{"title":"Decoding RNA Therapeutics: Precision Approaches in Women's Health.","authors":"Nazanin Pazhouhesh Far, Hoda Nouri Boroujerdi, Mahshid Seyed Karimi, Payam Vezvaei, Mahsa Behfar, Roya Mirzaei, Reza Habibi, Mahsa Manafi Varkiani, Amir Reza Aref, Nasim Ebrahimi","doi":"10.1016/j.ejphar.2025.178275","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178275","url":null,"abstract":"<p><p>RNA-based technologies are innovating precision medicine, offering novel opportunities for addressing complex and underdiagnosed conditions in women's health. This review provides a structured overview of current RNA-targeted therapies-including messenger RNA (mRNA) vaccines, RNA interference (RNAi), antisense oligonucleotides, and non-coding RNA modulators-and their applications in gynecological cancers, reproductive disorders, pregnancy complications, and hormone-related conditions. We highlight key advances in drug delivery systems (e.g., lipid nanoparticles), companion diagnostics, and precision-informed treatment approaches informed by pharmacogenomics. Special emphasis is placed on the biological and hormonal differences affecting treatment response, as well as the ethical, regulatory, and equity considerations in deploying RNA therapeutics for female populations. Ongoing clinical trials and emerging technologies such as (clustered regularly interspaced short palindromic repeats) CRISPR-based tools and AI-guided biomarker discovery suggest a rapidly expanding frontier. By synthesizing multidisciplinary research, this review underscores the transformative potential of RNA therapeutics in tailoring interventions and improving outcomes for women globally.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178275"},"PeriodicalIF":4.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354213","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}
Chunyang Zhang, Shunfei Liu, Dan Han, Lulu Zeng, Panhui Guo, Zhiwei Gao, Xiaoyuan Luo, Bo Guan, Jiong Gu, Xiangpeng Hu, Jun Liu
{"title":"Neoprzewaquinone A Suppresses Hepatocellular carcinoma through Promoting the Ubiquitin-Related Degradation of EGFR and Inhibiting PI3K-AKT Pathway.","authors":"Chunyang Zhang, Shunfei Liu, Dan Han, Lulu Zeng, Panhui Guo, Zhiwei Gao, Xiaoyuan Luo, Bo Guan, Jiong Gu, Xiangpeng Hu, Jun Liu","doi":"10.1016/j.ejphar.2025.178274","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178274","url":null,"abstract":"<p><strong>Background: </strong>Traditional Chinese medicine (TCM), with its multitargeted effects against tumors and holistic regulatory properties, is a promising candidate for hepatocellular carcinoma (HCC) therapy. Neoprzewaquinone A (NEO), a phenanthrenequinone derivative of Salvia miltiorrhiza Bunge with anti-tumor effect, inhibits the migration and proliferation of breast cancer and human megakaryocytic leukemia cells. However, its function and the mechanism of action in HCC remain unclear.</p><p><strong>Methods: </strong>To evaluate the anti-HCC effectiveness of NEO, we employed patient-derived organoids, HepG2 cell-derived xenograft model, and hepatoma cell lines. Techniques such as molecular docking, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), immunofluorescence staining, immunohistochemistry, quantitative polymerase chain reaction (qPCR), and western blot analysis were used to investigate the underlying molecular mechanisms.</p><p><strong>Results: </strong>In the current study, the anti-HCC effectiveness of NEO was validated using human HCC organoids and HepG2 cell-derived xenograft model. Meanwhile, NEO treatment reduced the viability, proliferation, migration, invasion of hepatoma cells, and increased the apoptosis ratio of hepatoma cells. Next, we found that NEO directly engaged with epidermal growth factor receptor (EGFR) with molecular docking, DARTS, and CETSA. NEO decreased the level of EGFR through promoting ubiquitin-related degradation. NEO treatment suppressed phosphorylated AKT (p-AKT) levels and increased Cleaved Caspase-3 protein expression, as shown by KEGG pathway analysis, which also indicated that NEO modulates the PI3K-AKT signaling pathway.</p><p><strong>Conclusions: </strong>NEO induces apoptosis and suppresses HCC progression by promoting ubiquitin-mediated degradation of EGFR and inhibiting the PI3K-AKT signaling pathway. Our data show that NEO may represent a promising therapeutic agent for HCC.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178274"},"PeriodicalIF":4.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354214","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}
Javier Castro Hernández, Sergio Santos Concepción, José David Machado, Federico Díaz González
{"title":"Role of myeloid cell alpha2-adrenergic receptors in the regulation of inflammatory responses.","authors":"Javier Castro Hernández, Sergio Santos Concepción, José David Machado, Federico Díaz González","doi":"10.1016/j.ejphar.2025.178276","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178276","url":null,"abstract":"<p><p>Inflammation is a complex protective response to harmful aggression that becomes problematic when it is uncontrolled. Macrophages, a type of myeloid cell, play a key role in both initiating and maintaining inflammation. It is well known that dysregulated recruitment of macrophage into tissue can lead to chronic inflammation and the development of several human diseases. The α2-adrenergic receptors are cell surface proteins expressed in several cell-types including macrophages to which recent evidence suggests that they play an important role in the modulation of inflammation. This study aimed to investigate the role of α2-adrenergic receptors in macrophage activation, survival, and cytokine production. Additionally, it explored their influence on myeloid cell infiltration and overall clinical outcomes in two in vivo mouse models of inflammation. In the air pouch model, an acute mouse model of inflammation, guanfacine, an α2 adrenergic agonist, reduces myeloid cell infiltration and levels of pro-inflammatory cytokines by specifically targeting the α2A adrenergic receptor subtype. In the K/BxN arthritis mouse model, guanfacine significantly modulated the clinical and functional outcome of arthritis. In vitro, guanfacine facilitated programmed cell death of pro-inflammatory macrophages and inhibited the accumulation of large macrophages. This study highlights the role of macrophages in inflammation and suggests that α2A adrenergic receptor activation may help control inflammation by modulating macrophage accumulation at the inflammatory foci.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178276"},"PeriodicalIF":4.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354215","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":"Impact of four-week rifaximin treatment on abdominal symptoms, psychological state and gut microbiome in diarrhea-predominant irritable bowel syndrome: a pilot study","authors":"Gaichao Hong , Yajuan Zhao , Xiaohua Hou","doi":"10.1016/j.ejphar.2025.178271","DOIUrl":"10.1016/j.ejphar.2025.178271","url":null,"abstract":"<div><div>Previous studies have revealed the effect of two-week rifaximin treatment on abdominal symptoms and gut microbiota in diarrhea-predominant irritable bowel syndrome (IBS-D), but they failed to observe the influence of rifaximin intervention for a longer period. This pilot study is designed to describe gut microbial profiles in IBS-D and to evaluate the impact of four-week rifaximin treatment on IBS-associated symptoms and gut microbiota for the first time. IBS-D patients who fulfilled the Rome III criteria and healthy controls (HC) were enrolled in the study. Then, 400 mg rifaximin was orally administered to IBS-D patients three times daily for four weeks. Abdominal symptoms and mental state were evaluated before treatment, after two weeks of treatment, and after four weeks of treatment. Fecal samples were collected to characterize the gut microbiota by performing 16S rRNA sequencing. A total of 40 healthy volunteers and 33 IBS-D patients were recruited, and all IBS-D patients agreed to receive rifaximin treatment. IBS-D patients exhibited decreased microbial diversity and a different microbial structure compared with HC. Microbial composition differed between HC and IBS-D at the phylum and genus levels. Administration of rifaximin for four weeks improved abdominal symptoms and anxiety in IBS-D patients. Potential enteropathogens including <em>Haemophilus</em>, <em>Escherichia,</em> and <em>Veillonella</em> were inhibited by rifaximin. Rifaximin upregulated arginine and proline metabolism in the gut microbiota. This is the first study demonstrating that four-week rifaximin treatment exerts good efficacy in relieving abdominal symptoms and anxiety in IBS-D, possibly through suppressing three potential enteropathogens and enhancing arginine and proline metabolism.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1007 ","pages":"Article 178271"},"PeriodicalIF":4.7,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145322125","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}
Fuxue Meng , Xiaofeng Feng , Qifang Zhang , Heng Luo , Hua Bai
{"title":"CA-074 methyl ester, an inhibitor of cathepsin B, combined with the calcium channel blocker Nimodipine inhibits NLRP3 inflammasome activation and alleviates the lesions of Alzheimer’s disease transgenic mice","authors":"Fuxue Meng , Xiaofeng Feng , Qifang Zhang , Heng Luo , Hua Bai","doi":"10.1016/j.ejphar.2025.178263","DOIUrl":"10.1016/j.ejphar.2025.178263","url":null,"abstract":"<div><div>This study aims to investigate the effects of CA-074 methyl ester (CA-074Me) alone or in combination with Nimodipine on NLRP3 inflammasome activation; and evaluate therapeutic effects on transgenic mice of Alzheimer's disease (AD). APP/PS1 mice were fed with Cathepsin B inhibitor CA-074Me and Nimodipine, respectively. Morris water maze test was used to detect the changes in the learning and memory capacities of AD mice. ELISA was performed to detect IL-1β and IL-18 proteins. Immunohistochemistry was used to detect the NLRP3 and caspase-1 proteins. Immunoblotting was performed to detect NLRP3 in the brain tissue of mice in each group. Unlike the control group, the latency threshold of the CA-074Me group was significantly lower. In the space exploration experiment of mice, the time to find the platform in the CA-074Me group was significantly shorter than that in the control group, with a statistically significant difference. IL-1β in the CA-074Me group was significantly lower (t = 15.836, P < 0.001). Caspase-1 protein expression was significantly lower in the CA-074Me group than in the control group, with a statistically significant difference. As for the NLRP3 protein detected by immunoblotting, the (CA-074Me + Nimodipine) group was significantly lower than that in the control group; The relative expression of Aβ protein in CA-074Me group was significantly lower than that in the control group. In animal experiments on AD transgenic mice, CA-074Me alone or in combination with the calcium channel blocker Nimodipine effectively suppressed NLRP3 inflammasome activation, thereby inhibiting the progression of AD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1007 ","pages":"Article 178263"},"PeriodicalIF":4.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312623","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}
María Ángeles Chico, Kevin Doello, Raul Ortiz, Consolación Melguizo, Cristina Mesas, Jose Prados
{"title":"Evaluation of siramesine, β-Lapachone, and palbociclib as novel maintenance therapies after chemotherapy in small cell lung cancer.","authors":"María Ángeles Chico, Kevin Doello, Raul Ortiz, Consolación Melguizo, Cristina Mesas, Jose Prados","doi":"10.1016/j.ejphar.2025.178273","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178273","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) represents approximately 15% of all lung cancer cases and is characterized by rapid proliferation and a high metastatic potential. In the search for new treatments, drug repurposing has gained increasing attention, particularly with FDA-approved agents such as palbociclib (PB). Other compounds with reported antitumor activity, including siramesine (SR) and β-Lapachone (LP), are also under investigation, although they remain unapproved for clinical use. In this study, we evaluated the antitumor activity and underlying mechanisms of SR, LP, and PB in the H69 cell line. Antiproliferative effects, apoptosis (via PARP1 and Bcl-2), autophagy (via LC3β and p62), and senescence (via p21) were analyzed. Antitumor activity was further investigated using the chick chorioallantoic membrane (CAM) assay in ovo. Additionally, in vivo therapeutic efficacy was evaluated in subcutaneous murine models bearing H69 tumors, both as monotherapy and as maintenance treatment. All three compounds reduced cell proliferation and colony formation. PB increased reactive oxygen species (ROS) levels and induced cellular senescence. In the CAM assay, tumors appeared less dense and showed reduced expression of the proliferation marker Ki-67. Interestingly, SR, LP, and PB significantly reduced tumor volume when administered as monotherapies in murine models of SCLC. Furthermore, when they were used as maintenance therapy following chemotherapy, these drugs enhanced the antitumor response. Therefore, our findings highlight SR, LP, and PB as promising therapeutic candidates for the treatment of SCLC.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178273"},"PeriodicalIF":4.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328504","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":"Schisandrin B combined with vitamin D inhibits NLRP3 inflammasome to improve cognitive dysfunction and Alzheimer's disease.","authors":"Yu Wang, Lili Deng, Lianghui Wang, Wen Liu","doi":"10.1016/j.ejphar.2025.178268","DOIUrl":"10.1016/j.ejphar.2025.178268","url":null,"abstract":"<p><strong>Purpose: </strong>This study investigates the therapeutic effects of Schisandrin B (Sch B) combined with vitamin D (VD) on cognitive dysfunction and Alzheimer's disease (AD)-like pathology in aged rats induced by a high-fat and high-sugar (HFHS) diet, with a focus on the inhibition of NLRP3 inflammasome activation as a potential mechanism.</p><p><strong>Methods: </strong>Eighteen-week-old male Sprague-Dawley rats were randomly assigned to five groups: Control, HFHS, HFHS + Sch B, HFHS + VD, and HFHS + Sch B + VD. After 20 weeks of treatment, metabolic parameters (body weight, fasting blood glucose, insulin resistance, lipid profiles), inflammatory markers, and hippocampal protein expression were assessed. Cognitive function was evaluated using the Morris water maze, novel object recognition, open field, and elevated plus maze tests.</p><p><strong>Results: </strong>Combined Sch B and VD markedly attenuated body weight gain, fasting blood glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), while improving lipid profiles (TG, TC, LDL-C). Behavioral tests revealed significant improvements in spatial learning, memory, and object recognition (p < 0.01), with combined therapy outperforming monotherapy. Additionally, the combination downregulated hippocampal NLRP3 inflammasome components (ASC, cleaved caspase-1, IL-1β, IL-18) and reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).</p><p><strong>Conclusion: </strong>In this HFHS diet-induced aging rat model, Sch B combined with VD improved cognitive performance and reduced AD-like lesions, likely via inhibition of NLRP3 inflammasome-mediated neuroinflammation. These findings provide mechanistic insights and support further preclinical evaluation of this combination as a potential strategy for AD prevention and intervention.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178268"},"PeriodicalIF":4.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328478","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":"Amlexanox alleviates renal inflammation and fibrosis by inhibiting cGAS/STING/TBK1 and TGF-β1/Smad signaling.","authors":"Shobhit Gairola, Ravinder K Kaundal","doi":"10.1016/j.ejphar.2025.178266","DOIUrl":"10.1016/j.ejphar.2025.178266","url":null,"abstract":"<p><strong>Background: </strong>The cGAS/STING/TBK1 signaling is a key regulator of the renal innate immune response, driving sterile inflammation and fibrosis. This study explores the therapeutic efficacy of amlexanox (AMX), a TANK-binding kinase 1 (TBK1) inhibitor, in attenuating renal inflammation and fibrosis.</p><p><strong>Methods: </strong>Normal rat kidney fibroblast (NRK-49F) cells were induced with transforming growth factor-β1 (TGF-β1) to evaluate myofibroblast transition. Renal inflammation and fibrosis were induced in mice via unilateral ureteral obstruction (UUO), followed by oral administration of AMX at 3, 10, and 30 mg/kg doses. Renal injury and extracellular matrix (ECM) remodeling were evaluated through histopathology and immunohistochemistry. To elucidate the underlying molecular mechanisms, immunoblotting and immunofluorescence were performed.</p><p><strong>Results: </strong>AMX attenuated TGF-β1-induced Smad phosphorylation, thereby suppressing myofibroblast activation and the subsequent overexpression of fibronectin and collagen I. In vivo, AMX reduced oxidative stress, ameliorated histopathological renal damage, and improved kidney function. Mechanistically, AMX downregulated the expression of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), pSTING, and pTBK1, thereby inhibiting nuclear factor kappa B (NF-κB)-dependent transcription of pro-inflammatory mediators and interferon regulatory factor (IRF3)-mediated type I interferon (IFN) response. Furthermore, AMX attenuated ECM remodeling by modulating the TGF-β1/Smad pathway.</p><p><strong>Conclusion: </strong>AMX exerts renoprotective effects by targeting both inflammation and fibrosis through the inhibition of the cGAS/STING/TBK1 and TGF-β1/Smad signaling pathway.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178266"},"PeriodicalIF":4.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328513","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":"Applying spectral analysis to the arterial pulse to discriminate cardiovascular side effects following administration of Moderna's mRNA-1273 vaccine.","authors":"Chun-Chao Chen, Wen-Ting Chang, Chun-Chih Chiu, Tsung-Yeh Yang, Wen-Rui Hao, Tzu-Wei Huang, Kuan-Jie Lin, Yu-Ann Fang, Min-Huei Hsu, Tsung-Lin Yang, Yu-Hsin Lai, Hung-Chang Jong, Ju-Chi Liu, Hsin Hsiu","doi":"10.1016/j.ejphar.2025.178269","DOIUrl":"10.1016/j.ejphar.2025.178269","url":null,"abstract":"<p><p>Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have demonstrated strong efficacy in preventing symptomatic disease, but adverse cardiovascular side effects have been reported. This study investigated whether noninvasive arterial pulse waveform analysis could help identify cardiovascular responses following administration of Moderna's mRNA-1273 vaccine. Radial blood pressure waveforms were recorded for 1 min in 203 individuals who received the vaccine at a medical center. Participants were categorized into four groups: no side effects (n = 18), cardiac side effects (n = 45), vascular side effects (n = 68), and combined cardiac or vascular side effects (n = 72). Spectral analysis was performed on 40 harmonic indices derived from the pulse waveform, including amplitude proportions, phase angles, and variability indices. These features were analyzed using both a self-developed pulse distribution method and a standard machine learning (ML) algorithm. Significant changes in spectral indices were observed post-vaccination. The pulse distribution method achieved an area under the curve (AUC) of 0.76 in detecting cardiovascular side effects, outperforming the ML approach. The performance was not significantly influenced by potential confounders. These findings suggest that vaccine-induced vascular stiffness may cause a mismatch in elastic properties of the vasculature, and that spectral analysis of the arterial pulse may offer a noninvasive approach to assess such changes.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178269"},"PeriodicalIF":4.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328490","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}