Pharmacology最新文献

Introduction Atrial fibrillation is the most common sustained cardiac arrhythmia, primarily caused by arrhythmogenic activity within the pulmonary veins (PVs). Enhanced ketone body utilization can prevent heart failure by reducing inflammation and oxidative stress, factors crucial for atrial fibrillation pathogenesis. However, the role of ketone bodies in PV arrhythmogenesis remains unclear. This study investigated the effect of 3-hydroxybutyrate (3-OHB), the most abundant ketone body, on PV arrhythmogenesis and explored the underlying mechanisms. Methods Using conventional microelectrodes and the patch-clamp technique, we analyzed electrophysiological characteristics and ionic currents in isolated rabbit PV tissues and single PV cardiomyocytes. Results The effects of 3-OHB (10 mM) on reactive oxygen species (ROS) production, calcium homeostasis, and phosphorylated calcium/calmodulin-dependent protein kinase II (CaMKII) expression were analyzed through confocal microscopy and Western blotting. The results indicated that 3-OHB dose-dependently reduced PV spontaneous activity, contractility and diastolic tension. However, these effects were blocked by KN93 and AIP, a CaMKII inhibitor. Moreover, 3-OHB reduced late sodium and L-type calcium currents in PV cardiomyocytes; these effects were blocked by KN93 and AIP. Furthermore, 3-OHB reduced cytosolic ROS levels and phosphorylated CaMKII expression. Conclusion 3-OHB prevents PV arrhythmogenesis by modulating ionic currents, reducing ROS production, and regulating CaMKII signaling. Thus, 3-OHB holds promise as an antiarrhythmic agent.

Background: ALK mutations are key oncogenic drivers in non-small-cell lung cancer (NSCLC). Although ALK tyrosine kinase inhibitors (TKIs) elicit high initial response rates, relapse due to acquired resistance is common. Conventional approaches fail to resolve tumor heterogeneity and epigenetic control, necessitating multi-omic integration to dissect molecular differences between ALK-mutant and wild-type (WT) tumors.

Methods: Single-cell RNA sequencing (scRNA-seq) and matched chromatin accessibility (scATAC-seq) data of 5 WT and 4 ALK-mutant NSCLC samples from GEO (GSE274934) were integrated. "Seurat" and "Harmony" packages in R were used for data preprocessing and batch correction. "Monocle" package reconstructed epithelial differentiation trajectories. "CellChat" package delineated cell-cell communication. "Signac" package integrated multiple omics data and analyzed the differentially accessible chromatin regions. Motif enrichment based on the JASPAR database identified key transcription factors. The role of CEACAM6 in the malignant progression of ALK-mutant-mutant NSCLC was assessed by qRT-PCR, CCK-8, colony formation, and wound-healing assays.

Results: ALK-mutant epithelial cells exhibit disrupted differentiation trajectories, characterized by loss of SPINK1 expression and pan-expression of MARCKSL1. ALK-mutant cells relied on CEACAM5/6 signaling for communication; WT cells primarily engaged in multi-directional MIF interactions. ALK-mutant cells showed increased global chromatin accessibility. Motif analysis revealed enrichment of PRC pathway components and EGR1 binding sites (survival/drug resistance-associated) in ALK-mutant cells, whereas WT cells specifically enriched KLF5, ZNF148, and GLIS3 motifs. In vitro, CEACAM6 expression was significantly upregulated in ALK-mutant compared to WT cells. CEACAM6 knockdown significantly inhibited cell proliferation and migration, and reduced p-AKT and EGR1 protein levels, indicating that CEACAM6 promotes malignant progression of ALK-mutant NSCLC through the AKT-EGR1 signaling axis.

Conclusion: ALK mutations drive tumor stemness and drug resistance by blocking epithelial cell differentiation, activating CEACAM6-mediated signaling, enhancing chromatin accessibility, and remodeling the EGR1/PRC regulatory network. Targeting CEACAM6 and its downstream effector EGR1 may represent an effective strategy to overcome ALK-TKI resistance.

Introduction: One serious consequence of sepsis that has a direct impact on patient outcomes is intestinal barrier disruption brought on by sepsis. Although the polyphenolic molecule resveratrol (RE) is well-known for its anti-inflammatory and antioxidant properties, it is unknown how it affects the NADPH oxidase 1 (NOX1)/sirtuin 1 (SIRT1) pathway and against intestinal barrier failure by sepsis.

Methods: This work adopted a lipopolysaccharide (LPS)-treated Caco-2 cell and sepsis mice model (cecal ligation and puncture) to assess the protective effects of RE. We employed quantitative reverse transcription PCR, enzyme-linked immunosorbent assay, histological analysis, immunohistochemistry, and Western blot to assess survival rates, inflammatory cytokine levels, autophagy markers, and intestinal barrier function. The role of NOX1 and SIRT1 in RE-mediated protection was explored through NOX1 overexpression and related molecular analyses.

Results: RE significantly improved survival rates in sepsis mice, reduced inflammatory cytokines, and restored intestinal barrier function. RE reversed the increase of NOX1 and the decrease of SIRT1 observed in sepsis. Histological analysis showed that RE protected the intestinal structure, maintained the expression of tight junction proteins, and alleviated intestinal damage. In LPS-treated Caco-2 cells, RE inhibited inflammation, autophagy suppression, and reactive oxygen species (ROS) production. NOX1 overexpression partially reversed the protective effects of RE.

Conclusion: By modifying the NOX1/SIRT1 signaling pathway, RE guards against intestinal barrier failure by sepsis. These results underline the critical involvement of the NOX1/SIRT1 pathway in autophagy and inflammation control and imply that RE may be a viable treatment approach for intestinal damage associated with sepsis.

Background: Wedelolactone (WED) is a polyphenolic compound with a coumarin skeleton isolated from marigold. Despite its wide application in traditional medicine, its mechanisms of action and safety profile require further investigation.

Summary: The key contributions of this review lie in: (1) the first systematic integration of WED's multi-target mechanisms across diseases through the AMPK/NF-κB/NLRP3 network; (2) clarification of its dose-effect relationship (effective therapeutic window: 5-100 mg/kg) and toxicity thresholds; (3) proposal of clinical translation strategies, including nanodelivery systems to address bioavailability issues. Recent studies revealed novel mechanisms such as WED's inhibition of ferroptosis via GPX4 and modulation of the FXR-bile acid axis, demonstrating efficacy in acute lung injury and liver fibrosis.

Key messages: This article provides a comprehensive framework integrating mechanistic insights and translational research for WED's clinical development.

Introduction: Escitalopram oxalate (ESC) was extensively reported to improve insomnia in patients with depression/anxiety. The serotonin transporter gene (SLC6A4) was involved in regulating insomnia. However, it is still unclear whether ESC improves insomnia by regulating SLC6A4 expression. Therefore, this study aimed to investigate whether ESC improves insomnia by regulating SLC6A4 based on clinical and animal experiments.

Methods: The clinical and animal experiments were involved in this study. For clinical experiments, after all 110 participants were divided into four groups, the portable sleep electroencephalogram monitor, HAMA₁₄ scale, and HAMD₂₄ scale were used to evaluate patients' sleep quality, anxiety, and depression. For animal experiments, after all 18 ICR male mice were randomly divided into three groups (n = 6), the sodium pentobarbital-induced sleeping test, locomotor activity test, elevated plus maze, and open field test were used to evaluate mice's sleep quality and anxiety- and depression-like behaviors. The H&E staining was used to determine pathological injuries in mice's hippocampal tissues. The ELISA kits were adopted to detect the 5-HT, norepinephrine (NE), gamma-aminobutyric acid (GABA), and glutamate (Glu) levels in the hypothalamus tissue and the corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol (CORT) levels in the serum. The PubChem, DrugBank, and Therapeutic Target Database were employed to predict the potential targets of ESC. The immunohistochemical staining and Western blot were applied to assay the SLC6A4, 5-HTR1A, and 5-HTR2A expression levels in the hippocampal tissues of mice.

Results: ESC shortened the sleep latency, extended the sleep time, enhanced the sleep efficiency, and improved anxiety and depression in patients and mice. ESC mitigated the pathological injuries in mice's hippocampal tissues. ESC effectively regulated mice's neurotransmitter levels and hypothalamic-pituitary-adrenal (HPA) axis homeostasis, including upregulating 5-HT and GABA and downregulating NE, Glu, CRH, ACTH, and CORT. Moreover, SLC6A4 was predicted as the potential target of ESC. ESC prominently inhibited SLC6A4 expression (p < 0.001) and regulated 5-HTR1A and 5-HTR2A expression (p < 0.001) in hippocampal tissues.

Conclusion: Taken together, ESC was suitable for treating insomnia in the clinic and improved insomnia by targeting SLC6A4 to regulate the HPA axis in mice.

The article "Tanshinone IIA Affects Autophagy and Apoptosis of Glioma Cells by Inhibiting Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway" [Pharmacology. 2017;99(3-4):188-195. https://doi.org/10.1159/000452340] by Lijuan Ding, Shudong Wang, Weiyao Wang, Peng Lv, Donghai Zhao, Feier Chen, Tianjiao Meng, Lihua Dong and Ling Qi has been retracted by the Publisher and the Editor.After the publication of this article, concerns were raised about the integrity of some of the data presented. Specifically, similar features appear between the two panels "FITC-A 740 Y-P" and "FITC-A Mixed" in Figure 3b of the article. In addition, panels in Figure 3b of this article are the same as panels in Figure 3 of another article by different authors, published subsequently in a different journal [1], specifically:Figure 3b panel "FITC-A Tan IIA" is the same as Figure 3c of [1].Figure 3b panel "FITC-A 740 Y-P" is the same as Figure 3a of [1].Figure 3b panel "FITC-A Mixed" is the same as Figure 3b of [1].The authors did not respond to requests to comment on the concerns and provide the raw data within the given timeframe despite multiple attempts of contact. We contacted the authors' institution to request an investigation. However, we did not receive a response. Given the severity of the concerns raised, this article is being retracted. The authors have not responded to our correspondence regarding this retraction despite multiple attempts of contact.

Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide, and the liver is its main site of distant metastasis. Colorectal cancer liver metastasis (CRLM) is a major cause of CRC-related death. Current treatments, including surgery, chemotherapy, and immunotherapy, have limited efficacy and often cause substantial side effects.

Summary: This review examines the emerging role of traditional Chinese medicine (TCM) in managing CRLM, focusing on its ability to modulate the tumor microenvironment (TME) by inhibiting epithelial-mesenchymal transition, suppressing angiogenesis, and reversing immune evasion. TCM provides a holistic, multi-targeted approach, but most supporting evidence comes from preclinical studies in cell and animal models, with limited clinical validation.

Key messages: TCM shows promise for targeting the CRLM-related TME. Most evidence is preclinical; well-designed clinical trials are urgently needed. Standardization, pharmacokinetics, and regulatory issues remain major barriers to clinical application.

Introduction: Proton-pump inhibitor (PPI) monotherapy is standard for artificial ulcer healing after gastric endoscopic submucosal dissection, but evidence on the efficacy of PPI combined with gastric mucosal protectants remains inconclusive. This network meta-analysis aimed to compare the efficacy of 10 mucosal protectants combined with PPIs.

Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov until January 2025. Included were 20 randomized controlled trials (n = 2,000) comparing PPI monotherapy versus PPI combined with protectants (e.g., rebamipide, ecabet, polaprezinc) or active controls. Primary outcomes included ulcer area reduction, healing rates (4/8 weeks), longest ulcer diameter, and bleeding risk. Frequentist random-effects models synthesized risk ratios (RRs) and MDs with 95% CIs. Consistency was evaluated using design-by-treatment interaction and node splitting. Risk of bias (RoB 2.0) was assessed at the outcome level. Certainty of evidence was graded with GRADE.

Results: Bismuth subcitrate-magnesium granules (BMG) + PPI most effectively reduced 4-week ulcer area (MD: -62.50 mm2, 95% CI: -87.25 to -37.75 vs. PPI; SUCRA = 94%). Ecabet sodium (EB) + PPI achieved the highest 8-week healing rate (RR: 7.71, 95% CI: 5.52-9.91). Hydrotalcite (HT) + PPI best reduced ulcer diameter (MD: -1.87 mm), while teprenone (TN) + PPI optimally prevented bleeding (RR: -3.41, 95% CI: -5.43 to -1.38). Rebamipide + PPI showed efficacy heterogeneity, particularly in large ulcers (>40 mm).

Conclusions: PPI-based combinations likely accelerate healing versus PPI alone, but conclusions are hypothesis generating given indirect evidence and regional concentration of trials. Combination therapy outperforms PPI monotherapy. BMG + PPI is optimal for early ulcer healing, EB + PPI for long-term healing, HT + PPI for diameter reduction, and TN + PPI for bleeding prevention. Stratified regimens by ulcer characteristics are recommended.

Introduction: Considering the global burden of atherosclerosis-related cardiovascular mortality, this study investigates the anti-atherosclerotic potential of Actein, a 9,19-cyclobutane triterpenoid isolated from Cimicifuga spp.

Methods: The study employed both in vitro and in vivo experiments. In vitro, the effect of Actein on oxLDL-induced macrophage foam cells was examined. In vivo, ApoE-deficient mice were fed a high-fat diet to induce atherosclerosis and were then treated with actein (10 mg/kg) or atorvastatin for 8 weeks.

Results: Actein significantly reduced lipid accumulation in oxLDL-induced foam cells. In the in vivo model, actein treatment significantly lowered serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol. Furthermore, actein diminished the levels of inflammatory markers (interleukin [IL]-6, IL-1β, tumor necrosis factor-α, and matrix metalloproteinase-9 [MMP-9]) and upregulated the expression of ABCG1 and LXR proteins in liver tissue. The efficacy of actein was comparable to, and in some aspects superior to, that of atorvastatin.

Conclusion: These findings establish actein as a promising natural compound for the treatment of atherosclerosis, warranting further investigation into its therapeutic potential.

Introduction: Alpha-linolenic acid (ALA) is a well-known n-3 polyunsaturated fatty acid. Our previous study showed that ALA inhibits coronary contractions induced by U46619 (a thromboxane A₂ analog) and prostaglandin F_2α (PGF_2α) in pigs by antagonizing prostanoid TP receptors. In this study, we investigated the inhibitory effects of ALA on pig basilar artery contractions and explored the underlying mechanisms.

Methods: The effects of ALA on contractions of pig basilar arteries were assessed. The effects of K+ channel inhibitors on ALA-mediated attenuation were also evaluated.

Results: ALA inhibited TP receptor-mediated contractions induced by U46619 and PGF_2α in a concentration-dependent manner. It shifted the U46619 concentration-response curve to the right and reduced the maximal contraction. The slope of the regression line in the Schild plot analysis exceeded unity, although the difference was not statistically significant. ALA also inhibited PGF_2α-induced contractions (in the presence of SQ 29,548, a TP receptor antagonist) and endothelin-1-induced contractions, without affecting those induced by high-KCl. Among the tested K+ channel inhibitors, Ba2+, an inhibitor of inwardly rectifying K+ (K_ir) channels, most potently attenuated ALA's inhibitory effect on PGF_2α-induced contractions in the presence of SQ 29,548.

Conclusion: These findings indicate that ALA potently inhibits contractions induced by potentially spasmogenic substances in the pig cerebral artery. The inhibitory mechanisms likely involve both antagonism of prostanoid TP receptors and activation of K_ir channels.