European journal of pharmacology最新文献

{"title":"Delirium risk associated with esketamine, sevoflurane, propofol, and dexmedetomidine: A real-world study based on the FDA adverse event reporting system","authors":"Yichun Shuai,&nbsp;Yan Liu,&nbsp;Xiahong Yang,&nbsp;Qiaoqian Wan,&nbsp;Jie Zhao,&nbsp;Xin Wang","doi":"10.1016/j.ejphar.2025.177723","DOIUrl":"10.1016/j.ejphar.2025.177723","url":null,"abstract":"<div><h3>Objective</h3><div>Delirium is a serious postoperative complication, increasingly recognized for its heightened risk following the use of sedative drugs. This study aimed to assess the relationship of esketamine, sevoflurane, propofol, and dexmedetomidine with the risk of delirium.</div></div><div><h3>Methods</h3><div>Data were obtained from the FDA Adverse Event Reporting System (FAERS) database covering the period from the first quarter of 2004 to the second quarter of 2024. Cases of delirium associated with these medications were identified using preferred terms (PTs) defined by the Medical Dictionary for Regulatory Activities (MedDRA 20.0). Disproportionality analyses employed reported odds ratios (ROR) and multiple gamma-Poisson shrinkage (MGPS), while logistic regression assessed the effects of age and sex on the risk of delirium.</div></div><div><h3>Results</h3><div>A total of 21,433,114 adverse events (AEs) were recorded in the FAERS database, including 16 cases of delirium associated with esketamine, 189 with propofol, 90 with sevoflurane, and 103 with dexmedetomidine. Propofol (ROR: 5.44, EBGM05: 4.8), sevoflurane (ROR: 9.9, EBGM05: 8.26), and dexmedetomidine (ROR: 21.1, EBGM05: 17.67) were significantly associated with the delirium risk, whereas esketamine (ROR: 1.45, EBGM05: 0.96) did not show a significant association. Age was identified as a significant risk factor for delirium, particularly in patients aged 55 years and older.</div></div><div><h3>Conclusion</h3><div>The findings indicate a significant correlation between propofol, sevoflurane, and dexmedetomidine and the risk of delirium, whereas esketamine does not appear to have a significant association with delirium. Future studies should further explore drug administration and dosage effects on delirium risk to improve clinical safety.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177723"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of the novel σ1 receptor ligand (S)-L1 on brain endothelial cells and cerebrovascular reactivity challenged by ischemia","authors":"Szilvia Kecskés ,&nbsp;Mária Mészáros ,&nbsp;Szabolcs Dvorácskó ,&nbsp;Írisz Szabó ,&nbsp;Gergő Porkoláb ,&nbsp;Lilla Barna ,&nbsp;András Harazin ,&nbsp;Anikó Szecskó ,&nbsp;Ákos Menyhárt ,&nbsp;Ferenc Bari ,&nbsp;Mária A. Deli ,&nbsp;Botond Penke ,&nbsp;Eszter Farkas ,&nbsp;Szilvia Veszelka","doi":"10.1016/j.ejphar.2025.177724","DOIUrl":"10.1016/j.ejphar.2025.177724","url":null,"abstract":"<div><div>Intracellular sigma-1 receptors (σ₁ receptors) have a versatile function through the regulation of lipid rafts, neuroreceptors and ion channels, and can influence signal transduction and neuronal plasticity. Since decreased activity of σ₁ receptors is a common pathological feature in the early stages of many neurological diseases, σ₁ receptor agonists may represent a promising therapeutic tool for the treatment of these disorders. In this study, we aimed to comprehensively investigate the potential protective effects of the novel synthetic σ₁ receptor agonist (S)-L1 against endothelial endoplasmic reticulum (ER) stress and cerebral ischemia. In binding affinity experiments, we showed that (S)-L1 has a high affinity and selectivity for σ₁ receptor with virtually no affinity for any of the other receptors tested. Next, (S)-L1 exerted protection against endoplasmic reticulum stress in human brain endothelial cells, consistent with the localization of σ₁ receptors in endothelial cells. Furthermore, (S)-L1 penetration was demonstrated across the cell culture model of the blood-brain barrier, providing a rationale for neuronal action in addition to endothelial protection. Finally, (S)-L1 inhibited spreading depolarization, suppressed apoptosis and rescued astrocytes in a rat model of cerebral ischemia. Based on our results, (S)-L1 exerts a protective effect on both brain endothelial cells and neural tissue. Moreover, since these experiments revealed no affinity for serotonergic receptors, the compound holds promise as an adjuvant therapy for the treatment of cerebrovascular disease without potential psychedelic side effects.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177724"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of butyrate against heat Stress–Induced intestinal damage, systemic inflammation, and multiple organ Dysfunction: Insights from in vitro and in vivo experiments","authors":"Hung-Yen Ke ,&nbsp;Ming-Hua Chen ,&nbsp;Cheng-Ming Tsao ,&nbsp;Hiong-Ping Hii ,&nbsp;Chia-Wen Kuo ,&nbsp;Shuk-Man Ka ,&nbsp;Chin-Chen Wu ,&nbsp;Chih-Chin Shih","doi":"10.1016/j.ejphar.2025.177710","DOIUrl":"10.1016/j.ejphar.2025.177710","url":null,"abstract":"<div><div>Global warming is a major risk factor for life-threatening heat stroke (HS). Systemic inflammation plays a key role in the pathophysiology of HS, substantially affecting clinical outcomes. Reduced intestinal blood flow during HS causes ischemia-reperfusion injury, compromising the intestinal barrier and triggering systemic inflammation and organ damage. Butyrate, a short-chain fatty acid, plays a multifaceted role in maintaining intestinal health, inhibiting inflammation, and alleviating oxidative stress. Therefore, this study aimed to evaluate butyrate's therapeutic potential against HS and explored the mechanisms underlying its protective effects. Male Wistar rats were divided into 4 groups: control, control + butyrate, HS, and HS + butyrate. Hemodynamic changes, biochemical parameters, coagulation markers, cytokine levels, polymorphonuclear neutrophil infiltration, and survival rates were analyzed. Additionally, ileal samples (from rats) and LS174T cells were used to investigate the effect of butyrate on intestinal function. Heat stress induced cytotoxicity; reduced transepithelial resistance in intestinal goblet cells; and triggered intestinal inflammation, oxidative stress, and apoptosis in HS rats. These rats exhibited systemic inflammation, hypotension, tachycardia, coagulopathy, multiple organ dysfunction, and mortality. Butyrate treatment reduced cytotoxicity and improved transepithelial resistance in LS174T cells. Butyrate also reduced intestinal heat stress, inflammation, oxidative stress, and apoptosis, as well as systemic inflammation in HS rats. Furthermore, butyrate ameliorated hypotension, tachycardia, coagulopathy, and multiple organ dysfunction and increased survival in HS rats. These findings indicate that butyrate is a promising intervention for mitigating heat stress–induced intestinal damage, systemic inflammation, and multiple organ dysfunction.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177710"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OpiCa1 reduces inflammation and ROS levels counteracting heat stress-induced cardiac injury","authors":"Zhixiao Yang ,&nbsp;Xiaoyu Hua ,&nbsp;Fei Wang ,&nbsp;Yi Wang ,&nbsp;Xiaochuan Hou ,&nbsp;Fengling Yang ,&nbsp;XiaoXiao Chen ,&nbsp;Tianwen Liu ,&nbsp;Xiaofen Ma ,&nbsp;Héctor H. Valdivia ,&nbsp;Liang Xiao ,&nbsp;Baojing Li","doi":"10.1016/j.ejphar.2025.177711","DOIUrl":"10.1016/j.ejphar.2025.177711","url":null,"abstract":"<div><div>Heat stress exacerbates heart disease by increasing myocardial workload, and long-term exposure to high temperatures elevates cardiovascular risks. As a natural cell-penetrating peptide, OpiCa1 can rapidly bind to ryanodine receptors (RyRs), inducing a semi-open conformation and triggering calcium release. We explored OpiCa1's protective role against heat stress at 42 °C using cell viability assays, transcriptomics, and whole animal studies. Experiments showed that OpiCa1 treatment in heat-stressed H9C2 cells significantly reduced ROS, apoptosis, and inflammatory factors while increasing cell survival. OpiCa1 binds to RyRs, inducing a subconductive state and consequently restoring mitochondrial calcium homeostasis. It inhibits FOS-mediated apoptosis via modulation of the Bax/Bcl-2 ratio and suppresses inflammatory responses by regulating MAPK and PI3K signaling pathways. In heat-stressed mice, OpiCa1 significantly mitigated cardiac injury, reduced the expression levels of IL-1α and IL-6, and improved tissue integrity. Our findings reveal OpiCa1's dual function in mitigating oxidative stress and inflammation via critical apoptotic and signaling pathways, thereby presenting a promising therapeutic approach for heat-related cardiovascular disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177711"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydromyricetin restores mucus hypersecretion in Air–Liquid interface cultures in COPD by targeting the SRC-MAPK signaling pathway","authors":"Yiqi Liu ,&nbsp;Nan Di ,&nbsp;Changjiang Li ,&nbsp;Yachao Cui ,&nbsp;Jinlan He ,&nbsp;Liping Wei","doi":"10.1016/j.ejphar.2025.177703","DOIUrl":"10.1016/j.ejphar.2025.177703","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition characterized by chronic respiratory symptoms due to bronchitis and emphysema, often leading to persistent airflow obstruction. Dihydromyricetin (DHM), a Garcinia cambogia extract, exhibited anti-inflammatory, antitumor, and antioxidant effects without significant toxicity to normal cells in vitro and <em>in vivo</em>. This study aimed to investigate the effect of DHM on mucus hypersecretion in air–liquid interface (ALI) cultures in COPD and to explore the underlying mechanism. Bronchial epithelial cells from five COPD patients and five Non-COPD subjects were collected by bronchoscopy at ALI. ALI cultures from COPD and Non-COPD subjects, as well as airway organoids, were differentiated for 2 weeks subsequently treated with DHM (50 μM) for an additional 2 weeks. The potential molecular mechanisms of DHM were investigated using network pharmacology analysis and molecular docking techniques. DHM reduced mucus hypersecretion and increased cilia number in ALI cultures (Average fold change = 6.52, <em>P</em> = 0.0033; average fold change = 11.56, <em>P</em> = 0.0011) and airway organoids (average fold change = 1.68, <em>P</em> = 0.0096; average fold change = 1.60, <em>P</em> = 0.0130) from COPD patients. Network pharmacology analysis, supported by experimental validation, confirmed that DHM alleviated COPD-related mucus hypersecretion and improved ciliary morphology by binding to SRC and regulating autophagy-related proteins and the MAPK signaling pathway. These findings suggest that DHM could be a potential therapeutic agent for preventing mucus hypersecretion in COPD. This study is the first to combine network pharmacology analysis to investigate the mechanism of DHM in alleviating COPD-associated mucus hypersecretion.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177703"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of glucagon-like peptide-1 receptor in fisetin tetramethyl ether-enhanced insulin secretion in MIN6 cells","authors":"Kazunori Hashimoto ,&nbsp;Chihiro Ito ,&nbsp;Eka Takahashi ,&nbsp;Rico Nishio ,&nbsp;Ryoga Tsurigami ,&nbsp;Naoto Kato ,&nbsp;Satsuki Miyazaki ,&nbsp;Jun-ichi Miyazaki ,&nbsp;Motoyuki Shimizu ,&nbsp;Masashi Kato ,&nbsp;Hugh T.-W. Tan ,&nbsp;Tomiyasu Murata","doi":"10.1016/j.ejphar.2025.177722","DOIUrl":"10.1016/j.ejphar.2025.177722","url":null,"abstract":"<div><h3>Background</h3><div><em>Pongamia pinnata</em> (L.) Pierre, long used as a traditional medicine to treat diabetes and metabolic disorders, shows an insulinotropic effect.</div></div><div><h3>Objective</h3><div>This study aimed to determine the insulinotropic property and underlying mechanism of a constituent of <em>Pongamia pinnata</em>, fisetin tetramethyl ether (FTM).</div></div><div><h3>Methods</h3><div>The insulinotropic property of FTM was investigated using pancreatic beta cell line MIN6, while secreted insulin and residual insulin were detected by an insulin assay. Furthermore, the underlying mechanism was examined with use of an ATP assay, Ca²⁺ flux assay, and immunoblot analysis, as well as the insulin assay with pharmacological inhibitors.</div></div><div><h3>Results</h3><div>FTM increased insulin secretion in a dose-dependent manner. In addition, 10 mM or more of glucose increased insulin secretion regardless of the presence of FTM. Nimodipine, a voltage-dependent Ca channel antagonist, completely eliminated insulin secretion induced by glucose and FTM. However, FTM treatment had minimal effects on ATP and intracellular Ca²⁺ levels, suggesting its enhancement of glucose-stimulated insulin secretion (GSIS) independent of glucose metabolism. Additionally, a newly developed glucagon-like peptide-1 (GLP-1) receptor antagonist, VU0650991, reduced FTM-enhanced GSIS. Moreover, FTM-enhanced GSIS was reduced by barbadin, an inhibitor of the β-arrestins-mediated signaling pathway, as well as GSK215, a degrader of focal adhesion kinase (FAK), though not by HJC0350, an inhibitor of exchange protein activated by cAMP 2 involved in insulin granule exocytosis.</div></div><div><h3>Conclusion</h3><div>The GLP-1 receptor-β-arrestins/FAK pathway is involved in FTM-enhanced GSIS. This study showed that FTM, a constituent of <em>Pongamia pinnata</em>, is an insulinotropic phytochemical possessing biased GLP-1 receptor agonistic potential.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177722"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caffeine plays a prevention role in stress-induced depression by modulating gut-brain axis function","authors":"Wentao Wu ,&nbsp;Jiaolin Wang ,&nbsp;Jianjun Chen ,&nbsp;Jing Xie ,&nbsp;Ke Xu ,&nbsp;Yi Ren ,&nbsp;Qi Zhong ,&nbsp;Fei He ,&nbsp;Ying Wang ,&nbsp;Peng Xie","doi":"10.1016/j.ejphar.2025.177721","DOIUrl":"10.1016/j.ejphar.2025.177721","url":null,"abstract":"<div><h3>Background</h3><div>Caffeine intake is inversely associated with depression in epidemiological studies and can impact gut microbiota. Considering the close relationship between depression and gut microbiota, we conducted this study to investigate whether prophylactic caffeine use could influence the development of depression by affecting gut-brain axis.</div></div><div><h3>Methods</h3><div>Male C57BL/6J mice were randomly divided into three groups: a control group, one group receiving chronic unpredictable stress (CUS) as CUS group, and one group receiving CUS after intraperitoneal injection with caffeine (CAF) as CAF group. Depressive- and anxiety-like behaviors were assessed, and gut-brain axis related molecules were examined.</div></div><div><h3>Results</h3><div>Compared to control group, CUS group had significantly lower body weight, sucrose preference, center distance (%) and higher immobility time; however, the values of these indexes were similar between control group and CAF group. Furthermore, the significantly decreased intestinal barrier integrity-related factors (Zonula Occludens-1 (ZO-1), claudin-1 and Mucin2 (MUC2)) in CUS were not observed in CAF group; and the altered levels of two inflammation factors in plasma (lipopolysaccharide (LPS) and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3)) and four inflammation-related factors in hippocampus (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), adenylyl cyclase (AC) and brain-derived neurotrophic factor (BDNF)) in CUS group were not observed in CAF group. In addition, we found that six differential genera were identified between control group and CUS group, but not between control group and CAF group; and sucrose preference were significantly correlated with five of these six differential genera.</div></div><div><h3>Conclusions</h3><div>The results suggested that early caffeine intervention might prevent depression by regulating gut microbiota, intestinal barrier integrity and neuroinflammation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177721"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calycosin regulates gut microbiota-bile acid-FXR axis to protect rats from cerebral ischemia-reperfusion injury","authors":"Yujia Zhou ,&nbsp;Wenke Song ,&nbsp;Yaru Wang ,&nbsp;Simeng Li ,&nbsp;Chuchu Shan ,&nbsp;Jingyi Dong ,&nbsp;Zhengyuan Xu ,&nbsp;Haonan Zou ,&nbsp;Yifeng Pan ,&nbsp;Xingying Chen ,&nbsp;Yuyan Zhang ,&nbsp;Jingmei Song","doi":"10.1016/j.ejphar.2025.177707","DOIUrl":"10.1016/j.ejphar.2025.177707","url":null,"abstract":"<div><div>Recent reports have shown that metabolites derived from gut microbiota play a vital role in intestinal diseases, immune regulation, and neuroinflammation. Nowadays, calycosin has been revealed the protective mechanism from different perspectives on cerebral ischemia-reperfusion injury (CIRI), while the effect of gut microbiota-bile acid-farnesoid X receptor (FXR) axis on the inflammatory protection of CIRI has not been explored. To this end, we established a middle cerebral artery occlusion (MCAO) model firstly to assess the protection of calycosin in CIRI through neurological deficit scoring, TTC staining, and HE staining. Secondly, 16s RNA sequencing, ELISA, real-time qPCR, Western blot, and total bile acid (TBA) detection kit were utilized to detect the pharmacology of calycosin on MCAO rats. Our data indicated that calycosin could significantly improve nerve function scores, reduce cerebral infarction volume, lower serum levels of IL-10, IL-17 inflammatory factors, and TBA, increase mRNA and protein levels of ZO-1 and Occludin in brain, as well as FXR, ZO-1 and Occludin levels in colon. In summary, calycosin can exert a neuroinflammatory protective effect on CIRI in rats via regulating the gut microbiota to improve bile acid metabolism.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177707"},"PeriodicalIF":4.2,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sitagliptin reduces cytokine-induced β-cell apoptosis in prediabetes: A six-month interventional study","authors":"Rama Ayash ,&nbsp;Younes Kabalan ,&nbsp;Sahar Chamaa","doi":"10.1016/j.ejphar.2025.177708","DOIUrl":"10.1016/j.ejphar.2025.177708","url":null,"abstract":"<div><h3>Objective</h3><div>Islet inflammation, initiated by macrophage infiltration, which activates nuclear factor-kappa B (NF-κB), plays a crucial role in the early stage of diabetes. The study aimed to assess how initial treatment with sitagliptin affects inflammation-driven <strong>β-cell apoptosis by measuring plasma levels of</strong> Fas, Fas Ligand (Fas-L), and Interleukin-1β (IL-1β) in prediabetes.</div></div><div><h3>Patients and methods</h3><div>This prospective interventional study included 56 treatment-naïve patients with impaired fasting glucose (IFG). Participants received either 50 mg sitagliptin twice daily or 100 mg sitagliptin once daily for 6 months. Plasma levels of inflammatory apoptotic markers (Fas, Fas-L, and IL-1β) were measured by ELISA at baseline and after 6 months of treatment. Wilcoxon signed-rank test was used to evaluate changes in biomarker levels. Hierarchical multiple regression analysis was conducted to identify predictors associated with improved β-cell function, as assessed by HOMA-B.</div></div><div><h3>Results</h3><div>After 24 weeks of treatment, significant reductions were observed in plasma levels of Fas, Fas-L, and IL-1β (p &lt; 0.001). Glycemic parameters also improved significantly (p &lt; 0.001). Regression analysis levels were strong negative predictors of HOMA-B (R² = 29.8 %, p &lt; 0.001) and remained significantly associated with improved HOMA-B after treatment (R² = 73.8 %, p = 0.000), with additional contribution from IL-1β.</div></div><div><h3>Conclusion</h3><div>Sitagliptin demonstrates promising therapeutic effects in prediabetes by reducing inflammation-induced β-cell apoptosis. Its potential to suppress pro-apoptotic cytokines underscores its role as an early therapeutic approach.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"999 ","pages":"Article 177708"},"PeriodicalIF":4.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinol improves exemestane efficacy in estrogen receptor-positive breast cancer models: a comparative study with cannabidiol","authors":"Cristina Ferreira Almeida ,&nbsp;Maria João Valente ,&nbsp;Natércia Teixeira ,&nbsp;Susana Rocha ,&nbsp;Ana Paula Ribeiro ,&nbsp;Anne Marie Vinggaard ,&nbsp;Georgina Correia-da-Silva ,&nbsp;Cristina Amaral","doi":"10.1016/j.ejphar.2025.177712","DOIUrl":"10.1016/j.ejphar.2025.177712","url":null,"abstract":"<div><div>Cannabinoids have been used as anti-emetic agents in cancer. However, multiple studies suggest that cannabinoids present important anti-tumor actions as well. Estrogen receptor-positive (ER⁺) breast cancer is the most diagnosed breast cancer subtype, and despite the success of endocrine therapy, endocrine resistance development is a major challenge, demanding the discovery or implementation of alternative therapeutic approaches. In line with this, and following our previous work, the benefits of combining the aromatase inhibitors (AIs) used in the clinic, anastrozole (<strong>Ana</strong>), letrozole (<strong>Let</strong>), and exemestane (<strong>Exe</strong>), with cannabinol (<strong>CBN</strong>) were evaluated. Experiments were performed in MCF-7aro cells and spheroids to assess activity against specific molecular targets and underlying mechanisms of action. Among the three AIs studied, only the combination of <strong>CBN</strong> with <strong>Exe</strong> induced a significant beneficial impact on viability and growth of ER⁺ breast cancer cells and spheroids. Our results demonstrated that this combination was more effective than <strong>Exe</strong> in preventing the expression of aromatase and in modulating ERα and androgen receptor (AR) activity. In fact, the results revealed that <strong>CBN</strong> can prevent <em>de novo</em> synthesis of aromatase, surpass <strong>Exe</strong>'s weak estrogen-like effect, and avoid the unfavorable overexpression of AR. By comparing these two therapeutic strategies, as well as the previously studied combination of <strong>Exe</strong> plus cannabidiol (<strong>CBD</strong>), differential transcriptome profiles were detected, which may help to better understand the mechanism of action of cannabinoids and disclose their full potential in breast cancer treatment. In conclusion, this study strengthens the hypothesis that cannabinoids are important anti-cancer agents with attractive co-adjuvant properties.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1000 ","pages":"Article 177712"},"PeriodicalIF":4.2,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}