Frontiers in Pharmacology最新文献

The combination of pharmacological modulators such as lumacaftor, tezacaftor, and elexacaftor restore CFTR activity at the plasma membrane and improve lung function in patients carrying CFTR mutations such as F508del, their effects on inflammation are less clear. This study aimed to investigate whether the inflammatory response in CF airway epithelial cells depends solely on Cl^- transport or also on the structural integrity of the CFTR protein. We examined the effects of several CFTR modulators and wild-type CFTR overexpression on CFTR expression, trafficking, Cl^- channel activity, and inflammation in human CF bronchial epithelial cells. Our results demonstrate that overexpression of wild-type CFTR fully restores Cl^- secretion and normalizes the inflammatory response to levels observed in non-CF cells. In contrast, pharmacological correction of CFTR-F508del leads to partial recovery of Cl^- transport and only limited reduction of inflammation. Structural analysis revealed that corrected CFTR-F508del fails to achieve the same conformational stability as wild-type CFTR. These findings suggest that beyond ion transport, the proper folding and structural integrity of CFTR are important for regulating inflammation, potentially through interactions with other cellular proteins involved in inflammatory pathways. This work highlights the need to develop therapeutic strategies that not only restore chloride channel function but also fully correct CFTR misfolding to better control inflammation in CF.

As a key defense line for the body to resist pathogens and maintain internal environment stability, the intestinal barrier is crucial for maintaining human health, and its functional damage is closely related to the occurrence of various intestinal diseases, especially in the hypoxic environment of high altitude, the problem of intestinal barrier damage is more prominent. Natural active products are widely sourced and exhibit unique potential in regulating intestinal barrier function due to their multi-target and low-toxicity characteristics. This article comprehensively reviews the prevention and treatment effects of natural active products on common intestinal diseases and high-altitude intestinal injury, focusing on elucidating the mechanism by which they regulate intestinal barrier function through eight key signaling pathways such as NF-κB, Wnt/β-catenin, and mTOR, in which the HIF family is a key factor in regulating hypoxic stress response, and this signaling pathway is the "lifeline" for cells to cope with hypoxia, emphasizing its application potential in the prevention and treatment of high-altitude intestinal barrier injury, and providing a theoretical basis for the development of natural drugs for high-altitude environments and related intestinal diseases.

Objective: Laryngeal cancer (LC) is a significant and persistent therapeutic challenge worldwide. Gitogenin (GIT), a naturally occurring saponin, has demonstrated anticancer activity in lung cancer. However, its potential effects on LC remain unclear. This study aimed to elucidate the therapeutic efficacy of GIT and the mechanisms through which it acts against LC by integrating network pharmacology analysis with experimental validation.

Methods: Potential targets of GIT were established using the PharmMapper database, while LC-associated genes were retrieved from the GeneCards database. Common targets between GIT and LC were determined, and the top 20 genes were chosen for protein-protein and gene-gene interaction (PPI and GGI) network construction. Functional enrichment analyses were conducted. Finally, in vitro experiments were performed to validate how GIT affects LC.

Results: A total of 96 putative GIT targets for LC were identified. KEGG enrichment identified the PI3K-Akt axis a key regulatory mechanism. In vitro experiments provided confirmation that GIT inhibited LC cell proliferation, viability, migratory activity, and invasion ability by modulating PI3K-Akt signaling.

Conclusion: Using network pharmacology and experimental validation, it was demonstrated that GIT exerts potent anticancer effects on LC by targeting the PI3K-Akt axis. The present findings suggest the potential of GIT for treating LC.

Purpose: Six non-ergot dopamine -receptor agonists (NEDAs), including pramipexole extended-release (ER), pramipexole immediate-release (IR), rotigotine patch, piribedil, ropinirole prolonged-release (PR), and ropinirole IR, are frequently used to treat early Parkinson's disease (PD). However, there is a paucity of comparative information about them. For making rational drug selections, six NEDAs were evaluated using a rapid health technology assessment method.

Methods: According to the rapid guidelines for drug evaluation and selection in Chinese medical institutions (the Second Edition), the pharmacological properties, efficacy, safety, economy, and other attributes of six NEDAs were scored on a percentage system.

Results: The composite scores of the six NEDAs are presented as follows: 74.99 points for pramipexole ER, 74.90 points for piribedil, 72.40 points for pramipexole IR, 70.78 points for rotigotine patch, 69.06 points for ropinirole PR and 68.41 points for ropinirole IR.

Conclusion: Based on our comprehensive multi-criteria assessment, pramipexole ER, pramipexole IR, rotigotine patch, and piribedil are strongly recommended for inclusion in the formularies of medical institutions as therapeutic options for patients with early PD.

Background: Lung cancer is a leading cause of cancer-related deaths, with cisplatin being a cornerstone of treatment. However, resistance to cisplatin presents a significant challenge. β-elemene, a natural compound, has demonstrated potential to reverse cisplatin resistance. LncRNA LINC00511 has been implicated in cisplatin resistance through its role in activating the PI3K/AKT/mTOR pathway, which supports tumor survival and proliferation.

Purpose: This study aims to investigate the mechanism by which β-elemene overcomes cisplatin resistance in lung cancer by regulating LINC00511.

Methods: Human lung adenocarcinoma cells (A549 and A549/DDP) were treated with β-elemene and cisplatin. Cell proliferation and apoptosis were assessed using CCK-8, EdU staining, and flow cytometry. LINC00511 expression was measured by qRT-PCR, and protein levels of PI3K, AKT, and mTOR were evaluated via Western blot. A xenograft model was used to confirm in vivo effects.

Results: β-elemene significantly enhanced cisplatin-induced apoptosis in A549/DDP cells, reduced LINC00511 expression, and inhibited the PI3K/AKT/mTOR pathway. LINC00511 knockdown further potentiated these effects, both in vitro and in vivo. Xenograft models confirmed the enhanced anti-tumor effects of the combination treatment.

Conclusion: β-elemene overcomes cisplatin resistance in lung cancer by downregulating LINC00511 and inhibiting the PI3K/AKT/mTOR pathway. These findings propose a promising therapeutic strategy for treating cisplatin-resistant lung cancer.

Ferroptosis is a unique form of iron-dependent programmed cell death, characterized by the abnormal accumulation of lipid peroxides, which plays a important role in various physiological and pathological processes. Crucially, the activity and stability of core ferroptosis regulators (including GPX4, ACSL4, FSP1, and iron/lipid metabolism proteins) are dynamically controlled by diverse post-translational modifications (PTMs), positioning PTMs as central molecular switches modulating cellular ferroptotic susceptibility across pathophysiological contexts. Elucidating the regulatory mechanisms of PTMs in ferroptosis is of great significance for understanding the complex network of cell death and providing new perspectives for disease treatment and diagnosis. This review focuses on four emerging PTMs-lactylation, crotonylation, succinylation, and β-hydroxybutyrylation-and their roles in promoting ferroptosis progression via protein regulatory systems. Additionally, it explores their clinical potential as therapeutic targets and diagnostic biomarkers. The definitions, functional mechanisms, and enzymatic regulation of these PTMs are systematically elucidated.

Objective: To develop a value assessment index system of anti-tumour commercial Chinese polyherbal preparation (CCPP).

Methods: A modified two-round Delphi method was conducted to establish consensus within a field to reach an agreement via questionnaire among a multidisciplinary panel of experts. In addition, the analytic hierarchy process was used to conduct weight analysis of indicators.

Results: In two rounds of Delphi consultation, the experts' positive coefficient was over 90%, and the authoritative coefficient was over 0.70. The Kendall's W of two rounds was 0.401 and 0.438, and the P-value of Kendall's W test was all <0.001 for each round. The final value assessment index system consisted of 7 primary indicators, 24 secondary indicators, and 50 tertiary indicators.

Conclusion: This value assessment index system could promote the clinical rational use of CCPP and the development of the drug catalog and clinical guideline in China.

Heart failure with preserved ejection fraction (HFpEF) is a clinically diverse disease characterized by intricate pathophysiological pathways, for which effective treatment options remain limited. Aberrant activation of the mineralocorticoid receptor (MR) significantly contributes to the development and progression of HFpEF. Finerenone, an innovative non-steroidal mineralocorticoid receptor antagonists (MRAs), has enhanced MR selectivity, more potent anti-fibrotic and anti-inflammatory effects, and improved safety relative to conventional steroidal MRAs like spironolactone and eplerenone. Therefore, future large-scale phase III head-to-head randomized controlled trials comparing finerenone and spironolactone in the HFpEF population, with cardiovascular outcomes as the primary endpoint, will be crucial. In preclinical models, finerenone has demonstrated improvement in multiple pathophysiological parameters of HFpEF. The FIDELIO-DKD and FIGARO-DKD trials in individuals with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) initially demonstrated finerenone's cardiorenal advantages, including substantial decreases in cardiovascular events and the risk of renal function decline. The FINEARTS-HF trial has expanded this data to patients with HFmrEF/HFpEF, showing a significant decrease in the incidence of total worsening HF events and mortality from cardiovascular causes. Additionally, the potential for combining finerenone with sodium-glucose cotransporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is gaining attention. Current trials, including REDEFINE-HF, CONFIRMATION-HF, and FINALITY-HF, are examining its effectiveness across various HF phenotypes. These research will elucidate finerenone's function in the management of cardiometabolic disorders. This review focuses on the clinical evidence of finerenone in patients with HFpEF and concomitant CKD, along with its potential cardiorenal protective mechanisms. It aims to provide new evidence-based medical evidence and theoretical support for the clinical management of HFpEF patients.

Background: Yanhuanglian (YHL), derived from the dried herb of Corydalis saxicola Bunting, can inhibit diarrhea and alleviate bleeding in traditional Chinese medicine. YHL is used to treat dysentery and hematochezia, which are recognized as ulcerative colitis (UC) in traditional Chinese medicine. However, the effectiveness and mechanisms of YHL treating UC remain largely unknown. This study aimed to reveal anti-colitis effect and mechanisms of YHL's total alkaloids (YTA) against UC.

Methods: Three graded doses of YTA were introduced to DSS-induced colitis mice for 7 days to evaluate the anti-colitis effect. Colon, serum, and fecal untargeted metabolomics were applicated to analyze the differential metabolites. 16S rRNA sequencing was used to analyze changes in the gut bacteria, while gut microbiota depletion and fecal microbiota transplantation further verified the effects of gut microbiota. Lactobacillus spp. isolated from the mice feces were screened based on the enrichment abundance of YTA in vivo and in vitro, and the therapeutic effect of Lactobacillus johnsonii enriched with YTA was evaluated in colitis mice.

Results: YTA alleviated weight loss, diarrhea, and hematochezia in colitis mice, reducing inflammation and oxidative stress while restoring intestinal barrier impairment. Untargeted metabolomics profiling of colon, serum, and feces demonstrated that YTA restored the disrupted metabolite profiles, with linoleic acid consistently identified as a key differential metabolite. Through the pathway enrichment, linoleic acid metabolism pathway was highlighted. YTA also ameliorated imbalance of the gut microbiota by significantly increasing the abundance of Lactobacillus. Gut microbiota depletion and fecal microbiota transplantation confirmed that the benefits of YTA depended on the presence of gut microbiota. Furthermore, Lactobacillus johnsonii enriched by YTA protected colitis mice against UC.

Conclusion: YTA exhibited potential anti-colitis activity by modulating metabolomic profiles and the gut microbiota, suggesting its potential as a complementary and alternative therapy in phytomedicine.

Background: Excessive salt intake is a well-established risk factor for hypertension. However, the molecular mechanisms by which salt-induced endothelial dysfunction contributes to blood pressure elevation remain incompletely understood.

Methods and results: In this study, mice were fed a normal-salt diet (NSD) or high-salt diet (HSD) for 4 weeks, and primary bovine aortic endothelial cells (BAECs) were treated with varying concentrations of NaCl. HSD mice showed increased diastolic blood pressure and impaired acetylcholine-induced vasodilation, while sodium nitroprusside responses remained intact. In vitro experiments further confirmed salt-induced vascular endothelial dysfunction, high NaCl treatment reduced the proliferation, migration, and tube formation abilities of BAECs. Western blot analysis revealed that high salt exposure significantly increased O-GlcNAc modification of eNOS and upregulated O-GlcNAc transferase (OGT) expression, without altering total eNOS protein levels. Notably, nitric oxide (NO) bioavailability was significantly reduced both in vivo and in vitro. Treatment with the OGT inhibitor OSMI-1 reversed these changes and restored endothelium-dependent relaxation in HSD mice.

Conclusion: Our findings suggest that high salt intake impairs endothelial function by enhancing O-GlcNAc of eNOS, thereby contributing to elevated diastolic blood pressure. The ability of OGT inhibition to reverse endothelial dysfunction highlights the therapeutic potential of targeting eNOS O-GlcNAc could be a promising approach for preventing salt-induced vascular damage and subsequent diastolic blood pressure elevation.