Frontiers in Pharmacology最新文献

[This retracts the article DOI: 10.3389/fphar.2021.628988.].

Background: Sepsis remains a major cause of hospital mortality. Sepsis-induced intestinal injury is regarded as the driving force behind the rapid progression of critical conditions such as shock and sepsis, and serves as the initiating factor of subsequent organ dysfunction. Therefore, the development of effective therapeutic agents to restore intestinal barrier function is crucial for improving outcomes in sepsis.

Methods: A caecal ligation and puncture (CLP) model was established in mice to induce sepsis, and intestinal epithelial cells (IEC-6) were treated with lipopolysaccharide (LPS) to simulate sepsis in vitro. These models were used to investigate the protective efficacy and molecular mechanisms of hydroxysafflor yellow A (HSYA) against sepsis-induced intestinal barrier dysfunction.

Results: HSYA alleviated intestinal barrier dysfunction in septic mice, markedly reduced levels of inflammatory factors, and improved survival. In vitro, HSYA enhanced barrier function of IECs, reduced mitochondrial fragmentation and reactive oxygen species (ROS) accumulation, promoted proliferation and inhibited apoptosis by upregulating the expression of Bcl-2 and SOD2.

Conclusion: The study demonstrated the therapeutic potential and underlying mechanisms of HSYA in ameliorating sepsis-induced intestinal barrier injury, providing a new strategy for sepsis treatment.

Background: Paclitaxel-induced peripheral neuropathy is a frequent chemotherapy complication that causes nerve damage and profoundly reduces patients' quality of life. Despite extensive preclinical evidence supporting the neuroprotective potential of trimetazidine against peripheral neuropathy, its clinical efficacy remains unexplored.

Objectives: This proof-of-concept randomized controlled trial aimed to investigate the effect of trimetazidine administered during the early phase of treatment on the incidence of paclitaxel-induced peripheral neuropathy in patients with non-metastatic breast cancer.

Methods: This parallel randomized placebo-controlled blinded endpoint trial was conducted at the Oncology Center, Minia University, Egypt, involving 60 breast cancer patients scheduled to receive weekly paclitaxel 90 mg/m². Patients were randomized to receive either trimetazidine 35 mg once daily or placebo alongside standard care. Measurements included the incidence of paclitaxel-induced neuropathy assessed by the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, patient quality of life via the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx) subscale, and exploratory serum biomarkers, specifically nerve growth factor (NGF) levels. Neuropathy and biomarkers were evaluated over an 8-week period.

Main results: The incidence of grade 2 and 3 peripheral neuropathies was significantly lower in the trimetazidine group compared to controls, with notable reductions in paresthesia (p = 0.037), peripheral motor neuropathy (p = 0.004), and dysesthesia (p = 0.045), except for peripheral sensory neuropathy (p = 0.152). Clinically significant worsening in neuropathy-related quality of life was more frequent in the control group compared to the trimetazidine group (p = 0.001). Additionally, the trimetazidine group exhibited a significantly greater percentage increase in serum nerve growth factor from baseline (p = 0.003).

Conclusion: Trimetazidine offers a safe and effective option for mitigating early paclitaxel-induced peripheral neuropathy in breast cancer patients. Further large-scale studies with longer follow-up are warranted to confirm these findings and explore effects across different chemotherapy regimens.

Clinical trial registration: https://clinicaltrials.gov/study/NCT06459193, identifier NCT06459193.

Metformin, a cornerstone therapy for type 2 diabetes mellitus, has emerged as a promising cardioprotective agent with effects that extend well beyond glycemic control. This review synthesizes current evidence on the molecular and cellular mechanisms underlying metformin's glycemic control and cardiovascular benefits, highlighting both AMPK-dependent and AMPK-independent pathways. We examine its modulation of mitochondrial function, oxidative stress, inflammation, autophagy, and apoptosis across major cardiac conditions, including ischemia/reperfusion injury, heart failure, diabetic cardiomyopathy, and anthracycline-induced cardiotoxicity. By integrating evidence from both preclinical and clinical studies, we evaluate the translational potential of metformin's pleiotropic actions across specific cardiac pathologies and outline key directions for future research and therapeutic innovation. Together, these insights highlight metformin's promise in reshaping cardiovascular care beyond its traditional role in diabetes management.

Pro-inflammatory and pro-thrombotic stimuli can activate endothelial cells (ECs) and predispose them to thrombotic microangiopathies (TMAs). Drug-induced TMA (DITMA) may occur in clinical practice during treatment with interferon-β1a (IFN-β1a), ciclosporin A (CsA), and gemcitabine (GEM). DITMA may also trigger the complement system and induce membrane attack complex (MAC, C5b-9) deposition in vivo, although their role and the benefit of inhibition remain unclear. In an experimental in vitro model of microvascular ECs exposed to these three drugs, we searched for MAC deposits and drug-specific pro-inflammatory and pro-thrombotic traits to gain insights into the mechanisms potentially involved in DITMA. Human microvascular endothelial cells line-1 (HMEC-1) was treated with 10% normal human serum, CsA, GEM, and IFN-β1a. Cell viability for each drug was measured using the resazurin assay. Cell component expression of the following markers involved in endothelial pathogenic activation was measured via immunofluorescence and flow cytometry: C5b-9, interleukin (IL)-1α, IL-6, E-selectin, platelet EC adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), and von Willebrand factor (vWF). Levels of plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) were measured in the supernatants using the enzyme-linked immunosorbent assay (ELISA). Significantly increased C5b-9 deposits were found with each drug, and increased drug-specific activation marker expressions appeared in HMEC-1s when exposed to CsA (IL-1α, IL-6, ICAM-1, E-selectin, vWF, and uPA), GEM (IL-1α, IL-6, PECAM-1, ICAM-1, E-selectin, and vWF), and IFN-β1a (PECAM-1, ICAM-1, PAI-1, and uPA). Each drug induces MAC deposits on HMEC-1s and singular endothelial activation profiles, potentially leading to thrombogenesis observed in DITMA.

Colorectal cancer (CRC) patients with a microsatellite-stable (MSS) status exhibit poor responsiveness to PD-1/PD-L1 blockade. Pyroptosis induction may resensitize MSS tumors to PD-1/PD-L1 blockade; however, the expression of GSDME, a key executor of pyroptosis, is often downregulated in CRC. Here, curcumin (CUR), a natural polyphenol, was identified as a potentiator of GSDME-dependent pyroptosis in CRC. We discovered that CUR upregulates GSDME expression by inhibiting the ubiquitin-proteasome system (UPS) in the MSS-type CT26 and HT29 cell lines and activating the caspase-3/GSDME signalling axis, resulting in increased pyroptosis. In CT26 tumors, CUR-enhanced pyroptosis reshaped tumor-infiltrating immune subsets and potentiated the efficacy of anti-PD-1 therapy. Notably, the synergistic antitumor activity of CUR combined with PD-1 blockade in CT26 tumors is strictly dependent on the caspase-3/GSDME axis, as the therapeutic benefit was abolished in GSDME-knockout tumors. These findings establish CUR as a safe and effective adjuvant for PD-1/PD-L1 blockade in MSS CRC, particularly in tumors with low GSDME expression.

Objective: To develop and validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for ciprofol in elderly surgical patients, delineating its pharmacokinetic profile and concentration-effect relationship to inform precision dosing.

Methods: Twenty patients (aged ≥65 years) undergoing elective surgery were enrolled. We performed population PK/PD analysis using nonlinear mixed-effects modeling on 386 arterial blood samples and synchronized Bispectral Index (BIS) data. A linear three-compartment model and a sigmoid Emax model described the PK and PD (BIS), respectively. Covariates (age, weight, gender, and laboratory parameters) were tested via stepwise selection. Model performance was evaluated using goodness-of-fit plots, bootstrap (n = 1,000), and prediction-corrected visual predictive checks. Dosing regimens were optimized via Monte Carlo simulation.

Results: A three-compartment model best described the PK. The center volume (V₁) was generally approximated at 2.95 L, but the peripheral volumes (V₂ and V₃) were 45.15 L and 76.79 L, respectively. The clearance (CL) was assessed at 1.01 L min^-1. Body weight and age significantly influenced CL. PD analysis showed rapid effect-site equilibration (K_e0: 1.09 min^-1), with an EC₅₀ of 233.91 ng mL^-1 and a Hill coefficient of 3.00. No covariates significantly affected PD parameters. The model exhibited sufficient fit and strong predictive efficacy. The simulation results confirmed that administering an intravenous loading dose of 0.4 mg kg^-1 over 1 min, followed by an initial continuous infusion at a rate of 0.6 mg kg^-1·h^-1 for 2 h, could stably maintain the patients' BIS values within the target range of 40-60.

Conclusion: A population PK/PD model for ciprofol in elderly patients was successfully established and validated. The model supports optimized, individualized dosing to achieve target anesthesia depth in this population.

The core pathophysiological mechanism of type 2 diabetes mellitus (T2DM) is closely associated with gut microbiota dysbiosis and its consequential impairment of enteroendocrine glucagon-like peptide-1 (GLP-1) secretion. T2DM mouse model was established using high-fat diet (HFD) feeding combined with streptozotocin (STZ) administration. Diabetic mice received 30 or 60 mg/kg of leonurine (LEO) via daily gavage for 12 weeks. Gut microbiota composition was profiled by metagenomic sequencing, fecal short chain fatty acids (SCFAs) concentrations were quantified via enzyme-linked immunosorbent assay (ELISA), and GLP-1 expression was assessed using oral glucose tolerance tests (OGTT), ELISA, and immunofluorescence. In vitro, high-glucose (25 mM)-challenged GLUTag enteroendocrine cells were employed to delineate the butyrate-mitochondrial pyruvate carrier 2 (MPC2) regulatory network using qPCR and Western blotting. LEO intervention significantly ameliorated glucose intolerance in diabetic mice and elevated GLP-1 levels in serum and colonic tissues. Metagenomic analysis revealed that LEO (60 mg/kg) remodeled gut microbiota structure, markedly enhancing α-diversity and specifically enriching butyrate-producing Alistipes. Mechanistically, butyrate activated MPC2 expression, effectively restoring cristae architecture defects observed by transmission electron microscopy, thereby promoting GLP-1 secretion. Crucially, MPC2 knockdown abrogated the secretagogue effect of butyrate on GLP-1 in GLUTag cells. LEO alleviates T2DM by remodeling the gut microbiota ecosystem, enhancing butyrate biosynthesis, and activating an MPC2-dependent mitochondrial energy metabolism pathway to reverse GLP-1 secretory dysfunction in intestinal L cells. This study establishes MPC2-mediated mitochondrial functional repair as a core mechanism through which microbial metabolites regulate enteroendocrine hormone secretion, identifying a novel therapeutic target within the "gut-islet axis" for diabetes intervention. Future studies should identify its active constituents, elucidate downstream effectors, and validate this mechanism in germ-free models.

In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative determination of amantadine in human plasma, with the incorporation of an internal standard to improve analytical accuracy. Plasma samples collected from volunteers were processed using acetonitrile-methanol (3:1, v/v) as the extraction solvent, followed by protein precipitation and purification via the QuEChERS (Quick, Easy, Cheap, Efficacious, Rugged, and Safe) method. Analysis was performed using LC-MS/MS under multiple reaction monitoring mode, with a total run time of 8 min. Quantification was carried out using the internal standard method. After a single oral administration of 200 mg amantadine hydrochloride, plasma concentrations were measured at various time points. Pharmacokinetic parameters were derived by fitting the data to a pharmacokinetic model using specialized software. The results demonstrated good linearity over the range of 0.5-20 ng/mL, with a correlation coefficient (R²) of 0.9978. The extraction recovery ranged from 94.5% to 110.1%, and both intra-day and inter-day relative standard deviations (RSD) were below 10%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.15 ng/mL and 0.5 ng/mL, respectively. The absorption and elimination processes of amantadine in plasma followed first-order kinetics, with R² > 0.9. Notably, gender-specific differences were observed in the time to maximum concentration (T_max) and maximum concentration (C_max): females achieved a C_max of 670.23 ng/mL at 4 h, whereas males reached a C_max of 650.87 ng/mL at 8 h. This LC-MS/MS method is simple, rapid, and accurate, rendering it suitable for pharmacokinetic studies of amantadine in humans. Additionally, the established kinetic model provides valuable references for clinical medication guidance.