Frontiers in Pharmacology最新文献

{"title":"Mechanistic study on the restoration of intestinal barrier integrity and alleviation of inflammatory bowel disease by rhynchophylline via the AhR-NR4A1 pathway.","authors":"Xuwen Mao, Lufeng Cheng, Yu Liu, Yuche Wu","doi":"10.3389/fphar.2025.1629012","DOIUrl":"10.3389/fphar.2025.1629012","url":null,"abstract":"<p><strong>Background: </strong>Restoring intestinal barrier function is considered an effective strategy for the treatment of Inflammatory Bowel Disease (IBD). Rhynchophylline (Rhy), a bioactive alkaloid sourced from the traditional herbs Uncariarhynchophylla used in Chinese medicine, is known for its antihypertensive, anti-asthmatic, and antitumor properties. This study explores the pharmacological effects and molecular mechanisms of Rhy in treating IBD.</p><p><strong>Methods: </strong>In vitro cell inflammation injury model was established, and the inflammatory factors, cell permeability, cell proliferation, and intercellular tight junction protein expression were measured after Rhy intervention, which verified the anti-inflammatory activity and enhancement of intestinal barrier function of Rhy. In vivo animal model of acute and chronic colitis was established, and Rhy was administered orally at three dose levels to evaluate the protective effects of Rhy on acute and chronic colitis in animals. The signaling pathways that enhance the intestinal barrier function of Rhy were identified through transcriptomics, gene knockout techniques, and molecular dynamics simulations.</p><p><strong>Results: </strong>In vitro results indicate that the levels of inflammatory markers-including IL-6, TNF-α, and NO-can be decreased by Rhy, demonstrating anti-inflammatory activity. It significantly lowers cellular permeability, promotes the proliferation of intestinal epithelial cells, and upregulates the expression of tight junction proteins Claudin4, Occludin, and ZO-1. These effects improve cellular morphology and improve the robustness of the intestinal barrier. In vivo, using three types of colitis animal models, Rhy shows significant protective effects on mice with acute and chronic colitis. It markedly reduces weight loss and Disease Activity Index (DAI) scores, prevents colonic shortening, reduces intestinal permeability, and decreases serum levels of IL-6, TNF-α, CXCL1, and IL-1β. These effects restore the structural integrity of colonic tissues and alleviate symptoms of acute and chronic colitis. Additionally, Rhy activates the AhR-NR4A1 pathway. This activation upregulates Claudin4, Occludin, and ZO-1 to repair the intestinal barrier and exert anti-colitic effects.</p><p><strong>Conclusion: </strong>These findings highlight Rhy improve the function and inhibits inflammation, providing dual beneficial activities in the epithelial lining of the gut to prevent and treat colitis.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1629012"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of dexmedetomidine with short-term outcome in patients with cardiogenic shock: a retrospective propensity score-matched cohort study from MIMIC-IV.","authors":"Linfeng Xie, Jing Chen, Bryan Richard Sasmita, Yuanzhu Li, Suxin Luo, Bi Huang","doi":"10.3389/fphar.2025.1644635","DOIUrl":"10.3389/fphar.2025.1644635","url":null,"abstract":"<p><strong>Background: </strong>Dexmedetomidine has been demonstrated to have cardioprotective effects in previous studies, prompting our investigation into its potential to improve survival outcomes in patients with cardiogenic shock (CS).</p><p><strong>Methods: </strong>This retrospective cohort study analyzed data from the Medical Information Mart for Intensive Care (MIMIC) IV database, focusing on patients with CS. Exposure was defined as intravenous dexmedetomidine administration during intensive care unit (ICU) stay. The primary endpoints included 7-day and 30-day all-cause mortality. External validation was conducted using the eICU 2.0 database.</p><p><strong>Results: </strong>The pre-matched and propensity score matched cohorts comprised 2,341 and 1,038 patients, respectively. Multivariable Cox regression analysis of the overall cohort revealed that dexmedetomidine administration was significantly associated with reduced risk of both 7-day (hazard ratio (HR) = 0.473, 95% confidence interval (CI): 0.359-0.624, p < 0.001) and 30-day all-cause mortality (HR = 0.606, 95% CI: 0.500-0.735, p < 0.001). This protective association persisted after propensity score matching (PSM) for 7-day (HR = 0.418, 95% CI: 0.317-0.552, p < 0.001) and 30-day mortality (HR = 0.579, 95% CI: 0.475-0.705, p < 0.001). Subgroup analyses demonstrated that patients older than 75 years, those with chronic pulmonary disease, or those with lower systolic blood pressure may not benefit from dexmedetomidine. External validation using 1411 CS patients from the eICU 2.0 database confirmed these findings, with PSM-adjusted analyses showing reduced in-hospital (HR = 0.597; 95% CI: 0.395-0.901; p = 0.014) and in-ICU mortality (HR = 0.425; 95% CI: 0.262-0.689; p < 0.001) among dexmedetomidine treated patients.</p><p><strong>Conclusion: </strong>Dexmedetomidine administration was associated with reduced risk of 7-day and 30-day all-cause mortality in CS patients, though this protective effect may not be significant in patients over 75 years, those with chronic pulmonary disease, or those with lower systolic blood pressure. Prospective studies are required to validate these findings.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1644635"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prescription of EPs 7630 is associated with short- and long-term benefits in acute bronchitis: a real-world data analysis.","authors":"Adrian Gillissen, Thorsten Reineke, Martin Burkart, Petra Funk, Charles Christian Adarkwah, Karel Kostev","doi":"10.3389/fphar.2025.1652203","DOIUrl":"10.3389/fphar.2025.1652203","url":null,"abstract":"<p><strong>Introduction: </strong>Acute bronchitis is caused by an infection of the lower respiratory tract, resulting in considerable distress of patients and substantial economic costs due to lost workdays. Although acute bronchitis is mostly caused by viruses, antibiotics are frequently used. The aim of this study was to evaluate whether a prescription of EPs 7630 for patients with acute bronchitis is associated with a lower recurrence rate of the disease or fewer complications, a reduced need for antibiotic therapy, or fewer lost workdays.</p><p><strong>Methods: </strong>A retrospective analysis was conducted using the IQVIA™ Disease Analyzer database, which contains information from nearly 3,000 office-based physicians, representing around 3%-5% of all German practices. We analyzed the rates of recurrence of acute bronchitis, antibiotic prescription, duration of sick leave, and incidence of complications (pneumonia, chronic bronchitis) with regard to their association with prescriptions of EPs 7630, ambroxol, acetylcysteine, or antibiotics for acute bronchitis.</p><p><strong>Results: </strong>Of the 376,366 patients suffering from acute bronchitis between January 2005 and December 2022, 1,994 received prescription of EPs 7630, 14,952 ambroxol, 24,149 acetylcysteine, and 335,271 antibiotics. EPs 7630 prescription was associated with a significantly lower likelihood of re-consultation due to acute bronchitis within 365 days compared to ambroxol (HR: 0.74; 95% CI: 0.65-0.83), acetylcysteine (HR: 0.78; 95% CI: 0.69-0.88), and antibiotics (HR: 0.75; 95% CI: 0.67-0.85) (p < 0.001 each). The incidence of an antibiotic prescription following an initial EPs 7630 prescription was significantly lower compared to acetylcysteine (HR: 0.89; 95% CI: 0.81-0.98) (p = 0.020). EPs 7630 was also associated with a lower risk of pneumonia and chronic bronchitis and a lower proportion of patients with sick leave lasting >3 and ≥7 days, respectively, compared to the other prescription groups.</p><p><strong>Conclusion: </strong>Prescribing EPs 7630 is associated with a lower incidence of disease recurrence and complications, a reduced need for antibiotic therapy, and a reduction in lost workdays. The results of this retrospective analysis thus emphasize the overall benefits of EPs 7630 as an effective treatment option for managing acute bronchitis.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1652203"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical pharmacist prescriber in primary care in Slovenia: prospective non-randomised interventional study focused on clinical outcomes and quality of life.","authors":"Matej Stuhec, Alenka Kovacic, Marjetka Korpar, Ana Banovic Koscak, Barbara Koder, Dunja Mahoric, Spela Bernik Golubic, Eva Gorup Cedilnik, Vesna Homar, Aleksandar Stepanovic, Danica Rotar Pavlic","doi":"10.3389/fphar.2025.1690480","DOIUrl":"10.3389/fphar.2025.1690480","url":null,"abstract":"<p><strong>Introduction: </strong>Clinical pharmacist prescribers in primary care settings and their impact on patient-reported outcomes (PROs) and clinical outcomes have not been described outside English-speaking countries.</p><p><strong>Aim: </strong>The aim of this prospective interventional pilot study was to assess the impact of pharmacist prescribers on clinical results and patient-reported outcomes (PROs), while describing their development, evaluation, and implementation in Slovenia.</p><p><strong>Methods: </strong>This prospective, 6-month, interventional, non-randomised study started in November 2024 and concluded in June 2025 in four primary care settings in Slovenia. Clinical pharmacists reviewed medications of patients and additionally prescribed medications based on the Collaborative Practice Agreement (CPA). In this process, they cooperated with patients and general practitioners (GPs). Only patients with an established diagnosis for selected non-communicable chronic conditions were included. The primary outcomes were changes in PROs, including quality of life (assessed via EQ-5D-VAS), and the Medication Appropriateness Index (MAI). Secondary outcomes included the prescription acceptance rate by GPs (percentage) and adherence to treatment guidelines. Tertiary outcomes involved the number of prescriptions that met the predefined clinical outcomes.</p><p><strong>Results: </strong>The study included 119 patients, with a mean age of 72.3 years (SD = 10.0). Quality of life improved from 63.6/100 (SD = 18.7) at baseline to 71.4/100 (SD = 15.9) at the end of the study (p = 0.000), with a corresponding QALY difference of 0.0252. The effect size (Cohen's d) was 0.448 (95% CI: 0.084 to 0.812. The number needed to treat (NNT) was 4.0. During the study, clinical pharmacists prescribed 264 prescriptions to 119 patients, resulting in an acceptance rate of 91.3%. Adherence to treatment guidelines improved significantly (29.8% vs. 90.9%; p = 0.000). The effect size, expressed as an odds ratio (OR), was 25.7 (95% CI: 15.6-42.4). The number of prescriptions achieving the predefined clinical outcomes was significantly higher at the end of the study (70.8% vs. 6.4%; p = 0.000), with an OR of 33.9 (95% CI: 19.1-60.4). Deprescribing accounted for 25.3% of all protocols.</p><p><strong>Conclusion: </strong>This study demonstrates that prescriptions made by clinical pharmacists in collaboration with GPs, as specified in the CPA, improved PROs and clinical outcomes for predefined conditions.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1690480"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persimmon leaf extract in dyslipidemia: a systematic review and meta-analysis.","authors":"Chenxuan Dong, Tianying Chang, Xiaoli Wang, Lei Zhou, Lisha Wang, Xiaodan Wang, Yu Sun, Xing Liao, Yingzi Cui, Jiajuan Guo","doi":"10.3389/fphar.2025.1572678","DOIUrl":"10.3389/fphar.2025.1572678","url":null,"abstract":"<p><strong>Aim: </strong>This study aims to evaluate the effects of the combined application of <i>Diospyros kaki</i> Thunb. [Ebenaceae; <i>Kaki folium</i>] (Persimmon leaf) extract on lipid profiles in adults and to explore its potential role in preventing and treating lipid disorders and associated diseases, including common comorbidities such as cardiovascular and cerebrovascular diseases, as well as medication-induced dyslipidemia.</p><p><strong>Methods: </strong>From the inception of the database to 1 November 2024, we retrieved randomized controlled trials (RCTs) from eight English and Chinese databases.</p><p><strong>Results: </strong>A total of 704 articles were retrieved, from which 16 studies were selected for inclusion in the systematic review and meta-analysis. These studies encompassed 1,572 patients, with 790 assigned to the treatment group and 782 to the control group. Among the dyslipidemia patients included in the study, the most common comorbidities were coronary artery disease, hypertension, ischemic cerebrovascular disease, and dyslipidemia induced by olanzapine, among others. Compared with the control group, the use of combined Persimmon leaf extract (PLE) significantly reduced total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, while demonstrating a certain degree of improvement in high-density lipoprotein cholesterol (HDL-C) levels.</p><p><strong>Conclusion: </strong>PLE has been shown to be effective in improving blood lipid profiles in patients, suggesting its potential for widespread clinical application. However, the significant heterogeneity observed across existing studies, coupled with the frequent occurrence of methodological flaws, emphasizes the need for well-designed clinical trials with large sample sizes and extended follow-up periods.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=562090, identifier CRD42024562090.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1572678"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision dosing of voriconazole in immunocompromised children under 2 years: integrated machine learning and population pharmacokinetic modeling.","authors":"Li Shen, Mengdi Hu, Xiaoyong Xu, Yuxuan Zhou, Wei Wu, Xilin Ge, Guangfei Wang, Yi Wang, Zhiping Li","doi":"10.3389/fphar.2025.1671652","DOIUrl":"10.3389/fphar.2025.1671652","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to develop an individualized dosing strategy for voriconazole (VRZ) in children under 2 years of age by integrating machine learning (ML) and population pharmacokinetic (PopPK) modeling.</p><p><strong>Methods: </strong>This retrospective observational study included 76 eligible pediatric patients for model development, analyzing their baseline characteristics and laboratory parameters. A population pharmacokinetic (PopPK) model using NONMEM^® software was performed to assess the clearance (CL) and volume of distribution (V) of VRZ. The individual CL and V were included as input variables. The Boruta algorithm was employed for feature selection, after which six machine learning algorithms were applied. The models were evaluated using Mean Squared Error (MSE), Root Mean Squared Error (RMSE), Mean Absolute Error (MAE), and coefficient of determination (R²) to identify the optimal algorithm, which then underwent independent external validation. The selected final model was analyzed for interpretability using Shapley Additive Explanations (SHAP).</p><p><strong>Results: </strong>A total of 76 pediatric patients were enrolled for model development, consisting of 58 males (76.3%) and 18 females (23.7%), with a median age of 11 months and a median weight of 8.05 kg. We analyzed 110 therapeutic drug monitoring (TDM) samples of VRZ from these participants. A one-compartment model with first-order absorption and elimination described the population pharmacokinetics of VRZ. Population estimates for apparent clearance (CL/F) and volume of distribution (V/F) were 17.9 L/h/70kg (RSE, 10.8%) and 788 L/70kg (RSE, 15.4%), respectively. An XGBoost model accurately predicted voriconazole concentrations (R² = 0.81, RMSE = 0.53) with a relative error of ±20% for most observations. In the external validation, the XGBoost model demonstrated an R² of 0.75, RMSE of 0.14. SHAP analysis identified clearance, weight, and laboratory values as significant predictors.</p><p><strong>Conclusion: </strong>This study emphasized the importance of personalized treatment in utilizing VRZ for children under 24 months. The XGBoost model demonstrated potential in identifying an initial dose recommendation for VRZ.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1671652"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breaking the cancer code: a novel DNA minicircle to disable STAT3 in ovarian cancer cells SKOV3.","authors":"Adina-Gabriela Vasilescu, Andrei-Mihai Vasilescu, Livia Elena Sima, Natalia Baran, Ștefan-Eugen Szedlacsek","doi":"10.3389/fphar.2025.1673427","DOIUrl":"10.3389/fphar.2025.1673427","url":null,"abstract":"<p><strong>Introduction: </strong>Ovarian Cancer remains a significant global health concern, with high mortality rates, largely due to late-stage diagnosis and limited treatment options. These extrinsic factors are driven or exacerbated by intrinsic mechanisms such as persistent activation or upregulation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 promotes tumor growth, inhibits apoptosis, accelerates angiogenesis and metastasis, facilitates immune evasion, and contributes to chemoresistance. Consequently, STAT3 activation fosters an aggressive ovarian cancer phenotype, contributing to treatment failure, poor prognosis and low survival rates, highlighting the urgent need for novel, safe, effective and affordable STAT3-targeted therapeutic strategies. In this study, we developed a novel double-stranded DNA minicircle (mcDNA) inhibitor, designed to act as a decoy for STAT3, preventing its binding to target gene promoters.</p><p><strong>Methods: </strong>Utilizing the SKOV3 ovarian cancer cell line, we evaluated the effects of our inhibitor <i>in vitro</i> on cell viability through MTS assay, its apoptotic and necrotic effects using flow cytometry and the expression modulation of downstream STAT3-regulated genes, assayed through RT-qPCR and Western blot analysis.</p><p><strong>Results: </strong>We demonstrate that anti-STAT3 mcDNA significantly reduces the viability of SKOV3 cells at low nanomolar concentrations, while sparing the control group. The effect observed was dose-dependent. Mechanistically, anti-STAT3 mcDNA induces apoptosis and necrosis in treated cells, also revealing a certain dose-dependency, while also decreasing cell proliferation. Finally, our inhibitor significantly downregulates STAT3-dependent anti-apoptotic genes <i>MCL1</i> and <i>PIM1</i>.</p><p><strong>Conclusion: </strong>These findings suggest that anti-STAT3 mcDNA is a promising, effective and specific candidate for targeted STAT3 inhibition in SKOV3 ovarian cancer cells, warranting further validation in ovarian cancer, <i>in vivo</i> exploration and potential application in other types of malignancies, where STAT3 acts as an oncogenic factor.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1673427"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytochemical combinations of lichen <i>Evernia prunastri</i> (L.) Ach. reduce drug resistance to temozolomide but not to paclitaxel <i>in vitro</i>.","authors":"A Shcherbakova, L Nguyen, A Koptina, A Backlund, S Banerjee, E Romanov, G Ulrich-Merzenich","doi":"10.3389/fphar.2025.1633978","DOIUrl":"10.3389/fphar.2025.1633978","url":null,"abstract":"<p><strong>Introduction: </strong>Temozolomide (TMZ) and Paclitaxel (PXT), crucial anti-cancer drugs for glioblastoma (GBM) and primary breast cancer (BC), respectively, face drug resistance. Therefore, we investigated the adjuvant potential of characterized extracts of the lichens <i>Evernia prunastri</i> (L.) Ach. (Epr), <i>Cladonia arbuscula</i> (Wallr.) Flot (Car) and their metabolites, evernic acid (EA) and usnic acid (UA) alone or in combination with TMZ and PTX for their immunomodulatory and chemosensitivity increasing potential.</p><p><strong>Methods: </strong>TMZ-resistant U-87 cells, MCF7 BC-cells, and normal human skin fibroblasts (HSKF) were treated with hexane (Hex), dichloromethane (DCM), and acetonitrile (ACN) extracts of Epr (EprDCM, EprACN), Car (CarHex, CarACN), and with EA and UA to measure cell metabolic activity. Molecular mechanisms were predicted using ChemGPS-NP and validated by Western blot, RNA sequencing, quantitative RT-PCR, and Wnt inhibitory factor 1 (WIF1) protein expression. Combinatory effects were calculated by Combination Index (CI) and Zero Interaction Potency methods (ZIP).</p><p><strong>Results: </strong>Extracts and selected metabolites reduced concentration-dependent cellular metabolic activity in U-87 and MCF7 cells. EprACN and EA (U-87 cells: IC₅₀ 30 μg/mL), safe to HSKF, regulated key proteins in MAP kinases pathways, supporting predictions made by ChemGPS-NP. The combination EA-TMZ showed additive effects (TMZ-reduction: 3.4 fold), reduced transcription of Wnt pathway members, and increased in U-87 cells protein releases of WiF1, the central inhibitor of Wnt-signaling. Further gene expression data (GE) suggest involvement of IL-17 receptor and BDNF.</p><p><strong>Discussion: </strong>The combination EA-TMZ interacts with the Wnt pathway regulation associated with sensitizing U-87 cells, without increasing GEs of pro-inflammatory cytokines. EA deserves further investigation as an adjuvant.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1633978"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Stephania tetrandra S.</i> Moore: a promising candidate drug for treating diabetic kidney disease.","authors":"Wenru Wang, Jixin Li, Yan Yan, Qin Zeng, Lei Yan, Xinhui Wang, Ying Liang, Renhuan Yu","doi":"10.3389/fphar.2025.1651023","DOIUrl":"10.3389/fphar.2025.1651023","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a common microvascular complication of diabetes. With the continuous rise in the prevalence of diabetes, it has become the primary cause of end-stage renal disease. Currently, there are no effective clinical treatments available to reverse the progression of DKD. <i>Stephania tetrandra S.</i> Moore, a traditional Chinese medicine, has demonstrated significant value in the prevention and treatment of DKD due to its active components. This study focuses on exploring the molecular mechanisms through which the primary active components of <i>S. tetrandra</i>, tetrandrine/sinomenine and fangchinoline, exert renal protective effects via multiple pathways, including regulating inflammatory responses, antagonizing oxidative stress, improving glomerular endothelial function, modulating podocyte damage, and intervening in lipid metabolism disorders. These findings provide a theoretical basis for the development of novel therapeutic agents for DKD.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1651023"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual GSK3β/SIRT1 modulators for Alzheimer's: mechanisms, drug discovery and future perspectives.","authors":"Afeez I Kareem, Erika Kapp, Jacques Joubert, Xiaoqin Zou","doi":"10.3389/fphar.2025.1662241","DOIUrl":"10.3389/fphar.2025.1662241","url":null,"abstract":"<p><p>Alzheimer's disease (AD) remains without effective disease-modifying therapies, in part due to the limited efficacy of single-target approaches. Dual modulation of glycogen synthase kinase-3β (GSK3β), a key driver of tau hyperphosphorylation and amyloid-β (Aβ) production, and sirtuin-1 (SIRT1), a neuroprotective NAD⁺-dependent deacetylase, has emerged as a promising therapeutic strategy. This review explores the mechanistic rationale for concurrently inhibiting GSK3β and activating SIRT1 to disrupt AD's pathological cascade while enhancing endogenous neuroprotective pathways. Natural compounds such as resveratrol, berberine, pterostilbene, and quercetin exhibit this dual activity and provide scaffolds for rational drug design. However, challenges related to target selectivity, blood-brain barrier penetration, and clinical translation persist. Advances in multi-target drug discovery, including pharmacophore hybridization, structure-based modelling, cheminformatics, nanoformulation and delivery strategies offer new avenues to overcome these hurdles. A dual GSK3β/SIRT1-targeting strategy exemplifies a systems-level approach to restoring neurophysiological balance and holds potential to achieve more effective, disease-modifying outcomes in AD.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1662241"},"PeriodicalIF":4.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}