Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"Dehydrocostus lactone induces apoptosis and mitophagy in gastric cancer cells through the ROS-mediated mitochondrial pathway.","authors":"Qiuxiong Chen, Ying Li, Junjie Mu, Qian Ming, Chaohong Zhu, Ziyue He, Mengyue Ma, Xiaoqin Long, Hui Wu, Baoli Qiu, Lihe Zhang, Xian Yang, Xue Zhang","doi":"10.1007/s00210-025-04645-3","DOIUrl":"https://doi.org/10.1007/s00210-025-04645-3","url":null,"abstract":"<p><p>Dehydrocostus lactone (Dehy) is a sesquiterpenoid compound extracted from the dried roots of Aucklandia lappa Decne, a plant in the Compositae family, and has been shown to have significant efficacy in anti-tumor and gastrointestinal diseases. However, the anti-cancer molecular mechanisms of Dehy in gastric cancer (GC) are unclear, and further in-depth studies are needed to elucidate its potential molecular pathways and therapeutic capabilities. This study systematically studied the anti-GC effect of Dehy and its molecular mechanism by integrating network pharmacology (NP) prediction and in vitro experimental verification strategies. The effects of the compound on proliferation, apoptosis, and expression of mitophagy marker proteins in GC cells were evaluated by CCK-8 assay, plate cloning assay, flow cytometry, and Western blotting techniques. NP analysis revealed its potential targets and key signaling pathways, which were further verified by experiments such as mitochondrial membrane potential detection and reactive oxygen species (ROS) level determination. The results showed that Dehy significantly inhibited the proliferation of GC cells and caused changes in cell morphology. Its mechanism of action involves promoting the accumulation of intracellular ROS, thereby activating mitochondria-dependent apoptosis pathways and mitophagy processes. Notably, ROS is a therapeutic target for Dehy, and the mitochondrial pathway is its key mechanism of action in this context. The results confirm that Dehy is a potential drug for the treatment of GC.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213103","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":"Prognostic, mutational, and immunologic analysis of CD90 in pan-cancer and validation of DHDK as a drug candidate.","authors":"Jingtao Zhao, Yuqing Wang, Fangyu Zhang, Xinyue Wang, Lin Meng, Jing Hong, Dingjia Guo, Xin Di, Yunli Zhao","doi":"10.1007/s00210-025-04598-7","DOIUrl":"https://doi.org/10.1007/s00210-025-04598-7","url":null,"abstract":"<p><p>The CD90 gene encodes a cell surface glycoprotein that plays an important role in the development and progression of cancer. Regarding CD90 gene, pan-cancer analysis of investigating the correlation between CD90 and immune filtration, patients prognosis is still unclear. TCGA, GTEx, TIMER 2.0, GEPIA2 databases and web tool were used for analyzing CD90 gene impacts among multiple cancer types. The data visualization of KEGG and GO enrichment analysis were achieved through R codes. In addition, molecular docking and molecular dynamics showed the binding ability of the candidate compounds to proteins, which was verified by in vitro experiments. On the whole, CD90 expression differences exist between tumor tissues and their corresponding normal controls. Meanwhile, CD90 has a significant impact on patient prognosis in multiple cancers. Specifically, CD90 high expression levels are correlated with poor Overall survival (OS) and Disease-free survival (DFS), Disease specific survival (DSS) in the TCGA KIRP and UVM cancer datasets. Additionally, it is worth mentioning that the highest CD90 gene mutation frequency occurs on the cancer type of UVM. Moreover, CD90 expression levels were significantly associated with immune cell infiltration, including cancer associated fibroblast and Endothelial cells. (1E,4E)- 1,7-bis(4-hydroxyphenyl) Hepta- 1,4-dien- 3-one (DHDK) docked well with CD90 protein and the experimental results showed that DHDK interfered with the expression of CD90 in cancer cells. Preliminary experimental results indicate that DHDK holds potential in the future targeted therapy of the CD90 gene.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213096","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":"Real-world safety profile of bisoprolol: signal detection and demographic stratification using the FAERS database.","authors":"Kun Lai, Lan Luo, Tengyao Kang, Fuzhao Zhang, Xinrong Chen","doi":"10.1007/s00210-025-04650-6","DOIUrl":"https://doi.org/10.1007/s00210-025-04650-6","url":null,"abstract":"<p><p>Bisoprolol, a selective β₁-blocker, is widely prescribed for cardiovascular disease. Real-world pharmacovigilance can clarify adverse drug reactions (ADRs) across demographic strata and identify signals not fully characterized in trials. We analyzed bisoprolol-associated reports in the FDA Adverse Event Reporting System. Disproportionality was assessed using complementary algorithms-reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC with IC025), and empirical Bayes geometric mean (EBGM with EBGM05). To stabilize sparse strata, we required a ≥ 3 and multi-algorithm concordance (EBGM05 > 2, IC025 > 0, lower95_ROR > 1). Multiple testing was controlled using Benjamini-Hochberg FDR and Bonferroni adjustments. Signals were summarized overall and stratified by sex and age (< 40, 40-80, ≥ 80 years). Class-expected cardiovascular ADRs showed robust signals, including bradycardia, sinus bradycardia, bradyarrhythmia, atrioventricular block, hypotension, syncope/presyncope (all meeting stability and multiplicity criteria). Several hypothesis-generating signals with strong effect sizes were detected: cardiospasm (ROR≈285; EBGM05≈178), palmoplantar keratoderma (ROR≈217; EBGM05≈137), and hyperkalemia (ROR≈16.7; EBGM05≈13). Sex- and age-stratified analyses revealed clinically relevant patterns: in younger patients (< 40), bradyarrhythmia-type signals were most pronounced; in middle-aged adults (40-80), cardiospasm and palmoplantar keratoderma ranked among the top signals; in older adults (≥ 80), conduction-slowing events remained prominent. Overall reporting skewed female (≈55%) and older age. A qualitative EudraVigilance cross-check identified parallel case clusters for cardiospasm and palmoplantar keratoderma, corroborating cross-jurisdictional presence. FAERS data reaffirm bisoprolol's known bradycardic and hypotensive risks and highlight novel, biologically plausible signals-particularly cardiospasm and palmoplantar keratoderma-that vary by demographic subgroup. These findings support targeted clinical vigilance (heart-rate/conduction, electrolytes, dysphagia/chest pain, palmoplantar skin changes) and motivate confirmatory studies (prospective cohorts, nested case-controls). While robust to multiplicity control, signals remain hypothesis-generating given spontaneous-reporting biases; cautious interpretation and validation are warranted.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225539","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":"Microencapsulated Lactiplantibacillus plantarum ZGP-Lpl.19 modulates growth and virulence gene expression of Shigella flexneri ATCC 12022 in vitro.","authors":"Zahra Ghorbani, Mohammad Shayestehpour, Mohammad Esmaeil Shahaboddin, Azad Khaledi, Merat Karimi, Reyhaneh Maleki, Mitra Motallebi","doi":"10.1007/s00210-025-04623-9","DOIUrl":"https://doi.org/10.1007/s00210-025-04623-9","url":null,"abstract":"<p><p>Encapsulation of Lactiplantibacillus plantarum (L. plantarum) ZGP-Lpl.19 in alginate-pectin-chitosan microcapsules significantly improved its survival under simulated gastrointestinal conditions and attenuated Shigella flexneri (S. flexneri) growth and pathogenicity through downregulation of the mdoH and IcsA virulence genes. Microencapsulation was achieved via extrusion using a polysaccharide blend, yielding an encapsulation efficiency of 98.44%. Structural integrity of the microcapsules was confirmed by scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR). Encapsulation markedly enhanced probiotic survivability, with viable counts of 5.37 log CFU/mL after 60 min in gastric fluid and 120 min in intestinal fluid, compared with 2.25 log CFU/mL for free cells. Both encapsulated and free L. plantarum ZGP-Lpl.19 demonstrated potent antimicrobial activity against S. flexneri ATCC 12022, with comparable antimicrobial metabolite production. The minimum inhibitory concentration (MIC) of cell-free supernatants from both forms was 1/8 of the original concentration. Importantly, real-time PCR analysis confirmed that both encapsulated and free cells significantly downregulated mdoH and IcsA expression. Overall, these findings demonstrate that alginate-pectin-chitosan microencapsulation provides effective protection for L. plantarum and enhances its functional delivery, positioning encapsulated L. plantarum as a promising therapeutic strategy to mitigate S. flexneri infections.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213170","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":"β-sitosterol attenuates hepatic lipid accumulation and fibrosis via NLRP3 signaling in MASH mice.","authors":"Xuan Wang, Kaixia Wang, Wenlan Gao, Zhenxiu Liu, Jiaojiao Zhou, Feng Tao, Yi Chen","doi":"10.1007/s00210-025-04614-w","DOIUrl":"https://doi.org/10.1007/s00210-025-04614-w","url":null,"abstract":"<p><p>Β-sitosterol (SIT), a natural phytosterol, has not been fully explored for its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH). In this study, MASH was induced in mice via a high-fat, high-cholesterol (HFHC) diet, and lipid accumulation in HepG2 cells was triggered with oleic acid (OA), while the role of the NLRP3 inflammasome was explored in NLRP3-knockout (NLRP3^-/-) mice treated with or without SIT. SIT treatment significantly alleviated HFHC-induced hepatic injury, evidenced by reduced alanine aminotransferase and aspartate aminotransferase levels, improved liver histology, and decreased hepatocyte apoptosis. SIT also reduced hepatic triglyceride and cholesterol levels, inhibited lipid droplet accumulation, and modulated genes involved in lipogenesis and β-oxidation. Furthermore, SIT reduced hepatic inflammation by decreasing macrophage and neutrophil infiltration and suppressing pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). SIT also exhibited antifibrotic effects, confirmed by histological and gene expression analysis. Mechanistically, SIT inhibited NLRP3 inflammasome activation, with diminished hepatoprotective effects in NLRP3^-/- mice. In conclusion, SIT offers potent hepatoprotective effects in MASH, likely through NLRP3 inflammasome inhibition, positioning it as a promising therapeutic candidate for MASH.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206898","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":"Pubertal exposure to glyphosate-based herbicide aggravates diet-induced steatosis and hormonal dysregulation in adult mice.","authors":"Jakeline Liara Teleken, Ana Paula Farina Rosolen, Joseane Morari, Sandra Lucinei Balbo, Rosane Aparecida Ribeiro, Maria Lúcia Bonfleur","doi":"10.1007/s00210-025-04652-4","DOIUrl":"https://doi.org/10.1007/s00210-025-04652-4","url":null,"abstract":"<p><p>Glyphosate-based herbicide (GBH) exposure during critical life development periods can interfere with hormonal and metabolic regulation. Puberty may be particularly vulnerable to such disruptions, leading to long-term health consequences. However, whether GBH exposure limited to puberty increases susceptibility to obesity and its comorbidities in adulthood remains poorly understood. So, we investigated the effects of pubertal exposure to GBH on glucose and lipid homeostasis, as well as on sex, thyroid, and cortisol hormone levels, in male and female mice subjected to a high-fat diet (HFD) in adulthood. From 30 to 60 days of age, male and female C57Bl/6 mice received a daily gavage of either distilled water [control (CTL group)] or 50 mg/kg of GBH (GBH group). Following this period until 150 days old, CTL and GBH female and male were fed on a HFD. GBH-exposed females showed exacerbated HFD-induced increases in body weight, abdominal adiposity, and hyperphagia. However, the hypothalamic mRNA expression of the neuropeptides Agrp, Cart, and Pomc remained unaltered. GBH exposure did not change HFD effects on glucose homeostasis between OB-GBH and OB-CTL groups. In both sexes, GBH exposure aggravated HFD-induced hepatic steatosis. These effects were accompanied by elevated plasma levels of T3 and cortisol in OB-GBH groups, along with increased testosterone and estradiol levels in OB-GBH males and females, respectively. GBH exposure restricted to the pubertal period led to increased ectopic fat accumulation in the liver and dysregulation of T3, cortisol, and sex hormone levels in female and male mice exposed to an obesogenic challenge.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206844","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":"Clinical pharmacokinetics and pharmacometabolomics of Andrographis paniculata capsules: Bridging drug disposition and metabolic response to precision medicine.","authors":"Khim Boon Tee, Didi Erwandi Mohamad Haron, Ili Nadhirah Jamil, Wei Lim Chong, Zaril Harza Zakaria, Lee-Ling Lim, Najihah Mohd Hashim, Hasniza Zaman Huri","doi":"10.1007/s00210-025-04656-0","DOIUrl":"https://doi.org/10.1007/s00210-025-04656-0","url":null,"abstract":"<p><p>Andrographis paniculata (Burm. F.) Nees (AP) is a phytomedicinal plant traditionally used for colds, infections, and diabetes in Southeast Asia. The bioactive diterpenoids such as andrographolide, 14-deoxyandrographolide, and neoandrographolide has anti-inflammatory, antimicrobial, and glucose-lowering effects. Although widely used, clinical studies integrating AP's drug composition with its pharmacometabolomics responses remain limited. This study integrated pharmacokinetics (PK) and pharmacometabolomics (PMx) to understand dose-response relationships and pharmacological effects of orally administered AP capsules (1000 mg and 2000 mg) to 12 healthy volunteers under fasting conditions. Three biomarkers were measured from five AP brands to determine the highest-concentration AP capsule for dosing. PK analysis used 75 plasma samples while PMx analysis involved 96 plasma and urine samples. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used for both analyses. Statistical analysis included multivariate analyses (PCA, PLS-DA), followed by peaks-to-pathway analysis via MetaboAnalyst 5.0. Time to reach maximum plasma concentration (Tmax) for andrographolide, 14-deoxyandrographolide, and neoandrographolide was 1.5 h, with maximum plasma concentration (Cmax) of 10.15 ng mL^-1, 7.02 ng mL^-1 and 58.45 ng mL^-1, respectively. At 1000 mg, AP enhanced steroid hormone biosynthesis, while 2000 mg induced broader metabolic shifts, enriching pathways such as biosynthesis of unsaturated fatty acids, alanine/aspartate/glutamate metabolism, and lysine degradation. No free bioactive compounds were detected in urine, indicating metabolism into conjugated forms. Clinical PK guided PMx revealed metabolic responses supporting AP's potential as a therapeutic agent for inflammation and glucose lowering effect. Further clinical research could optimize dosing and advance AP as a precision medicine candidate.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213167","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":"Investigating the impact of ramelteon on all-cause mortality in ischemic stroke ICU patients: a retrospective propensity-matched study from the MIMIC-IV database.","authors":"Qiang Li, Minheng Zhang, Haixia Fan, Hongwei Liu, Miaomiao Hou","doi":"10.1007/s00210-025-04653-3","DOIUrl":"https://doi.org/10.1007/s00210-025-04653-3","url":null,"abstract":"<p><p>The study's objective was to assess the connection between ramelteon usage and mortality from any cause in ischemic stroke patients in the intensive care unit (ICU). Utilizing the MIMIC-IV database, we analyzed a cohort of adult patients who had been diagnosed with ischemic stroke. During their time in the hospital, patients were sorted into ramelteon and non-ramelteon groups according to drug exposure. To achieve balance in baseline covariates, propensity score matching (PSM) was utilized. The primary focus was on mortality from all causes over 28 days, with secondary focuses on all-cause mortality over 90 and 365 days. Using Cox proportional hazards models, hazard ratios (HR) and 95% confidence intervals (CI) were estimated, taking into account potential confounding factors. Subgroup analyses were done to assess effect modification across clinical strata. The study encompassed 3413 patients, with 535 pairs matched after PSM. Ramelteon use was significantly associated with decreased 28-day all-cause mortality rates both before and after PSM, with adjusted HR of 0.34 and 0.23, both with P < 0.001. The fully adjusted post-PSM models showed similar protective associations for 90-day (HR = 0.43) and 365-day (HR = 0.55) all-cause mortality, both with P < 0.001. Prolonged use of ramelteon for more than 14 days and cumulative doses exceeding 300 mg were consistently linked to lower all-cause mortality at all time intervals. Through subgroup and sensitivity analyses, the associations were confirmed to be consistent across different clinical strata. In critically ill patients with ischemic stroke, ramelteon usage was independently associated with lower short- and long-term all-cause mortality.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206889","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":"Psilocin alleviates acute itch in mice: possible involvement of 5-HT2A receptors and kynurenine pathway.","authors":"Arya Afrooghe, Elham Ahmadi, Ali Lesani, Mahya Soleymani Mehranjani, Mohammad Elahi, Mohammadreza Babaei, Maryam Shayan, Hamed Shafaroodi, Razieh Mohammad Jafari, Alireza Foroumadi, Mohammad Amin Manavi, Ahmad-Reza Dehpour","doi":"10.1007/s00210-025-04152-5","DOIUrl":"10.1007/s00210-025-04152-5","url":null,"abstract":"<p><p>We aimed to investigate whether psilocin, the bioactive metabolite of the well-known psychedelic, psilocybin, may have antipruritic effects in mice by interfering with the kynurenine pathway and interacting with 5-HT2A receptors. Eight mice were randomly assigned to each of the study groups receiving either normal saline, compound 48/80, psilocin (0.3, 1, and 3 mg/kg), or psilocin (1 mg/kg) + 1-MT (0.3 mg/kg). The scratching bouts were documented in each group. The hallucinogenic properties of psilocin were documented using the head-twitch response (HTR) test. To confirm their involvement, we also quantified the expression levels of TNF-α, TLR-4, indoleamine-2,3-dioxygenase (IDO), and 5-HT2A receptors across various study groups. We found that psilocin (1 mg/kg) exerted the most significant antipruritic and hallucinogenic effects (P < 0.0001). The activity of 5-HT2A receptors in the skin tissue of mice was confirmed by western blot. When psilocin (1 mg/kg) was given together with 1-MT (0.3 mg/kg), the antipruritic effects became more pronounced as compared to when psilocin was given alone (P < 0.05). TLR-4 and TNF-α expression levels considerably reduced after psilocin was applied, both alone and together with 1-MT (P < 0.05, P < 0.01, respectively). We also observed significantly decreased activity of IDO in the treatment groups (P < 0.05, P < 0.01 after giving psilocin alone, and together with 1-MT, respectively). To our knowledge, this is the first study to confirm the effectiveness of psychedelics in battling pruritus. Our findings offer a novel repositioning for psilocin. This may be particularly beneficial for psychological conditions accompanied by pruritus.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"13881-13894"},"PeriodicalIF":3.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990464","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 intersection of GRK2 and PGE2 in rheumatoid arthritis: a comprehensive update on pathophysiology and treatment.","authors":"Pankaj Singh, Gaurav Doshi, Siddhi Bagwe Parab","doi":"10.1007/s00210-025-04163-2","DOIUrl":"10.1007/s00210-025-04163-2","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) has made significant progress in the treatment zone passing on from traditional disease-modifying anti-rheumatic drugs (DMARDs) to novel biologics and targeted synthetic agents with the goal of individualized therapy regimens. However, these novel biological treatments necessitate careful evaluation due to their effectiveness and side effects. In recent decades, new therapy methods have emerged to understand the underlying causes of RA better, highlighting the need to update current treatments. It is observed that in the context of RA pathophysiology, there was prolonged stimulation of the human prostaglandin E2 receptor 4 (EP4) by prostaglandin E2(PGE2), and also M2 macrophage polarization is promoted by PGE2 through the cyclic adenosine monophosphate - response element binding protein (cAMP-CREB) pathway which leads to the recruitment of G protein-coupled receptor kinase 2 (GRK2) to the membrane and, as a result, there is under expression of membrane-associated EP4. This review emphasizes the significant role of GRK2 in the pathophysiology of RA by regulating the PGE2-EP4 pathway, fibroblast-like synoviocyte (FLS) proliferation, and peroxisome proliferator-activated receptor gamma (PPAR γ) - Tyr473(Flt-1 transcription). Recent research has highlighted the regulatory function of PGE2 and its receptor, EP4, in initiating RA pathogenesis. Additionally, it discusses the mechanism of action supported by current literature, existing therapies, and novel drugs undergoing pre-clinical and clinical trials, which could help future researchers explore them in treating this ancient autoimmune disorder RA.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"13109-13120"},"PeriodicalIF":3.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982667","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}