Frontiers in Pharmacology最新文献

Background: Per and polyfluoroalkyl substances (PFAS), including the legacy compound perfluorooctanesulfonic acid (PFOS), are persistent organic pollutants with long biological half-lives. Emerging evidence suggests a significant accumulation of PFAS/PFOS in the human lung, potentially contributing to inflammation and altered immune responses. However, the role of peroxisome proliferator-activated receptor gamma (PPARγ) signaling in PFAS/PFOS-induced pulmonary toxicity remains unclear.

Methods: Primary human bronchial epithelial (NHBE) cells were exposed to 15 µM binary PFAS mixture (PFOS + PFOA) or quaternary mixture (PFOS, PFOA, PFHxS, GenX) with or without the PPARγ antagonist (15 µM) and/or the PPARγ agonists rosiglitazone (10 µM) or pioglitazone (10 µM) for 24 h. BALB/c mice were orally administered PFOS (2 mg/kg/day) or vehicle control for 2 weeks.

Results: In NHBE cells, PFAS exposure significantly increased IL-6 and IL-8 secretion. Treatment with rosiglitazone or pioglitazone reversed these cytokine increases, whereas co-treatment with the PPARγ antagonist elevated IL-6 and IL-8 levels compared to PFAS exposure alone in epithelial cells. PFOS exposure in mice caused a reduction in lung PPARγ protein levels, while PPARα expression remained unchanged.

Conclusion: These findings demonstrate that PFAS-induced pro-inflammatory cytokines is mediated, at least in part, through PPARγ signaling, and that pharmacological activation of PPARγ signaling can attenuate PFAS-triggered pro-inflammatory cytokine responses in lung epithelial cells.

Introduction: Ivonescimab (AK112), a novel bispecific antibody targeting PD-1 and VEGF, has emerged as a promising therapeutic agent in the treatment of non-small cell lung cancer (NSCLC). This study aims to comprehensively evaluate its efficacy and safety.

Materials and methods: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library (from inception to January 2026) to identify studies reporting the clinical efficacy and safety outcomes of AK112 in NSCLC. Pooled analyses were conducted for efficacy endpoints, including objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS), as well as adverse events (AEs). For randomized controlled trials (RCTs), odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated for binary and time-to-event outcomes, respectively. Subgroup analyses were performed by cancer type and treatment regimen.

Results: 5 studies comprising 1,365 patients were included. AK112-based regimens significantly improved ORR (OR = 1.65, 95% CI: 1.31-2.09) and DCR (OR = 2.29, 95% CI: 1.18-4.44) compared to control treatments. A significant progression in PFS was observed (HR = 0.53, 95% CI: 0.45-0.62). The PFS benefit was consistent across all PD-L1 expression subgroups. Safety analysis revealed that AK112-based regimens increased the risk of all-grade AEs (OR = 2.05, 95% CI: 1.20-3.51) and grade ≥3 AEs (OR = 1.51, 95% CI: 1.19-1.92).

Conclusion: AK112 demonstrates significant efficacy and a manageable safety profile in advanced NSCLC, supporting its role as a valuable treatment option. Further studies are needed to confirm long-term survival benefits.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251176434.

Achieving optimal antibiotic exposure in critically ill pediatric patients is difficult due to (their) dynamic physiology and variability. Conventional weight-based regimens often fail to reach pharmacokinetic/pharmacodynamic (PK/PD) targets for narrow therapeutic index agents such as vancomycin and amikacin. Model-Informed Precision Dosing (MIPD), which integrates Bayesian forecasting with population pharmacokinetics (popPK), offers a potentially valuable yet underexplored approach in pediatric intensive care to better attain and sustain target exposure. This study was designed as a prospective, pragmatic feasibility study with a comparator arm, employing observational analyses to evaluate the implementation and methodological performance of MIPD in a tertiary pediatric intensive care unit. Pediatric patients receiving vancomycin or amikacin were managed either with MIPD-guided dosing using a clinical decision support platform or with standard-of-care (SoC) dosing. Primary outcomes included prediction accuracy (a priori vs. a posteriori) and model fit, defined by the agreement between observed and model-predicted concentrations and categorized as poor, intermediate, or good. Secondary outcomes assessed dose optimization, inflammatory response, renal safety, treatment duration, and mortality. Forty-one patients (median age 38.6 months) were enrolled; Patients were initially allocated to either MIPD or SoC; however, the final analytic groups were defined as-treated, with 12 receiving active MIPD-guided dose adjustments and 29 managed under SoC dosing. Some baseline differences were observed between groups, particularly in inflammatory markers. Clinical outcomes were similar between groups, with numerically greater but nonsignificant reductions in CRP and procalcitonin in the MIPD group. However, these findings were confounded by baseline imbalances and should be interpreted cautiously. Model fit remained unchanged in the SoC group but showed modest improvement for vancomycin under MIPD. Larger, multicenter trials are warranted to confirm clinical benefit and optimize implementation in pediatric intensive care.

Clinical trial registration: ClinicalTrials.gov, identifier NCT07315438.

Background: The chemokine CXCL9, induced by interferon-γ (IFN-γ), is a hallmark of type 1 (T1) inflammation. Its role in chronic respiratory diseases remains unclear, with conflicting evidence suggesting it may reflect steroid-responsive inflammation in interstitial lung disease (ILD) but correlate with worse function in chronic obstructive pulmonary disease (COPD).

Methods: Serum levels of CXCL9, KL-6, SP-A, and CRP were measured in 83 ILD patients (with paired samples before and after treatment), 94 COPD patients, and 100 healthy controls (50 smokers and 50 non-smokers). Lung function and biomarker correlations were analyzed, and unsupervised cluster analysis was used to explore inflammatory phenotypes.

Results: CXCL9 levels were markedly elevated in both ILD (median: 57.4 pg/mL) and COPD (70.1 pg/mL) compared to healthy smokers (32.5 pg/mL) and non-smokers (37.0 pg/mL). In COPD, CXCL9 correlated with KL-6 (r = 0.459) and SP-A (r = 0.274), indicating neutrophilic inflammation and epithelial injury. In ILD, higher baseline CXCL9 levels predicted subsequent improvement in lung function and declined following treatment. Cluster analysis revealed divergent CXCL9 and KL-6 trajectories linked to disease outcomes, underscoring their value as dynamic, disease-specific biomarkers.

Conclusion: CXCL9 levels correlate with divergent roles in ILD and COPD. It may serve as a prognostic marker, identifying treatable inflammation in ILD and inflammatory burden in COPD.

Introduction: Olanzapine (OLZ), haloperidol (HALP), and their combination, are widely used antipsychotics; the majority of studies focuses on their therapeutic efficacy, leaving significant gaps in understanding their systemic impacts. Hence, the present study was conducted to investigate their systemic, metabolic, and inflammatory impact on schizophrenic patients.

Methods: A total of 75 schizophrenic patients and 25 healthy volunteers were involved and monitored over a six-month period. Study groups were as follow; normal control, OLZ (20 mg/day), HALP (10 mg/day), and OLZ (20 mg/day) + HALP (5 mg/day). The parameters of metabolic, inflammatory, and neuronal transmitters, along with cardiovascular, hepatic, and renal functions were determined.

Results: In this study we found that OLZ and HALP produced a noticeable decrease in potassium and chloride ions, while their combination decreased potassium, chloride and calcium. OLZ and OLZ + HALP significantly prolonged QTc, while OLZ and HALP individual administration increased SBP and CK-MP respectively. HbA1C levels not significantly affected by tested drugs, while OLZ produced a significant reduction in LDL and HDL levels, while OLZ + HALP modestly decreased LDL levels. renal assessment revealed a significant increase in both creatinine and urea concentrations in the OLZ + HALP group compared to other groups, whereas hepatic function showed no significant differences between the treated groups. OLZ significantly decreased total bilirubin and increased ALP activity, while HALP significantly reduced total and direct bilirubin levels. OLZ and OLZ + HALP produced a significant increase in body weight and waist circumference, which was not found in HALP-treated patients. Schizophrenic patients had reduced dopamine levels that was not significantly affect by OLZ or OLZ + HALP administration, while HALP administration normalized dopamine levels. Schizophrenic patients had significantly higher levels of serotonin compared to controls, that was normalized by our tested drugs. Ghrelin levels were significantly lower in schizophrenic patients, and it was significantly increased by HALP administration. Leptin hormone significantly elevated in schizophrenics, and was significantly decreased by HALP administration. Schizophrenic patients exhibited markedly elevated levels of IL-17, IL-6, and TNF-α, that dramatically decreased by tested drugs, and the combined regimen showed the highest impact.

Conclusion: This study provides valuable insights into the systemic, metabolic, and inflammatory effects of tested drugs, support the individualized therapeutic approaches in schizophrenic patients to optimize clinical outcomes and minimizing long-term systemic risks.

[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.