Frontiers in Pharmacology最新文献

Background: Galgeun-tang (GGT) is a traditional Korean multi-component formulation composed of several botanical drugs and has long been prescribed for febrile and musculoskeletal disorders. With the global rise in obesity and obesity-related metabolic diseases, there is increasing demand for safer and multi-targeted therapeutic strategies. However, the systemic metabolic effects and anti-obesity potential of GGT remain incompletely understood.

Methods: The anti-obesity effects of GGT were evaluated using a tiered experimental approach comprising C2C12 myotubes, high-fat diet (HFD)-induced obese C57BL/6J mice, and Caenorhabditis elegans (C. elegans) exposed to high-glucose conditions. In vitro analyses assessed glucose uptake, gene expression, and protein signaling pathways. In mice, body weight, glucose tolerance, serum biochemical parameters, histological changes, and hepatic and adipose gene expression were examined. In C. elegans, lifespan, lipid and glucose accumulation, and insulin signaling-related gene expression were analyzed following treatment with GGT or metformin (MET).

Results: GGT enhanced glucose uptake and increased the expression of insulin-responsive and mitochondrial regulatory genes in C2C12 myotubes. In HFD-fed mice, GGT attenuated body weight gain, improved glucose tolerance and insulin sensitivity, and alleviated hepatic steatosis and adipose hypertrophy, accompanied by suppression of lipogenic genes and induction of β-oxidation markers. In C. elegans, GGT reduced lipid and glucose accumulation, prolonged lifespan, and modulated the expression of insulin signaling-related genes, including daf-16 and daf-2. Across models, GGT exerted metabolic benefits in a dose- and context-dependent manner, with effects comparable to those of MET.

Conclusion: GGT improves obesity-related metabolic dysfunction by coordinately regulating glucose homeostasis, lipid metabolism, and energy expenditure across cellular, nematode, and murine models. These findings provide preclinical evidence supporting GGT as a multi-targeted herbal intervention for obesity and metabolic disorders and warrant further targeted mechanistic studies and clinical investigations.

Phosphodiesterase 1B (PDE1B) and phosphodiesterase 10A (PDE10A), members of the phosphodiesterase superfamily, are responsible for cyclic nucleotide hydrolysis, thereby regulating key intracellular signaling pathways such as cAMP response element-binding protein (CREB) activation and brain-derived neurotrophic factor (BDNF) gene transcription. Both enzymes are predominantly expressed in the brain and co-localize with dopamine receptors, positioning them as potential targets for addressing schizophrenia, a disorder characterized by dopamine system dysfunction. PDE1B inhibition enhances D1-receptor signaling, ameliorating negative symptoms and cognitive deficits, while PDE10A inhibition modulates D2-receptor activity, potentially alleviating positive symptoms. Together, these mechanisms suggest that targeting PDE1B and PDE10A could offer an innovative avenue for the comprehensive management of schizophrenia. Recent advancements in structural and synthetic methodologies have significantly facilitated the design of small-molecule PDE1B and PDE10A inhibitors. Among these, ITI-214 (PDE1 inhibitors) and MK-8189 and EVP-6308 (PDE10A inhibitors) have proceeded to clinical trials, demonstrating promising therapeutic agents. Furthermore, dual PDE1B/10A inhibitors remain underexplored, with only compound 2 undergoing limited preclinical evaluation for its pharmacological efficacy and safety. Studies published between 2014 and 2025 were retrieved from the PubMed, Web of Science, and Scopus databases, highlighting advances in PDE1B and PDE10A inhibitors. This review provides a detailed overview of the structural and synthetic strategies employed in developing PDE1B, PDE10A, and dual PDE1/10 inhibitors, with a focus on their binding sites and structure-activity relationships (SARs). By addressing the limitations of current candidates and emphasizing the need for dual inhibitors, this review aims to guide future research efforts toward the discovery of more selective, potent, and clinically viable PDE1B and PDE10A inhibitors for schizophrenia.

Background: SET domain-containing 2 (SETD2), the sole histone H3 lysine 36 trimethyltransferase, has emerged as a critical tumor suppressor across multiple cancer types. Recent evidence suggests SETD2 orchestrates complex interactions between metabolic reprogramming and immune evasion in the tumor microenvironment.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)2020 guidelines, we systematically searched PubMed, EMBASE, Web of Science, and Cochrane databases from inception through April 2024. We included studies investigating SETD2's role in tumor metabolism and immunotherapy response. Meta-analysis was performed using random-effects models to assess the association between SETD2 status and clinical outcomes. Protocol was developed a priori but not registered due to the exploratory nature of this emerging field.

Results: Of 2,847 initially identified records, 78 studies met inclusion criteria, encompassing approximately 12,400 patients across 12 cancer types. SETD2 loss was associated with metabolic reprogramming (pooled OR: 2.34, 95% confidence interval (CI): 1.89-2.89, p < 0.001) and decreased immunotherapy response (hazard ratio (HR): 1.56, 95% CI: 1.32-1.84, p < 0.001). Substantial heterogeneity was observed (I-squared heterogeneity statistic (I²) = 52-68%) and explored through subgroup and sensitivity analyses. Mechanistically, SETD2 deficiency promoted glycolytic shift, lipid metabolism dysregulation, and immunosuppressive metabolite accumulation. Furthermore, SETD2 loss correlated with reduced CD8⁺ T cell infiltration and increased regulatory T cell presence.

Conclusion: This meta-analysis identifies SETD2 as an epigenetic regulator linking tumor metabolic reprogramming to antitumor immunity. SETD2 loss was associated with altered metabolic states and reduced clinical benefit from immune checkpoint inhibitors, with the strongest translational relevance observed in ccRCC and substantial evidence in NSCLC and CRC. These findings support further prospective validation and standardized assessment of SETD2, as well as exploration of rational metabolic-immunotherapy combination strategies in SETD2-deficient tumors.

Background: Rituximab has become an important therapeutic option for nephrotic syndrome (NS), and its adverse event profile is generally well characterized. However, reports of acute hypokalemia specifically occurring in the post-infusion period remain rare. We aimed to present and analyze cases of this distinct timing of electrolyte disturbance.

Case presentation: This case series describes two adult patients with NS who developed acute, severe hypokalemia in the hours immediately following a rituximab infusion. Case 1: A 20-year-old male with steroid-dependent minimal change disease developed progressive quadriceps weakness and severe hypokalemia (potassium 1.79 mmol/L) several hours after his fifth rituximab infusion. His previous four infusions had been uneventful. Case 2: A 46-year-old male with membranous nephropathy presented with marked mental fatigue and severe hypokalemia (potassium 2.34 mmol/L) shortly after his sixth cumulative rituximab infusion, following five prior tolerated infusions. Common precipitants of hypokalemia were absent. Both patients responded promptly to potassium supplementation, with full symptomatic recovery and normalization of serum potassium.

Conclusion: Severe hypokalemia can occur acutely after rituximab infusion in NS, even after prior uneventful exposures. Presentations may be delayed and nonspecific. Clinicians should monitor serum potassium before and after rituximab administration to enable timely recognition and management of this rare complication.

Renal cell carcinoma (RCC) is a prevalent, highly aggressive malignant tumor that affects the urinary system. RCC has a pronounced propensity for metastasis. Despite the widespread use of sunitinib as first-line therapy for advanced RCC, the occurrence of primary and acquired resistance is frequent and presents significant challenges for effective clinical management. Epithelial-mesenchymal transition (EMT) induction is mediated by hypoxia-HIF signaling, chronic inflammatory stimulation, stromal-tumor cell interactions, and metabolic reprogramming, which confers increased cellular plasticity, migratory potential, and survival benefits. EMT activation is closely associated with reorganization of cellular signaling networks under tumor microenvironment stress, the initiation of alternative angiogenic pathways, and the enhanced anti-apoptotic capacity, all of which contribute to the development of sunitinib resistance. This review systematically summarizes current evidence involving the molecular basis of EMT-driven sunitinib resistance in RCC and investigates potential therapeutic targets, establishing a conceptual foundation for the development of novel strategies to counteract resistance and enhance clinical efficacy.

This study investigated the clinical characteristics and risk factors of bone marrow suppression in rheumatoid arthritis (RA) patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) to provide evidence for improving medication safety. We retrospectively analyzed clinical data from 30 RA inpatients with csDMARDs-induced bone marrow suppression hospitalized at the Affiliated Hospital of Zunyi Medical University between August 2022 and January 2025. Methotrexate was part of the treatment regimen for twenty-seven patients, accounting for 90% of the cohort. Medication non-adherence was identified in fifteen patients, representing 50% of cases, with unauthorized dose escalation being the primary pattern. All patients developed severe Grade III to IV bone marrow suppression. Pancytopenia was observed in twenty patients, constituting 66.7% of the total. Common complications included febrile neutropenia, oral mucositis, and gastrointestinal bleeding. Following comprehensive treatment, all patients achieved hematologic recovery and were discharged. Our findings indicate that medication non-adherence, particularly self-driven escalation of methotrexate dosage, is a critical risk factor for life-threatening bone marrow suppression in rheumatoid arthritis patients. These results underscore the necessity of enhanced patient education, strict adherence monitoring, and rigorous hematologic surveillance for high-risk individuals.

Background: The extensively employed antineoplastic drug doxorubicin (DOX) is constrained in clinical utilization on account of its severe cardiotoxicity, and there persists a dearth of protective agents against doxorubicin-induced cardiotoxicity (DIC). Engeletin (ENG) is a natural product endowed with multiple biological activities and has manifested significant protective effects in various diseases. This study purports to explore the protective effects of ENG in DIC and elucidate the underlying mechanisms.

Methods: H9C2 cardiomyocytes and C57BL/6 mice were used to establish in vitro and in vivo models of DIC, and ENG was used for treatment. Cardiac function and structural changes in the mice were assessed by ultrasound, pathological section staining and transmission electron microscopy. Western blotting, Real-Time Quantitative PCR, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), serum biochemical detection, TUNEL staining, dihydroethidium (DHE) assay, and flow cytometry were employed to evaluate apoptosis, autophagy, oxidative stress, inflammation, mitochondrial damage, ANP and BNP both in vitro and in vivo. An AMPK inhibitor Compound C was utilized to validate the effect of ENG on the AMPK pathway.

Results: DOX diminished cardiac function and induced fibrosis in mice, resulting in significant cell apoptosis, oxidative stress, inflammation, autophagy dysregulation, and mitochondrial damage both in vitro and in vivo. Following ENG treatment, these conditions can be markedly ameliorated, especially in mitigating myocardial cell apoptosis, autophagy, and oxidative stress responses. It has been found that this effect is realized through the activation of the AMPK pathway. Moreover, utilization of an AMPK inhibitor CC impeded the protective effect of ENG on DIC.

Conclusion: ENG has mitigated DIC through the activation of the AMPK pathway, thereby rendering it a potential drug for the prevention and treatment of DIC.

Background: Post-marketing safety surveillance of Chinese Materia Medica (CMM) is challenged by multi-component chemical heterogeneity and the limited mechanistic interpretability of signals derived solely from spontaneous reports. The FDA Adverse Event Reporting System (FAERS) provides large-scale pharmacovigilance evidence, yet it is noisy, susceptible to reporting bias, and weakly linked to underlying biological mechanisms. We aimed to develop an FAERS-informed, clinically oriented framework to predict CMM-associated adverse drug reactions (ADRs).

Methods: We constructed an evidence-rich heterogeneous graph integrating CMMs, compounds, protein targets, and ADRs. To differentiate pharmacovigilance-derived statistical associations from binary molecular interactions, we augmented each CMM-ADR edge with a six-dimensional evidence feature vector (including semantic similarity, FAERS evidence as log-transformed report counts, source provenance, and topology-derived structural metrics) and used it to condition attention during message passing. We propose MSAT, a multi-scale heterogeneous graph neural network comprising: (i) an Evidence-Semantic Adaptive Gate to inject evidence-conditioned attention bias, (ii) a Hierarchical Signal Propagation layer to model cross-scale transduction from molecular mechanisms to clinical phenotypes, and (iii) a Hub-Calibrated Inference module to mitigate hub-driven bias. We evaluated MSAT using stratified 10-fold cross-validation, stress-tested robustness under increasing class imbalance up to a 1:10 positive:negative ratio, and assessed cold-start generalization. High-confidence predicted results were further examined via external database concordance and literature support.

Results: In stratified 10-fold cross-validation on 27,062 curated CMM-ADR associations, MSAT achieved strong performance (AUC = 0.9792, AUPRC = 0.9766) and outperformed representative heterogeneous GNN baselines. MSAT remained robust under severe class imbalance (up to 1:10) and demonstrated favorable generalization in cold-start settings. Among the top 15 high-confidence predicted results absent from the labeled positives, 13/15 (86.7%) were supported by independent database or literature evidence. For example, MSAT prioritized a potential liver-injury signal for Aiye (Artemisia argyi) (predicted ADR: drug-induced liver injury, DILI), consistent with external evidence.

Conclusion: By unifying FAERS pharmacovigilance evidence with multi-scale biomedical mechanisms in a heterogeneous graph learning framework, MSAT enables robust prediction and prioritization of CMM-associated ADR risks. This framework can support hypothesis generation and risk triage for post-marketing safety surveillance of complex Chinese Materia Medica products.

Background/objectives: Extracellular vesicles (EVs) carrying therapeutic cargos represent a promising strategy for cancer treatment by enabling the targeted delivery of genetic material directly to cancer cells. This study aimed to evaluate the effect of EVs loaded with the TIMP-2 gene on the expression of matrix metalloproteinases (MMPs 1, 2, and 9) in lung cancer cells (A549).

Methods: EVs derived from A549 cells were isolated by gradient centrifugation and ultracentrifugation. The coding sequence for TIMP-2 (tissue inhibitor of metalloproteinases 2) was amplified by PCR using cDNA derived from HUVEC cells. As-constructed plasmid (pTIMP-2) was introduced into the EVs by electroporation, and then the pTIMP-2-implanted EVs were subjected to PCR and NTA analysis. Additionally, the activity of MMP-1, MMP-2, and MMP-9 was determined by voltammetry in intact A549 cells and in A549 culture media.

Results: Electroporation was found to demonstrate a good potential as an exogenous technique for uploading plasmid DNA into EVs. The results demonstrated that the as-uploaded EVs carrying the pTIMP-2 gene cargo do not broadly alter the overall balance of MMP-1 in pristine A549 cells. However, pTIMP-2-loaded EVs significantly modulate MMP-2 and MMP-9 expression in these cells, highlighting their potential as biological therapeutic moieties.

Conclusion: Our findings suggest a rational approach for exploring EV-based gene transfer targeting MMPs in lung cancer.