Pharmacology最新文献

{"title":"A Network Meta-Analysis of Pharmacological Treatments for Gastric Mucosal Protection in Artificial Ulcers following Endoscopic Submucosal Dissection of the Stomach.","authors":"Zhiqun Chen, Sanhui Zhan, Haiyang Yu","doi":"10.1159/000550164","DOIUrl":"10.1159/000550164","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and <ext-link ext-link-type=\"uri\" xlink:href=\"http://ClinicalTrials.gov\" xmlns:xlink=\"http://www.w3.org/1999/xlink\">ClinicalTrials.gov</ext-link> 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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"59-73"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Escitalopram Oxalate Improved Insomnia by Targeting SLC6A4 to Regulate the Hypothalamic-Pituitary-Adrenal Axis.","authors":"Xin Gu, Jing An, Mingxue Zhang, Hongyan Zhang, Zhan Lou, Bu Wang","doi":"10.1159/000550304","DOIUrl":"10.1159/000550304","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Taken together, ESC was suitable for treating insomnia in the clinic and improved insomnia by targeting SLC6A4 to regulate the HPA axis in mice.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"101-113"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Actein, a 9,19-Cyclobutane Triterpenoid from <italic>Cimicifuga</italic> spp., Ameliorates Atherosclerosis via ABCG1 and LXR Upregulation.","authors":"Siyun Xu, Yongrui Yang, Honglu Liu, Yan Yang, Xiaofei Li, Yingrong Du, Nihong Lu","doi":"10.1159/000547674","DOIUrl":"10.1159/000547674","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>These findings establish actein as a promising natural compound for the treatment of atherosclerosis, warranting further investigation into its therapeutic potential.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"1-9"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144744397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wedelolactone: Unveiling the Multifaceted Anti-Inflammatory Potential.","authors":"Lu Zhang, Di Liu, Qiuyang Huang, Qingyu Zhang, Lingzhi Liu, Yuting Cui, Enkai Li, Kuilong Huang","doi":"10.1159/000550254","DOIUrl":"10.1159/000550254","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Summary: </strong>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.</p><p><strong>Key messages: </strong>This article provides a comprehensive framework integrating mechanistic insights and translational research for WED's clinical development.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"135-144"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3-Hydroxybutyrate Prevents Pulmonary Vein Arrhythmogenesis by Regulating Calcium/Calmodulin-Dependent Protein Kinase II Signaling and Oxidative Stress.","authors":"Chye-Gen Chin, Fong-Jhih Lin, Yao-Chang Chen, Yung-Kuo Lin, Yen-Yu Lu, Satoshi Higa, Yu-Hsun Kao, Shih-Ann Chen, Yi-Jen Chen","doi":"10.1159/000551614","DOIUrl":"10.1159/000551614","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>Using conventional microelectrodes and the patch-clamp technique, we analyzed electrophysiological characteristics and ionic currents in isolated rabbit PV tissues and single PV cardiomyocytes.</p><p><strong>Results: </strong>The effects of 3-OHB (10 m<sc>m</sc>) 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"174-189"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-Linolenic Acid Inhibits Contraction of Pig Basilar Arteries through Prostanoid TP Receptor Antagonistic Action and Activation of K_ir Channels.","authors":"Kento Yoshioka, Haruki Kimura, Keigo Osa, Ayu Kato, Sakika Ichihara, Yuka Saito, Daichi Ito, Ikuya Kogure, Keisuke Obara, Yoshio Tanaka","doi":"10.1159/000548780","DOIUrl":"10.1159/000548780","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"51-58"},"PeriodicalIF":3.2,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Stability of Drugs Commonly Used in Intensive Care Units Co-Administered via Feeding Tube and Its Dependence on pH: An in vitro Study.","authors":"Adriána Papiež, Pavel Suk, Radka Baránková, Pavlína Hančlová, Vladimír Šrámek, Klára Odehnalová","doi":"10.1159/000550187","DOIUrl":"10.1159/000550187","url":null,"abstract":"<p><p><p>Introduction: The administration of medication through feeding tubes (FTs) represents a critical aspect of routine nursing practice. Although guidelines recommend the separate administration of medications to minimize potential interactions, it is common practice in the clinical settings for medications to be combined and administered simultaneously. Since there is a lack of data on this topic, this study assesses the stability of drugs crushed and mixed in water solution concurrently for administration through FT.</p><p><strong>Methods: </strong>The drug compatibility was evaluated in vitro by monitoring the changes in drug content in water solution over time and identifying potential degradation products using a high-performance liquid chromatography system.</p><p><strong>Results: </strong>The majority of drugs (acetylsalicylic acid, clopidogrel, atorvastatin, furosemide, and prasugrel) maintained their stability during the entire preparation process. The only medication that showed degradation over time was pantoprazole (especially when combined with acetylsalicylic acid and clopidogrel), which was attributed to the acidic environment. The remaining drugs (acetylsalicylic acid, clopidogrel, atorvastatin, furosemide, and prasugrel) maintained their stability during the entire preparation process.</p><p><strong>Conclusion: </strong>This study proves that most drugs can be prepared and administered simultaneously, with the exception of acid-labile drugs, which undergo significant degradation in acidic solutions. </p>.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"145-152"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytochemicals as Emerging Antiproliferative Agents in Head and Neck Cancer: Molecular Mechanisms and Therapeutic Strategies.","authors":"Livia Ramos Santiago, Estéfani Alves Asevedo, Moon Nyeo Park, Trina E Tallei, Rosy Iara Maciel de Azambuja Ribeiro, Sang-Won Shin, Bonglee Kim","doi":"10.1159/000550172","DOIUrl":"10.1159/000550172","url":null,"abstract":"<p><p><p>Background: Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies beyond conventional treatments. The increasing interest in natural and synthetic antiproliferative compounds is driven by their ability to target oncogenic pathways implicated in tumor progression, metastasis, and drug resistance. This review explores the potential of bioactive phytochemicals and molecularly targeted therapies, particularly epidermal growth factor receptor (EGFR) inhibitors, in modulating cancer cell survival, proliferation, and immune evasion. A central focus is placed on the phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), JAK/STAT, and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways, which are frequently dysregulated in therapy-resistant cancers, particularly head and neck cancer. Summary: Emerging evidence suggests that phytochemicals such as curcumin, resveratrol, and flavonoids not only suppress oncogenic signaling but also enhance apoptosis, inhibit epithelial-mesenchymal transition, and regulate oxidative stress responses. Additionally, recent preclinical and clinical studies indicate that combinatorial applications of phytochemicals with targeted agents can sensitize resistant tumors to chemotherapy and immunotherapy, thereby improving therapeutic efficacy. However, a major challenge limiting the clinical translation of phytochemicals is their low bioavailability and rapid metabolism. Advances in nanoparticle-based drug delivery, synthetic derivatives, and CRISPR-mediated genome editing offer promising solutions to overcome these limitations, ensuring optimal stability, targeted delivery, and enhanced anticancer activity. Key Messages: By integrating traditional phytotherapy with modern molecular oncology, this review highlights novel synergistic strategies that may revolutionize cancer treatment, paving the way for personalized anticancer therapeutics. DBCs and herbal medicine influence key oncogenic pathways, including EGFR, PI3K/AKT, and MEK/ERK. Human papillomavirus (HPV)-positive and HPV-negative tumors exhibit distinct molecular profiles, affecting their response to conventional treatments and adjunctive therapies. Polyphenols such as curcumin, resveratrol, and quercetin, along with herbal extracts including Scutellaria baicalensis and Camellia sinensis, demonstrate the ability to modulate oxidative stress, apoptosis, and immune responses while reducing therapy resistance. Nanoparticle-based formulations improve the bioavailability of these compounds, enhancing their anticancer effects. However, their effectiveness varies based on the HPV status of the tumor, with HPV-positive cancers showing greater sensitivity to immune-modulating compounds. </p>.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"74-100"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12890273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity and Regulatory Mechanisms of ALK-Mutant and Wild-Type Epithelial Cells in Non-Small-Cell Lung Cancer: Single-Cell Transcriptomics and Chromatin Accessibility.","authors":"Yafu Zhou, Manni Yi, Jianhua Yan, Huiguo Chen, Jingsong Yang","doi":"10.1159/000550967","DOIUrl":"10.1159/000550967","url":null,"abstract":"<p><strong>Introduction: </strong>Anaplastic lymphoma kinase (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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 multidirectional MIF interactions. ALK-mutant cells showed increased global chromatin accessibility. Motif analysis revealed enrichment of polycomb repressive complex (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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"153-173"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sappanone A Targets Transcription Factor EB to Promote Lysosomal Autophagy and Attenuate High Glucose-Induced Myocardial Injury.","authors":"Chenchen Zhang, Chuanqi Zhang, Caiyun Yang, Li Zhang","doi":"10.1159/000551971","DOIUrl":"10.1159/000551971","url":null,"abstract":"<p><strong>Introduction: </strong>Diabetic cardiomyopathy (DCM) involves myocardial injury under hyperglycemia, where impaired autophagy and oxidative stress play critical roles. This study explores whether sappanone A (a natural compound) alleviates DCM by activating transcription factor EB (TFEB)-mediated lysosomal autophagy.</p><p><strong>Methods: </strong>In vitro: H9c2 cardiomyocytes were injured with high glucose (HG) and treated with sappanone A. Cell viability (Cell Counting Kit-8), apoptosis (flow cytometry), reactive oxygen species (ROS; DCFH-DA), and autophagy markers (LC3-II/I, p62, LAMP1 via WB/quantitative real-time PCR) were assessed. In vivo: STZ-induced DCM mice received sappanone A (10 mg/kg/day, 8 weeks). Cardiac function (echocardiography), serum atrial natriuretic peptide/brain natriuretic peptide (enzyme-linked immunosorbent assay), histopathology (H&E/Masson), and autophagy flux (TFEB/LAMP1) were analyzed. TFEB-knockout models and chloroquine (CQ, autophagy inhibitor) validated mechanistic links.</p><p><strong>Results: </strong>Sappanone A dose-dependently enhanced HG-injured cardiomyocyte survival, reduced apoptosis and ROS, while upregulating TFEB nuclear translocation and lysosomal function. In DCM mice, it improved ejection fraction, reduced fibrosis, and restored autophagic flux. These effects were abolished in TFEB-knockout models or with CQ co-treatment, confirming TFEB-dependent autophagy as the core mechanism.</p><p><strong>Conclusion: </strong>Sappanone A protects against DCM by activating TFEB-driven lysosomal autophagy, mitigating oxidative stress, and preserving cardiac function. It represents a novel therapeutic candidate for DCM.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"190-204"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}