Biochemical pharmacology最新文献_第3页

Visceral adipose stem cell-derived small extracellular vesicles inhibit EMT in renal tubular epithelial cells and attenuate diabetic kidney fibrosis. 内脏脂肪干细胞来源的细胞外小泡抑制肾小管上皮细胞的EMT并减轻糖尿病肾纤维化。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-24 DOI: 10.1016/j.bcp.2026.118395

Junyan Yu, Xiaosi Hong, Tianxin Zhu, Jiabin Lin, Yifan Du, Junru Dai, Shaoying Luo, Li Yan, Meng Ren, Kan Sun, Tingting Zeng

{"title":"Visceral adipose stem cell-derived small extracellular vesicles inhibit EMT in renal tubular epithelial cells and attenuate diabetic kidney fibrosis.","authors":"Junyan Yu, Xiaosi Hong, Tianxin Zhu, Jiabin Lin, Yifan Du, Junru Dai, Shaoying Luo, Li Yan, Meng Ren, Kan Sun, Tingting Zeng","doi":"10.1016/j.bcp.2026.118395","DOIUrl":"10.1016/j.bcp.2026.118395","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a leading cause of end-stage renal failure, with renal tubular epithelial cell injury serving as a core pathological driver. Visceral adipose-derived stem cells (ADSCs) exhibit enhanced proliferation and secretion under diabetic hyperglycemic conditions, yet their role in DN pathogenesis remains unclear. This work investigated the protective effects and molecular mechanism of small extracellular vesicles (sEVs) secreted by high glucose (HG)-treated visceral ADSCs against tubular damage and DN progression. Rat epididymal adipose ADSCs were cultured with HG or high mannitol (HM), and HK-2 tubular cells were incubated with ADSC conditioned medium or purified sEVs to evaluate cellular apoptosis, proliferation and epithelial-mesenchymal transition (EMT). GW4869 was used to inhibit sEV release to confirm vesicle-mediated effects. In diabetic rats, tail vein administration of HG-sEVs or HM-sEVs was conducted to detect renal function, histopathological injury and fibrotic marker expression, while proteomic and bioinformatic analyses were performed to identify functional cargos within HG-sEVs. Cellular assays revealed that HG-stimulated ADSC conditioned medium suppressed EMT in HK-2 cells without altering cell apoptosis or proliferation, and GW4869 treatment abrogated this anti-EMT activity. In vivo HG-sEV intervention reduced serum Cystatin C and urinary albumin-to-creatinine ratio (UACR), mitigated renal fibrosis and lowered renal EMT levels in diabetic animals. Proteomics verified abundant FGF18 enrichment in HG-sEVs, which represses tubular EMT and collagen synthesis via inhibiting the PI3K-Akt signaling pathway. In summary, HG-induced ADSC-derived sEVs alleviate tubular EMT, relieve renal fibrosis and improve renal function in diabetic rats, and the renoprotective effect is predominantly attributed to FGF18-mediated PI3K-Akt pathway suppression.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118395"},"PeriodicalIF":6.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNMT1 is associated with anti-PD-1 resistance and regulates the STAT3/PD-L1-CD8⁺ T-cell axis in melanoma. DNMT1与抗pd -1抗性相关，并调节黑色素瘤中STAT3/PD-L1-CD8+ t细胞轴。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-23 DOI: 10.1016/j.bcp.2026.118392

Yujia Sun, Chen Chen, Yingjie Wang, Chuanxin Cui

{"title":"DNMT1 is associated with anti-PD-1 resistance and regulates the STAT3/PD-L1-CD8<sup>+</sup> T-cell axis in melanoma.","authors":"Yujia Sun, Chen Chen, Yingjie Wang, Chuanxin Cui","doi":"10.1016/j.bcp.2026.118392","DOIUrl":"10.1016/j.bcp.2026.118392","url":null,"abstract":"<p><p>Transcriptomic analysis of melanoma (MM) patients receiving anti-programmed cell death protein 1 (anti-PD-1) blockade identified differentially expressed genes and co-expression modules associated with therapeutic response. Integrated transcriptomic and proteomic analyses, together with least absolute shrinkage and selection operator (LASSO) regression, identified deoxyribonucleic acid (DNA) methyltransferase 1 (DNMT1) as a key resistance-associated factor. Functional enrichment suggested that DNMT1 was involved in DNA methylation, immune activation, and extracellular matrix remodeling. Further immune infiltration and single-cell analyses showed that high DNMT1 expression was associated with reduced cluster of differentiation 8-positive (CD8<sup>+</sup>) T-cell infiltration and an immunosuppressive tumor microenvironment. Mechanistically, DNMT1 was linked to signal transducer and activator of transcription 3 (STAT3) activation and programmed death-ligand 1 (PD-L1) upregulation. In MM cell models, DNMT1 knockdown reduced STAT3/PD-L1 signaling and enhanced CD8<sup>+</sup> T-cell cytotoxic activity, as reflected by increased interferon gamma (IFN-γ) and Granzyme B production. Both genetic DNMT1 knockdown and pharmacological DNMT1 inhibition enhanced CD8<sup>+</sup> T-cell-mediated antitumor activity in MM-CD8<sup>+</sup> T-cell co-culture systems, and nivolumab further strengthened these effects under in vitro conditions. These findings identify DNMT1 as a resistance-associated epigenetic regulator and suggest that DNMT1 may participate in anti-PD-1 resistance through the STAT3/PD-L1-CD8<sup>+</sup> T-cell axis. Further in vivo studies are required to validate whether DNMT1 inhibition can enhance the therapeutic efficacy of anti-PD-1 therapy in MM.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118392"},"PeriodicalIF":6.5,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

eIF4A1 enhances p70S6K mRNA translation and promotes nuclear β-catenin levels to augment stemness and metastasis in gastric cancer cells. eIF4A1增强p70S6K mRNA翻译并促进核β-catenin水平，从而增强胃癌细胞的干性和转移。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-22 DOI: 10.1016/j.bcp.2026.118386

Xiangyu Su, Yingming Zhu, Xuemin Song, Zhengcheng Yun, Yueqi He, Yiting Wu, Chanchan Gao

{"title":"eIF4A1 enhances p70S6K mRNA translation and promotes nuclear β-catenin levels to augment stemness and metastasis in gastric cancer cells.","authors":"Xiangyu Su, Yingming Zhu, Xuemin Song, Zhengcheng Yun, Yueqi He, Yiting Wu, Chanchan Gao","doi":"10.1016/j.bcp.2026.118386","DOIUrl":"10.1016/j.bcp.2026.118386","url":null,"abstract":"<p><p>Gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide, with tumor stemness and metastasis driving poor prognosis. This study explores the role of eukaryotic translation initiation factor 4A1 (eIF4A1) in promoting these aggressive features in GC. eIF4A1 was found to be upregulated in stem-like (CD133<sup>+</sup>) GC cells. Gain- and loss-of-function experiments in cell lines, combined with xenograft, chemically induced, and organoid models, demonstrated that eIF4A1 enhanced cancer stemness, cell mobility, tumorigenesis, and metastasis. Mechanistically, eIF4A1 selectively promotes p70 ribosomal S6 kinase (p70S6K) mRNA translation, leading to increased glycogen synthase kinase 3 beta (GSK3β) phosphorylation, elevated nuclear β-catenin accumulation, and subsequent transcriptional activation of eIF4A1 via the β-catenin/transcription factor 7-like 2 (TCF7L2) complex, thus forming a positive feedback loop. Clinically, high expression of eIF4A1, p70S6K, and TCF7L2 correlates with unfavorable prognosis in GC patients. These findings highlight eIF4A1 as a key regulator of stemness and metastasis through a novel translational feedback mechanism, suggesting potential therapeutic targeting to disrupt tumor progression.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118386"},"PeriodicalIF":6.5,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The regulatory role of non-coding RNAs in taxane resistance of breast cancer. 非编码rna在乳腺癌紫杉烷耐药中的调控作用。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-19 DOI: 10.1016/j.bcp.2026.118371

Cuicui Sun, Lingling Lv, Qinzheng Xu, Shuang Wu, Faheem Ahmed Khan, Nuruliarizki Shinta Pandupuspitasari, Yuefeng Zhang, Chunjie Huang

{"title":"The regulatory role of non-coding RNAs in taxane resistance of breast cancer.","authors":"Cuicui Sun, Lingling Lv, Qinzheng Xu, Shuang Wu, Faheem Ahmed Khan, Nuruliarizki Shinta Pandupuspitasari, Yuefeng Zhang, Chunjie Huang","doi":"10.1016/j.bcp.2026.118371","DOIUrl":"10.1016/j.bcp.2026.118371","url":null,"abstract":"<p><p>Breast cancer remains a major health concern among women, characterized by a high risk and substantial mortality. Chemotherapy is widely employed as a standard treatment modality to eliminate malignant cells and improve patient survival. Nevertheless, recurrence and chemoresistance arising from taxane treatment have emerged as key factors driving the high mortality rates in cancer patients. Non-coding RNAs (ncRNAs), encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), represent a key functional output of the human genome and, via intricate regulatory networks, influence nearly all facets of cancer biology, including the development of chemoresistance. Importantly, in taxane-resistant breast cancer cells, the identified miRNAs displayed bifunctional roles: some promoted resistance, whereas others enhanced sensitivity. This functional duality is also observed in lncRNAs, highlighting their context‑dependent regulatory roles. Additionally, ncRNAs are enriched in taxane-resistant cells-derived exosomes, where they play a crucial role in spreading taxane resistance and chemotherapy failure through genetic modulation of taxane‑sensitive cells. Notably, targeting ncRNAs via various therapeutic approaches, including herbal compounds and synthetic peptides, has shown hopeful findings in reversing taxane resistance in breast cancer, highlighting a promising avenue for the management of taxane resistance in breast cancer.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118371"},"PeriodicalIF":6.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of ALPK1 attenuates myocardial ischemia-reperfusion injury in Nur77-deficient mice via suppressing XPO1-dependent pathway. 抑制ALPK1通过抑制xpo1依赖途径减轻nur77缺陷小鼠心肌缺血再灌注损伤。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-14 DOI: 10.1016/j.bcp.2026.118362

Yue Liu, Ruisi Hu, Yanteng Wang, Yingxi Wang, Qihe Zhao, Wenwei Guan, Difei Wang

{"title":"Inhibition of ALPK1 attenuates myocardial ischemia-reperfusion injury in Nur77-deficient mice via suppressing XPO1-dependent pathway.","authors":"Yue Liu, Ruisi Hu, Yanteng Wang, Yingxi Wang, Qihe Zhao, Wenwei Guan, Difei Wang","doi":"10.1016/j.bcp.2026.118362","DOIUrl":"10.1016/j.bcp.2026.118362","url":null,"abstract":"<p><p>Despite being the initial intervention of choice, revascularization for myocardial ischemia-reperfusion (I/R) injury remains constrained, making the exploration of novel therapeutic targets imperative. Alpha-kinase 1 (ALPK1) knockdown mitigates ischemic brain injury, whereas its function in cardiac I/R injury requires further investigation. Nur77 knockout (Nur77 KO) mice, with more severe post-acute myocardial infarction (post-AMI) cardiac dysfunction, fibrosis and hypertrophy than C57BL/6 mice, underwent 45 min LAD ligation plus 4 h reperfusion for modeling and genetic ALPK1 knockdown's impacts on this injury were examined in hypoxic AC16 cardiomyocytes via siRNA silencing, pharmacological ferroptosis rescue and siRNA-resistant ALPK1 plasmid functional recovery assays. The results demonstrated that genetic ALPK1 knockdown resulted in an improvement in cardiac function, the amelioration of pathological changes, a reduction in infarct size, and the suppression of apoptosis of myocardial cells in Nur77 KO mice post-I/R. Furthermore, genetic ALPK1 knockdown was observed to suppress lipid peroxidation and ferroptosis, while concomitantly activating Nrf2/HO-1 pathway in Nur77 KO mice post-I/R. Furthermore, genetic ALPK1 knockdown was observed to inhibit apoptosis and ferroptosis in vitro and pharmacological rescue experiments confirmed ferroptosis as the core downstream cell death pathway of ALPK1. ALPK1 was observed to interact with XPO1, thereby inhibiting XPO1 degradation. Moreover, XPO1 overexpression impeded the impact of ALPK1 knockdown on cell survival, lipid peroxidation, and ferroptosis. ALPK1 represents a potential novel target for pharmacological intervention in the treatment of myocardial I/R injury.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118362"},"PeriodicalIF":6.5,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HRX-215 attenuates cartilage fibrosis in osteoarthritis progression and microfracture repair by targeting MKK4. HRX-215通过靶向MKK4减轻骨关节炎进展和微骨折修复中的软骨纤维化。

IF 6.5 2区医学

Biochemical pharmacology Pub Date : 2026-08-08 DOI: 10.1016/j.bcp.2026.118336

Qing Zhou, Qixian Shen, Zeyuan Gao, Weili Shi, Qinwei Guo

{"title":"HRX-215 attenuates cartilage fibrosis in osteoarthritis progression and microfracture repair by targeting MKK4.","authors":"Qing Zhou, Qixian Shen, Zeyuan Gao, Weili Shi, Qinwei Guo","doi":"10.1016/j.bcp.2026.118336","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118336","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive cartilage degeneration. Cartilage fibrosis is one of the key pathological events and is also the direct cause of repair failure due to fibrocartilage formation after microfracture surgery. Mitogen-activated protein kinase kinase 4 (MKK4) is a MAP2 kinase that activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. It is a key kinase in the stress-activated protein kinase (SAPK)/mitogen-activated protein kinase (MAPK) signaling network. The OA-related data set from the GEO database showed that MKK4 expression was upregulated in the cartilage of OA patients. This phenomenon was also confirmed in the clinical samples we collected. Therefore, inhibiting MKK4 is a potential strategy for the treatment of cartilage fibrosis. HRX-215 is a recently discovered inhibitor of MKK4 that has been shown to have anti-fibrotic activity, but its therapeutic potential in osteoarthritis is not yet clear. This study found that HRX-215 promoted chondrocyte proliferation, increased the proportion of S-phase cells, and slowed down oxidative stress-driven extracellular matrix degradation by inhibiting MKK4. In in vivo experiments, HRX-215 significantly delayed cartilage degeneration and fibrosis in both the rat ACLT osteoarthritis model and the rat microfracture model. HRX-215 also has an inhibitory effect on the expression of MKK4 in human chondrocytes. Taken together, the results of this study indicate that HRX-215 inhibits cartilage fibrosis by targeting MKK4, providing a promising therapeutic candidate for osteoarthritis and microfracture repair.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118336"},"PeriodicalIF":6.5,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

5-Fluorouracil-induced intestinal mucositis: Pathogenesis and potential therapeutic interventions 5-氟尿嘧啶诱导的肠黏膜炎：发病机制和潜在的治疗干预措施

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2026-05-01 Epub Date: 2026-02-12 DOI: 10.1016/j.bcp.2026.117793

Sen-lin Li , Dao-chun Xiang , Ping Gao , Cheng Tian , Cheng-liang Zhang

{"title":"5-Fluorouracil-induced intestinal mucositis: Pathogenesis and potential therapeutic interventions","authors":"Sen-lin Li , Dao-chun Xiang , Ping Gao , Cheng Tian , Cheng-liang Zhang","doi":"10.1016/j.bcp.2026.117793","DOIUrl":"10.1016/j.bcp.2026.117793","url":null,"abstract":"<div><div>Intestinal mucositis is one of the most common toxicities of 5-fluorouracil (5-FU)-based chemotherapy, occurring in up to 80% of treated patients. Clinically, it presents as abdominal pain, watery or bloody diarrhea, malabsorption and body-weight loss, often forcing chemotherapy dose reduction or discontinuation, thereby aggravating the psychological burden of patients, prolonging hospital stay and potentially increasing mortality. Histologically, 5-FU-induced intestinal mucositis (FIM) is characterized by villus atrophy, crypt apoptosis, disruption of epithelial barrier and pronounced inflammatory infiltration. In this review, we delineate the mechanisms of FIM, a multi-stage pathogenesis that integrates direct epithelial cell apoptosis, oxidative stress, inflammation signal cascades, intestinal barrier disruption, dysbiosis, as well as more recently recognized factors such as impaired intestinal neuroregulation and intestinal senescence. Additionally, we summarize the potential pharmacological interventions, aiming to offer a reference for future basic and clinical research on FIM.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117793"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of CYP3A4 variants and drug–drug interactions on the metabolism of fexinidazole CYP3A4变异及药物-药物相互作用对非昔硝唑代谢的影响。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-20 DOI: 10.1016/j.bcp.2026.117730

Jinyu Hu , Haoxin Fu , Ruibin Li , Peiqi Wang , Jun Wu , Lu Cao , Chenjian Zhou , Ren-ai Xu

{"title":"Effects of CYP3A4 variants and drug–drug interactions on the metabolism of fexinidazole","authors":"Jinyu Hu , Haoxin Fu , Ruibin Li , Peiqi Wang , Jun Wu , Lu Cao , Chenjian Zhou , Ren-ai Xu","doi":"10.1016/j.bcp.2026.117730","DOIUrl":"10.1016/j.bcp.2026.117730","url":null,"abstract":"<div><div>Fexinidazole is a ctirical treatment for Human African trypanosomiasis in Africa, but its metabolic characteristics are not fully understood. This study investigated the impacts of CYP3A4 genetic polymorphisms and (−)-epigallocatechin gallate (EGCG) on the metabolism of fexinidazole <em>in vitro</em> (rat liver microsomes (RLM), human liver mircosomes (HLM), and nine CYP3A4 variants) and <em>in vivo</em> (rat) models. Ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was utilized to quantify fexinidazole and its metabolites. The results showed that fexinidazole was metabolized mainly by CYP3A4, which was significantly modulated by CYP3A4 polymorphisms. In addition, EGCG significantly inhibited the metabolism of fexinidazole in both RLM (IC<sub>50</sub> = 8.02 ± 0.28 μM) and HLM (IC<sub>50</sub> = 9.97 ± 0.43 μM) via mixed-type inhibition mechanisms. <em>In vivo</em>, co-administration of EGCG significantly altered the pharmacokinetic parameters of fexinidazole, increasing the AUC and C<sub>max</sub> by approximately 1.46 and 1.44-fold, respectively, while decreasing clearance (CL<sub>z/F</sub>). Furthermore, continuous administration of EGCG significantly downregulated key hepatic CYP450 (CYP3a1, CYP2d1/2, CYP2b1/2, and CYP2c11) at both the protein and mRNA levels. This study elucidated the major metabolic pathways of fexinidazole and reported the effects of genetic polymorphisms and the drug EGCG on its metabolism for the first time.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117730"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ginsenoside Rf promotes testosterone synthesis through the cAMP/PKA/CREB signaling pathway to improve obesity-related male hypogonadism 人参皂苷Rf通过cAMP/PKA/CREB信号通路促进睾酮合成，改善肥胖相关男性性腺功能减退

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2026-05-01 Epub Date: 2026-01-28 DOI: 10.1016/j.bcp.2026.117758

Zhang runqi , Zheng xiaoxing , Chen yuqing , Qi xiangyu , Lu chenglin , Guan qingbo , Yu chunxiao

{"title":"Ginsenoside Rf promotes testosterone synthesis through the cAMP/PKA/CREB signaling pathway to improve obesity-related male hypogonadism","authors":"Zhang runqi , Zheng xiaoxing , Chen yuqing , Qi xiangyu , Lu chenglin , Guan qingbo , Yu chunxiao","doi":"10.1016/j.bcp.2026.117758","DOIUrl":"10.1016/j.bcp.2026.117758","url":null,"abstract":"<div><div>Obesity, as a major global public health issue, triggers various diseases, including male hypogonadism. Ginsenoside Rf, natural compounds extracted from ginseng, has unclear roles in obesity-related male hypogonadism. This study aims to investigate the effects of ginsenoside Rf on obesity-related male hypogonadism and to preliminarily explore its underlying mechanisms. Eight-week-old male mice were divided into normal diet (ND), high-fat diet (HFD), and HFD + Rf groups. After 12-week HFD feeding followed by 5-week intervention, Rf reduced HFD-induced body weight, testicular stromal lipid deposition, and fibrosis, while increasing testicular testosterone and upregulating synthesis-related proteins (Steroidogenic acute regulatory protein (Star), Scavenger receptor class B type 1 (Srb1), Cytochrome P450 family 11 subfamily a member 1 (Cyp11a1), Cytochrome P450 family 17 subfamily a member 1 (Cyp17a1)). Network pharmacology identified Star, Cyp11a1, and cyclic adenosine monophosphate (cAMP) signaling as potential targets/pathways. In palmitic acid (PA)-treated Leydig cells, Rf elevated Star, Cyp11a1, the phosphorylation levels of protein kinase A (p-Pka), and phosphorylation levels of Creb(p-Creb)/Creb (cAMP response element-binding protein) levels; these effects were reversed by PKA inhibitor H89. Ginsenoside Rf may promote testosterone synthesis via activating the cAMP/PKA/CREB pathway, highlighting its potential in treating obesity-related male hypogonadism.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117758"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ATF5 activates LPAR5 to enhance macrophage pro-inflammatory responses to exacerbate rheumatoid arthritis ATF5激活LPAR5增强巨噬细胞促炎反应，加重类风湿关节炎。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2026-05-01 Epub Date: 2026-02-12 DOI: 10.1016/j.bcp.2026.117804

Caijie Liu , Yingnan Guo , Yanni Dong , Xiuzhen Wang

{"title":"ATF5 activates LPAR5 to enhance macrophage pro-inflammatory responses to exacerbate rheumatoid arthritis","authors":"Caijie Liu , Yingnan Guo , Yanni Dong , Xiuzhen Wang","doi":"10.1016/j.bcp.2026.117804","DOIUrl":"10.1016/j.bcp.2026.117804","url":null,"abstract":"<div><div>Macrophages (Mφ) are key effector cells in the pathogenesis of rheumatoid arthritis (RA) through their ability to polarize into different functional phenotypes. Even though lysophosphatidic acid receptor 5 (LPAR5) has been implicated in regulating Mφ in inflammatory diseases, its functional role in controlling Mφ remains unclear under the condition of RA. LPAR5 expression was significantly increased in synovial Mφ from RA patients, and correlated positively with severe pathological progression in RA patients. Adeno-associated virus-mediated specific knockdown of LPAR5 in Mφ blocked PI3K/AKT signaling to inhibit pro-inflammatory polarization of Mφ in DBA/1 mice with collagen-induced arthritis. Dysregulation of LPAR5 in RA was associated with activating transcription factor 5 (ATF5)-mediated transcriptional activation. Overexpression of LPAR5 reversed the restriction of pro-inflammatory responses of Mφ by ATF5 knockdown by activating the PI3K/AKT signaling. ATF5 activated the PI3K/AKT signaling pathway through LPAR5, and the activation of PI3K/AKT signaling further promoted ATF5 expression through a positive feedback loop, amplifying pro-inflammatory responses of Mφ. Overall, our findings support that ATF5/LPAR5/PI3K/AKT positive feedback signaling amplifies pro-inflammatory responses of Mφ to promote RA progression. Targeting the ATF5/LPAR5/PI3K/AKT cascade may emerge as a potential therapeutic strategy to alleviate RA.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117804"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0