DM) continues to rise, posing significant challenges for existing therapeutic strategies, which are often limited by poor bioavailability, high cost, and adverse effects. Natural polysaccharides have emerged as promising metabolites due to their broad sources, favorable safety profiles, and stable efficacy. This review systematically summarizes the sources, structural characteristics, and mechanisms of action of natural polysaccharides with anti-T2DM activity, with a particular focus on their multi-target regulatory effects in mitigating T2DM and its complications. By integrating structural diversity-such as molecular weight, glycosidic linkage patterns, and branching architecture-with functional outcomes across key pathogenic pathways including insulin resistance, inflammation, oxidative stress, gut microbiota dysbiosis, and mitochondrial dysfunction, this work elucidates fundamental structure-activity relationships. The review not only bridges existing knowledge gaps in multi-mechanistic integration but also provides a conceptual framework for the structure-based development of polysaccharide-based therapeutics against T2DM, highlighting future research directions.

Introduction: Infantile hemangioma (IH) is a common benign vascular tumor in infants, often requiring intervention due to potential functional impairment and cosmetic concerns. Propranolol, a nonselective β-adrenergic receptor blocker, is the first-line therapy for IH, yet its mechanisms remain incompletely elucidated.

Methods: This prospective study investigated the systemic angiogenic protein profile changes in response to propranolol in 14 treatment-naïve IH infants compared to 14 healthy controls using antibody array analysis.

Results: We identified twenty-six angiogenic proteins significantly downregulated in pretreatment IH patients compared to healthy controls. After 3 months of propranolol treatment, six proteins including HB-EGF, TGFα, ANGPTL4, Follistatin, Tie-1 and PLGF were significantly upregulated. Bioinformatic enrichment analysis revealed that these proteins are involved in key biological processes and signaling pathways, including epithelial cell proliferation, angiogenesis regulation, VEGF signaling, ERBB-EGFR axis, Ras-MAPK, and PI3K-Akt pathways.

Discussion: These results suggest that propranolol treatment is associated with a rebalancing of dysregulated angiogenic proteins in IH, through modulating both pro- and anti-angiogenic factors to rebalance vascular homeostasis. Our study provides novel insights into the systems-level pharmacological actions of propranolol and proposes potential biomarkers for treatment response evaluation.

Background: Platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) are currently regarded as the standard treatment modalities for advanced non-small cell lung cancer (NSCLC) characterized by EGFR exon 20 insertion (ex20ins) mutations; however, their efficacy is suboptimal. Recent developments in targeted therapies, including agents such as amivantamab, mobocertinib, and sunvozertinib, have shown promise in patients with pretreated ex20ins-positive NSCLC. However, a comprehensive systematic review assessing the efficacy and safety of these later-line Targeted therapies has not yet been conducted.

Methods: A systematic search for studies pertaining to later-line treatment options for patients with ex20ins mutations was conducted using PubMed, Embase, and the Cochrane Library, with a cutoff date of 31 March 2025, without language restrictions. The primary endpoints of this review were the objective response rate (ORR) and disease control rate (DCR), whereas the secondary endpoints included progression-free survival (PFS), overall survival (OS), and the incidence of treatment-related adverse events (TRAEs).

Results: Eleven studies were included in this analysis, with efficacy data encompassing 788 participants and safety data involving 861 participants. The pooled ORR for novel targeted therapies in the later-line setting was 41.8% (95% CI: 35.3%-48.3%), and the DCR was 85.6% (95% CI: 80.1%-91.1%). The pooled median PFS from eight studies was 8.020 months (95% CI: 7.203-8.930), and the pooled median OS from four studies was 20.804 months (95% CI: 16.713-25.896). Subgroup analysis indicated that there were differences in the pooled ORR for patients with near-loop insertions and far-loop insertions (44.4% vs. 34.5%) or patients with or without baseline brain metastasis (36.4% vs. 47.5%), although neither difference was significant (both P > 0.05). The most common all-grade TRAEs were diarrhea (66.8%),rash (66.7%), paronychia (42.0%). Among grade ≥3 events, diarrhea was the most frequently reported (10.1%), followed by rash (8.2%) and anemia (2.7%).

Conclusion: Novel targeted therapies demonstrate superior efficacy and acceptable safety compared to conventional later-line treatments in advanced NSCLC with EGFR ex20ins mutations, though further validation through randomized controlled trials is warranted.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251056825. No amendments were made to the registered protocol after commencement of the review. The full review protocol can be accessed on the PROSPERO database (Registration number: CRD420251056825).

Importance: Hydroxyurea reduces severe disease among individuals living with sickle cell disease (SCD). These individuals experience high acute care utilization, but the associations between patterns of hydroxyurea utilization and healthcare utilization are not well investigated.

Objective: This study aimed to determine the association between hydroxyurea use and healthcare utilization among individuals with SCD in Tennessee (TN).

Design: We conducted a population-based, retrospective cohort study of individuals with SCD using secondary data analysis of Tennessee Medicaid, Medicare, and BlueCross BlueShield of Tennessee (BCBS-TN).

Participants: A total of 4,901 individuals with SCD were included in the study.

Exposure: Hydroxyurea adherence was estimated using the medication possession ratio (MPR).

Main outcomes and measures: The incidence rate ratios of hospitalizations, emergency department visits, and mortality were calculated using negative-binomial models.

Results: The prevalence of hydroxyurea prescription dispensation for the state was low (21% for TennCare, 21% for Medicare, and 17% for BCBS-TN). In TennCare and BCBS-TN, those younger than 18 had more hydroxyurea utilization, and individuals with HbSS or HbSβ⁰ thalassemia filled more hydroxyurea than those with other subtypes (30.5% in TennCare and 23.4% in BCBS-TN). The MPR for the entire state was 19.7%. There was a dose-response relationship between hydroxyurea adherence and the incidence of acute healthcare utilization, except in 18-25-year-olds. We also found lower mortality in those with higher hydroxyurea adherence.

Conclusion and relevance: In our pooled statewide analysis, hydroxyurea MPR was low. Higher hydroxyurea use was associated with decreased acute healthcare utilization and lower mortality. Interventions to support patient adherence and provider prescribing are required to improve health outcomes among individuals with SCD.

Background: Knee osteoarthritis (KOA) is a prevalent degenerative joint disease with limited effective treatment options. Oleanolic acid (OA) possesses promising anti-inflammatory and cartilage-protective properties, but its clinical application is hindered by poor solubility and rapid metabolism.

Purpose: This study aimed to develop an oleanolic acid-loaded liquid crystalline nanogel (OANG) for intra-articular delivery and to systematically evaluate its therapeutic effects and potential mechanisms in a rat KOA model.

Methods: OA-loaded nanoparticles were prepared and incorporated into a thermosensitive Poloxamer gel base to form OANG. A papain-induced KOA rat model was established. Rats were administered OANG (high/low dose) intra-articularly, with celecoxib as a positive control. Evaluations included behavioral tests, micro-computed tomography, histological analyses (hematoxylin and eosin, transmission electron microscopy, immunohistochemistry), enzyme-linked immunosorbent assay of synovial fluid, serum, and hippocampus, Western blot (WB), network pharmacology, and molecular docking.

Results: OANG exhibited sustained-release properties and improved joint lubrication. Treatment with OANG significantly alleviated KOA-induced pain and depression-like behaviors, reduced cartilage degradation and subchondral bone sclerosis, and downregulated levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6) and cartilage degradation markers (C-terminal cross-linked telopeptide of type II collagen, cartilage oligomeric matrix protein) in synovial fluid. It also enhanced antioxidant capacity (increased superoxide dismutase, glutathione peroxidase; decreased malondialdehyde) and modulated the expression of key cartilage proteins (increased Collagen II; decreased matrix metalloproteinase 13; regulated glycogen synthase kinase-3β/SRY-box transcription factor 9, β-catenin, and Yes-associated protein). Furthermore, OANG ameliorated hippocampal oxidative stress and inflammation (decreased Cleaved caspase-3, Malondialdehyde; increased IL-10). Network pharmacology and docking suggested the involvement of peroxisome proliferator-activated receptor gamma, mitogen-activated protein kinase 3, prostaglandin-endoperoxide synthase 2, and pathways such as estrogen signaling and cyclic adenosine monophosphate signaling.

Background: Abhraka Bhasma (Mica nanoparticles) is an Ayurvedic herbomineral medicine traditionally used in the management of conditions similar to breast cancer. Its rationale is based on its Dhatu-Pushtikara (tissue-nourishing), Rasayana (rejuvenating) and Tridosha-balancing properties, suggesting its potential for evaluation in integrative oncology.

Objective: This work aims to examine the therapeutic potential of Mica nanoparticles (Abhraka Bhasma) as an alternative medicine in the management of breast cancer.

Methods type of evidence: This mini-review analyses the preclinical and limited clinical evidence supporting Abhraka Bhasma (mica nanoparticles) as a potential adjunct in breast cancer management. The mechanistic basis was evaluated from in vitro and in vivo models.

Key findings: In vitro: Abhraka Bhasma exhibits dose-dependent cytotoxicity, apoptosis, immunomodulatory activity and inhibition of teratoma-formation in different cell lines. In vivo: studies support these findings, indicating enhanced DNA repair capacity, reduced genotoxicity, chemopreventive responses, immunostimulatory effects and modulation of oxidative stress.

Conclusion: The traditional Ayurvedic rationale for Abhraka Bhasma correlates with reported preclinical mechanisms. Thus, the ancient wisdom and modern evidence make Abhraka Bhasma an important part of integrative oncology, which offers a complementary strategy to improve patient outcomes. Available evidence on Abhraka Bhasma in cancer treatment is currently preclinical data (Level 5) and hypothesis generating only. To date, no RCTs or cohort studies (Levels 1-3) on the safety and efficacy of Abhraka Bhasma as an adjunct in breast cancer treatment have been published. To bridge the gap between traditional use and evidence based clinical application, a structured and systematic research pathway is essential.

Introduction: Polygonum multiflorum Thunb. (PM) is a representative traditional Chinese medicine (TCM) that exerts different effects in raw and processed forms. The hepatotoxicity of PM is markedly reduced after processing, whereas its hepatoprotective effects are enhanced.

Purpose: This study aimed to establish a novel comprehensive two-dimensional (2D) biochromatography system based on farnesoid X receptor (FXR), which is an important target in cholestatic liver injury (CLI), to investigate the material basis and mechanisms underlying the enhanced hepatoprotection and reduced hepatotoxicity of processed PM (P-PM).

Methods: A comprehensive 2D FXR biochromatography system was established by immobilizing FXR on 3-mercaptopropyltrimethoxysilane (MPTS)-modified silica gel. This system was used to identify the FXR-binding components in raw PM (R-PM) and P-PM. Molecular docking, surface plasmon resonance, and frontal affinity chromatography were used to validate the interactions. The hepatoprotective effects of emodin and physcion were assessed in α-naphthylisothiocyanate (ANIT)-induced CLI mouse models, and an FXR antagonist (Z-guggulsterone) rescue experiment was performed. The expression of FXR signaling-related proteins, including FXR, small heterodimer partner (SHP), bile salt export pump (BSEP), Na+-taurocholate cotransporting polypeptide (NTCP), and inflammatory cytokines, was assessed by Western blotting, real-time quantitative reverse transcription PCR, and immunofluorescence.

Results: The comprehensive 2D FXR biochromatography system successfully identified emodin and physcion as key FXR-binding components, with significantly increased content in P-PM. These components may contribute to the enhanced hepatoprotection and reduced hepatotoxicity of P-PM. In vivo, emodin and physcion alleviated ANIT-induced CLI, as evidenced by improved histopathological features and decreased serum levels of liver function markers. Mechanistically, both components upregulated the expression of FXR, BSEP, SHP, and NTCP while suppressing inflammatory cytokine expression. Their hepatoprotective effects and FXR-related upregulation could be disrupted by FXR antagonist Z-guggulsterone. These results suggest that emodin and physcion are key components contributing to the hepatoprotective effects of P-PM, likely through activation of the FXR signaling pathway and suppression of inflammation.

Conclusion: This study established a novel, efficient, rapid, and accurate comprehensive 2D FXR biochromatography system, which is suitable for screening targeted components in TCM, and can be extended to research on other TCMs.

Background: Multilocus Inherited Neoplasia Allele Syndrome (MINAS) describes individuals who harbor pathogenic or likely pathogenic (LP/P) germline variants in two or more distinct cancer predisposition genes. With the broader implementation of next-generation sequencing (NGS) and multigene panel testing, MINAS has been increasingly recognized.

Methods: We retrospectively evaluated 655 Turkish patients referred for hereditary cancer testing using two validated NGS panels. MINAS was defined as the presence of LP/P variants in at least two different genes.

Results: 14 patients (2.13%) met the criteria for MINAS. An additional 156 patients (23.8%) had single-gene LP/P variants. MINAS cases accounted for 8.2% of mutation-positive individuals. These patients showed diverse tumor types. Common gene combinations included BRCA1+MUTYH and CHEK2+PALB2.

Conclusion: This is the first MINAS-focused analysis from a Turkish cohort. Although uncommon, MINAS represents a significant subset of genetically high-risk individuals requiring tailored clinical management.

Introduction: Environmental enrichment enhances hippocampal synaptic plasticity, yet its influence on anesthetic action remains poorly understood. This study tested the hypothesis that enriched environment (EE) rearing modifies the inhibitory effects of propofol and desflurane on synaptic transmission within a novel limbic circuit slice preparation preserving amygdala-hippocampal connections.

Methods: Slices were obtained from male rats reared in either a standard environment (SE) or an EE. Electrophysiological recordings measured population spike (PS) amplitudes in CA1 pyramidal neurons.

Results: In slices from EE rats, the inhibitory effects of both anesthetics on PS amplitude were markedly potentiated compared with SE rats. The IC50 of propofol decreased from 3.3 × 10-4 M [IQR: 2.7 × 10-4 -3.5 × 10-4] in SE to 5.4 × 10-5 M [IQR: 5.1 × 10-5 -5.6 × 10-5] in EE (P = 0.002), whereas that of desflurane decreased from 10.4 vol% [IQR: 10.3-11.5] to 6.5 vol% [IQR: 4.8-7.1] (P = 0.002). Potentiation was more pronounced for propofol, which acts primarily through GABA receptors, whereas desflurane, with multiple molecular targets, showed a smaller potency change accompanied by an increased Hill coefficient, suggesting altered receptor binding cooperativity. Recovery of inhibitory tone following stimulus-induced disinhibition was accelerated in EE slices. This effect was most prominent with propofol, for which the recovery time constant decreased from 146.0 s [IQR: 110.6-642.8] in SE to 36.6 s [IQR: 25.5-48.9] in EE (P = 0.008).

Discussion: These findings demonstrate that rearing in an enriched environment enhances anesthetic potency by strengthening GABAergic inhibitory circuits and modifying pharmacological profiles at the network level. This enhancement was most evident for propofol, indicating that environmental factors can significantly influence anesthetic sensitivity within hippocampal circuits. Clinically, an individual's life history and environment may represent critical yet overlooked determinants of anesthetic requirements. These results highlight the importance of personalized pharmacology in anesthesia and suggest that standardized dosing of GABAergic agents may cause overdose in individuals with enhanced inhibitory function. Overall, this study provides mechanistic insights into how environmental neuroplasticity modulates anesthetic pharmacodynamics, advancing our understanding of interindividual variability in drug response and perioperative safety.