Toxicology and applied pharmacology最新文献_第6页

The molecular signature of the peripheral cannabinoid receptor 1 antagonist AM6545 in adipose, liver and muscle tissue 外周大麻素受体 1 拮抗剂 AM6545 在脂肪、肝脏和肌肉组织中的分子特征

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-30 DOI: 10.1016/j.taap.2024.117081

{"title":"The molecular signature of the peripheral cannabinoid receptor 1 antagonist AM6545 in adipose, liver and muscle tissue","authors":"","doi":"10.1016/j.taap.2024.117081","DOIUrl":"10.1016/j.taap.2024.117081","url":null,"abstract":"<div><p>The endocannabinoid system plays an important role in the regulation of metabolism, growth and regeneration of peripheral tissues, including liver, adipose and muscle tissue. Studies in cells, rodents and humans showed that cannabinoid receptor 1 (CB<sub>1</sub>) antagonist treatment is an effective strategy to improve features of metabolic health such as substrate metabolism, at least in models of metabolic dysregulation. However, acute signaling events that might induce these metabolic adaptations are not understood. It is not clear whether, and to which extent, a single treatment with a CB<sub>1</sub> antagonist induces acute effects in peripheral, metabolic tissues. Therefore, the present study compared the phosphorylation status of signaling pathways and metabolic markers in liver, adipose and muscle tissue of mice treated with the peripherally restricted CB<sub>1</sub> antagonist AM6545 and vehicle-treated mice. Protein kinase A phosphorylation was downregulated in white and brown adipose tissue, whereas the mitogen-activated protein kinase, phospho-extracellular signal-regulated kinase, was higher in liver, white adipose and muscle tissue of AM6545-treated mice. Additionally, Akt-mammalian target of rapamycin activation was higher in all tissues of AM6545-treated mice, whereas the phosphorylation status of metabolic markers remained unaffected. These data indicate that acute CB<sub>1</sub> antagonism is effective to induce phosphorylation events of signaling cascades and metabolic markers in metabolic tissues of healthy, lean mice within a 90-min time window. The observed adaptations to AM6545 treatment do not fully align with earlier in vitro and in vivo findings, which could be ascribed to differences in cell type, exposure intensity (dose and time), health status and species.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096977","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}

引用次数: 0

Calcipotriol abrogates TGF-β1/pSmad3-mediated collagen 1 synthesis in pancreatic stellate cells by downregulating RUNX1 钙泊三醇通过下调 RUNX1 可抑制 TGF-β1/pSmad3 介导的胰腺星状细胞胶原蛋白 1 的合成。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-28 DOI: 10.1016/j.taap.2024.117078

{"title":"Calcipotriol abrogates TGF-β1/pSmad3-mediated collagen 1 synthesis in pancreatic stellate cells by downregulating RUNX1","authors":"","doi":"10.1016/j.taap.2024.117078","DOIUrl":"10.1016/j.taap.2024.117078","url":null,"abstract":"<div><p>RUNX1 with CBFβ functions as an activator or repressor of critical mediators regulating cellular function. The aims of this study were to clarify the role of RUNX1 on regulating TGF-β1-induced COL1 synthesis and the mechanism of calcipotriol (Cal) on antagonizing COL1 synthesis in PSCs. RT-qPCR and Western Blot for determining the mRNAs and proteins of RUNX1 and COL1A1/1A2 in rat PSC line (RP-2 cell). Luciferase activities driven by RUNX1 or COL1A1 or COL1A2 promoter, co-immunoprecipitation and immunoblotting for pSmad3/RUNX1 or CBFβ/RUNX1, and knockdown or upregulation of Smad3 and RUNX1 were used. RUNX1 production was regulated by TGF-β1/pSmad3 signaling pathway in RP-2 cells. RUNX1 formed a coactivator with CBFβ in TGF-β1-treated RP-2 cells to regulate the transcriptions of COL1A1/1A2 mRNAs under a fashion of pSmad3/RUNX1/CBFβ complex. However, Cal effectively abrogated the levels of COL1A1/1A2 transcripts in TGF-β1-treated RP-2 cells by downregulating RUNX1 production and hindering the formation of pSmad3/RUNX1/CBFβ complexes. This study suggests that RUNX1 may be a promising antifibrotic target for the treatment of chronic pancreatitis.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0041008X2400276X/pdfft?md5=ba8c5f3b4766ca15cbb6df70284d11e2&pid=1-s2.0-S0041008X2400276X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142112249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extracellular vesicles-derived long noncoding RNAs participated in benzene hematotoxicity by mediating apoptosis and autophagy 源于细胞外囊泡的长非编码 RNA 通过介导细胞凋亡和自噬参与苯的血液毒性作用

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-28 DOI: 10.1016/j.taap.2024.117076

{"title":"Extracellular vesicles-derived long noncoding RNAs participated in benzene hematotoxicity by mediating apoptosis and autophagy","authors":"","doi":"10.1016/j.taap.2024.117076","DOIUrl":"10.1016/j.taap.2024.117076","url":null,"abstract":"<div><p>Benzene is a common contaminant in the workplace and wider environment, which induces hematotoxicity. Our previous study has implicated that lncRNAs mediated apoptosis and autophagy induced by benzene. Nevertheless, the roles of extracellular vesicle(EVs)-derived lncRNAs in benzene toxicity are unknown. However, the role of EVs and EVs-derived lncRNAs in benzene-induced toxicity remains unclear. In this research, we explored the function of EVs and EVs-derived lncRNAs in cell-cell communication through benzene-induced apoptosis and autophagy. Our findings demonstrated that EVs derived from 1,4-BQ-treated cells treated cells and coculture with 1,4-BQ-treated cells enhanced apoptosis and autophagy via regulating the pathways of PI3K-AKT-mTOR and chaperone-mediated autophagy. Treating with GW4869 in 1,4-BQ-treated cells significantly inhibited EV secretion, which reduced apoptosis and autophagy. Furthermore, we identified a set of differentially expressed autophagy- and apoptosis-related lncRNAs using EVs-derived lncRNA sequencing. Among them, 8 candidate lncRNAs were upregulated in EVs derived from 1,4-BQ-treated cells, as determined by lncRNA sequencing and qRT–PCR. Importantly, these lncRNAs were also increased in the serum EVs of benzene-exposed workers. 1,4-BQ-treated cells released EVs that transfer differentially expressed lncRNAs, thereby inducing apoptosis and autophagy in the recipient cells. The above results support the hypothesis that EVs-derived lncRNAs participate in intercellular communication during benzene-induced hematotoxicity and function as potential biomarkers for risk assessment of benzene-exposed workers.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142096906","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}

引用次数: 0

The anti-cancer mechanism of Celastrol by targeting JAK2/STAT3 signaling pathway in gastric and ovarian cancer Celastrol 通过靶向 JAK2/STAT3 信号通路在胃癌和卵巢癌中的抗癌机制。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-22 DOI: 10.1016/j.taap.2024.117077

{"title":"The anti-cancer mechanism of Celastrol by targeting JAK2/STAT3 signaling pathway in gastric and ovarian cancer","authors":"","doi":"10.1016/j.taap.2024.117077","DOIUrl":"10.1016/j.taap.2024.117077","url":null,"abstract":"<div><h3>Background</h3><p>Celastrol is a natural triterpene exhibiting significant and extensive antitumor activity in a wide range of cancer. Due to unfavorable toxicity profile and undefined mechanism, Celastrol's application in clinical cancer therapy remains limited. Herein, we elucidate the pharmacological mechanism of Celastrol's anticancer effects, with a focus on STAT3 signaling pathway in cancers with high incidence of metastasis.</p></div><div><h3>Methods</h3><p>The safety profile of Celastrol were assessed in mice. <em>In vitro</em> analysis was performed in gastric cancer and ovarian cancer to assess the cytotoxicity, induction of reactive oxygen species (ROS) of Celastrol using <em>STAT3</em> knockout cancer cells. Effects of Celastrol on STAT3 activation and transcription activity, JAK2/STAT3 signaling protein expression were assessed. Additionally, proteomic contrastive analysis was performed to explore the molecular association of Celastrol with <em>STAT3</em> deletion in cancer cells.</p></div><div><h3>Results</h3><p>Celastrol has no obvious toxic effect at 1.5 mg/kg/day in a 15 days' administration. Celastrol inhibits tumor growth and increases ROS in a STAT3 dependent manner in gastric and ovarian cancer celllines. On molecular level, it downregulates IL-6 level and inhibits the JAK2/STAT3 signaling pathway by suppressing STAT3’ activation and transcription activity. Proteomic contrastive analysis suggests a similar cellular mechanism of action between Celastrol and <em>STAT3</em> deletion on regulating cancer progression pathways related to migration and invasion.</p></div><div><h3>Conclusion</h3><p>Our research elucidates the anti-cancer mechanism of Celastrol through targeting the JAK2/STAT3 signaling pathway in cancer with high incidence of metastasis. This study provides a solid theoretical basis for the application of Celastrol in cancer therapy.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056596","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}

引用次数: 0

Artesunate attenuates osteoarthritis in mice by promoting MTA1 transcription through a USP7/FoxO1 axis 青蒿琥酯通过 USP7/FoxO1 轴促进 MTA1 转录，从而减轻小鼠的骨关节炎。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-21 DOI: 10.1016/j.taap.2024.117075

{"title":"Artesunate attenuates osteoarthritis in mice by promoting MTA1 transcription through a USP7/FoxO1 axis","authors":"","doi":"10.1016/j.taap.2024.117075","DOIUrl":"10.1016/j.taap.2024.117075","url":null,"abstract":"<div><p>Artesunate (ART) is a derivative of artemisinin and has anti-inflammatory, anti-tumor, and anti-angiogenic properties. Although ART has been implicated in osteoarthritis (OA), the mechanism needs to be further dissected. Here, we explored the effects of ART on the development of OA and the underlying mechanism using destabilization of the medial meniscus (DMM) surgical instability model. Mice with OA were developed using DMM and treated with ART. The pathological morphology of knee joint tissues was examined, and the degeneration of joint cartilage was assessed. Mouse knee chondrocytes were isolated and induced with IL-1β, followed by ART treatment. ART alleviates OA in mice by elevating ubiquitin carboxyl-terminal hydrolase 7 (USP7) expression, and USP7 inhibitor (P22077) treatment mitigated the protective effects of ART on chondrocytes. We also showed that USP7 mediated the deubiquitination of forkhead box protein O1 (FoxO1), while FoxO1 alleviated chondrocyte injury. In addition, FoxO1 promoted metastasis-associated protein MTA1 (MTA1) transcription, and downregulation of MTA1 exacerbated chondrocyte injury. Our study identifies that USP7/FoxO1/MTA1 is a key signaling cascade in the treatment of ART on OA.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037116","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}

引用次数: 0

Muscarinic and nicotinic receptors stimulation by vagus nerve stimulation ameliorates trastuzumab-induced cardiotoxicity via reducing programmed cell death in rats 迷走神经刺激肌卡因和烟碱受体可通过减少大鼠程序性细胞死亡来改善曲妥珠单抗诱导的心脏毒性。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-20 DOI: 10.1016/j.taap.2024.117074

{"title":"Muscarinic and nicotinic receptors stimulation by vagus nerve stimulation ameliorates trastuzumab-induced cardiotoxicity via reducing programmed cell death in rats","authors":"","doi":"10.1016/j.taap.2024.117074","DOIUrl":"10.1016/j.taap.2024.117074","url":null,"abstract":"<div><p>Despite its efficacy in human epidermal growth factor receptor 2 positive cancer treatment, trastuzumab-induced cardiotoxicity (TIC) has become a growing concern. Due to the lack of cardiomyocyte regeneration and proliferation in adult heart, cell death significantly contributes to cardiovascular diseases. Cardiac autonomic modulation by vagus nerve stimulation (VNS) has shown cardioprotective effects in several heart disease models, while the effects of VNS and its underlying mechanisms against TIC have not been found. Forty adult male Wistar rats were divided into 5 groups: (i) control without VNS (CSham) group, (ii) trastuzumab (4 mg/kg/day, i.p.) without VNS (TSham) group, (iii) trastuzumab + VNS (TVNS) group, (iv) trastuzumab + VNS + mAChR blocker (atropine; 1 mg/kg/day, ip, TVNS + Atro) group, and (v) trastuzumab + VNS + nAChR blocker (mecamylamine; 7.5 mg/kg/day, ip, TVNS + Mec) group. Our results showed that trastuzumab induced cardiac dysfunction by increasing autonomic dysfunction, mitochondrial dysfunction/dynamics imbalance, and cardiomyocyte death including apoptosis, autophagic deficiency, pyroptosis, and ferroptosis, which were notably alleviated by VNS. However, mAChR and nAChR blockers significantly inhibited the beneficial effects of VNS on cardiac autonomic dysfunction, mitochondrial dysfunction, cardiomyocyte apoptosis, pyroptosis, and ferroptosis. Only nAChR could counteract the protective effects of VNS on cardiac mitochondrial dynamics imbalance and autophagy insufficiency. Therefore, VNS prevented TIC by rebalancing autonomic activity, ameliorating mitochondrial dysfunction and cardiomyocyte death through mAChR and nAChR activation. The current study provides a novel perspective elucidating the potential treatment of VNS, thus also offering other pharmacological therapeutic promises in TIC patients.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018738","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}

引用次数: 0

High-Throughput Transcriptomics Screen of ToxCast Chemicals in U-2 OS Cells 在 U-2 OS 细胞中对 ToxCast 化学品进行高通量转录组学筛选。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-17 DOI: 10.1016/j.taap.2024.117073

{"title":"High-Throughput Transcriptomics Screen of ToxCast Chemicals in U-2 OS Cells","authors":"","doi":"10.1016/j.taap.2024.117073","DOIUrl":"10.1016/j.taap.2024.117073","url":null,"abstract":"<div><p>New approach methodologies (NAMs) aim to accelerate the pace of chemical risk assessment while simultaneously reducing cost and dependency on animal studies. High Throughput Transcriptomics (HTTr) is an emerging NAM in the field of chemical hazard evaluation for establishing in vitro points-of-departure and providing mechanistic insight. In the current study, 1201 test chemicals were screened for bioactivity at eight concentrations using a 24-h exposure duration in the human- derived U-2 OS osteosarcoma cell line with HTTr. Assay reproducibility was assessed using three reference chemicals that were screened on every assay plate. The resulting transcriptomics data were analyzed by aggregating signal from genes into signature scores using gene set enrichment analysis, followed by concentration-response modeling of signatures scores. Signature scores were used to predict putative mechanisms of action, and to identify biological pathway altering concentrations (BPACs). BPACs were consistent across replicates for each reference chemical, with replicate BPAC standard deviations as low as 5.6 × 10<sup>−3</sup> μM, demonstrating the internal reproducibility of HTTr-derived potency estimates. BPACs of test chemicals showed modest agreement (R<sup>2</sup> = 0.55) with existing phenotype altering concentrations from high throughput phenotypic profiling using Cell Painting of the same chemicals in the same cell line. Altogether, this HTTr based chemical screen contributes to an accumulating pool of publicly available transcriptomic data relevant for chemical hazard evaluation and reinforces the utility of cell based molecular profiling methods in estimating chemical potency and predicting mechanism of action across a diverse set of chemicals.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005384","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}

引用次数: 0

Post-transplantation cyclophosphamide and cyclosporine A versus methotrexate and cyclosporine A for graft-versus-host disease prophylaxis after allogeneic peripheral stem cell transplantation in adult acute myeloid leukemia patients 成年急性髓性白血病患者异基因外周干细胞移植后预防移植物抗宿主病的移植后环磷酰胺和环孢素a与甲氨蝶呤和环孢素a的比较。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-17 DOI: 10.1016/j.taap.2024.117071

{"title":"Post-transplantation cyclophosphamide and cyclosporine A versus methotrexate and cyclosporine A for graft-versus-host disease prophylaxis after allogeneic peripheral stem cell transplantation in adult acute myeloid leukemia patients","authors":"","doi":"10.1016/j.taap.2024.117071","DOIUrl":"10.1016/j.taap.2024.117071","url":null,"abstract":"<div><h3>Background</h3><p>Different prophylactic protocols are available for preventing graft-versus-host disease (GVHD) after matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to compare the effectiveness of post-transplantation cyclophosphamide plus cyclosporine A (PT-CY/CSA) versus methotrexate plus CSA (MTX/CSA) as GVHD prophylaxis protocols in adult acute myeloid leukemia (AML) patients who received peripheral blood stem cells (PBSC) from fully matched donors.</p></div><div><h3>Methods</h3><p>The 1-year outcomes of 89 patients treated with PT-CY/CSA and 90 patients treated with MTX/CSA who had MSD allo-HCT for AML using unmanipulated mobilized PBSC were examined and compared.</p></div><div><h3>Results</h3><p>The cumulative incidence of acute GVHD at 100 days was considerably lower in the PT-CY/CSA group (4% vs 19.3%, <em>p</em> = 0.002), however there were no statistically significant difference in the cumulative incidence of chronic GVHD at 1-year (19.6% vs 37.4%, <em>p</em> = 0.053). Significant delays in neutrophil and platelet engraftments were reported in the PT-CY/CSA group (17 vs 12 days) and (13 vs 12 days), respectively (<em>p</em> < 0.001). The cumulative incidences of relapse (19.1% vs 13.7%, <em>p</em> = 0.470), overall survival (79.1% vs 77.3%, <em>p</em> = 0.986), non-relapse mortality (16.5% vs 16.8%, <em>p</em> = 0.837), and the GVHD and relapse-free survival (GRFS) (53.7% vs 46.6%, <em>p</em> = 0.478) did not differ statistically at 1-year.</p></div><div><h3>Conclusion</h3><p>PT-CY/CSA demonstrated a significant decrease in the rate of acute GVHD. However, it was associated with engraftment delay.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005385","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}

引用次数: 0

Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response 丹酚酸 B 通过增强 ATF5 介导的线粒体未折叠蛋白反应改善脓毒症心肌病的线粒体功能障碍

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-15 DOI: 10.1016/j.taap.2024.117072

{"title":"Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response","authors":"","doi":"10.1016/j.taap.2024.117072","DOIUrl":"10.1016/j.taap.2024.117072","url":null,"abstract":"<div><h3>Aims</h3><p>Septic cardiomyopathy is characterized by impaired contractile function and mitochondrial activity dysregulation. Salvianolic acid B (Sal B) is a potent therapeutic compound derived from the traditional Chinese medicine <em>Salvia miltiorrhiza</em>. This study explored the protective effects of Sal B on septic heart injury, emphasizing the mitochondrial unfolded protein response (UPRmt).</p></div><div><h3>Materials and methods</h3><p>An <em>in vivo</em> mouse model of lipopolysaccharide (LPS)-induced heart injury was utilized to assess Sal B's protective role in septic cardiomyopathy. Additionally, cell models stimulated by LPS were developed to investigate the mechanisms of Sal B on UPRmt. Quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence were employed for molecular analysis.</p></div><div><h3>Results</h3><p>Sal B, administered at doses of 10, 30, and 60 mg/kg, demonstrated protective effects on cardiac contractile function, reduced heart inflammation, and mitigated cardiac injury in LPS-exposed mice. In cardiomyocytes, LPS induced apoptosis, elevated mitochondrial ROS levels, promoted mitochondrial fission, and decreased mitochondrial membrane potential, all of which were alleviated by Sal B. Mechanistically, Sal B was found to induce UPRmt both <em>in vivo</em> and <em>in vitro</em>. ATF5, identified as a UPRmt activator, was modulated by LPS and Sal B, resulting in increased ATF5 expression and its translocation from the cytosol to the nucleus. ATF5-siRNA delivery reversed UPRmt upregulation, exacerbating mitochondrial dysfunction in LPS-stimulated cardiomyocytes and counteracting the mitochondrial function enhancement in Sal B-treated cardiomyocytes.</p></div><div><h3>Conclusions</h3><p>This study provides evidence that Sal B confers cardiac protection by enhancing UPRmt, highlighting its potential as a therapeutic approach for mitigating mitochondrial dysfunction in septic cardiomyopathy.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996554","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}

引用次数: 0

Extracellular cAMP elicits contraction of rat vas deferens: Involvement of ecto-5′-nucleotidase and adenosine A1 receptors 细胞外 cAMP 引起大鼠输精管收缩：外-5'-核苷酸酶和腺苷 A1 受体的参与。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-08-14 DOI: 10.1016/j.taap.2024.117070

{"title":"Extracellular cAMP elicits contraction of rat vas deferens: Involvement of ecto-5′-nucleotidase and adenosine A1 receptors","authors":"","doi":"10.1016/j.taap.2024.117070","DOIUrl":"10.1016/j.taap.2024.117070","url":null,"abstract":"<div><h3>Aims</h3><p>It is well established that intracellular cAMP contributes to the relaxation of vas deferens smooth muscle. In many tissues, intracellular cAMP is actively transported to the extracellular space, where it exerts regulatory functions, via its metabolite adenosine. These actions take place through the cAMP conversion to adenosine by ectoenzymes, a process called “extracellular cAMP-adenosine pathway”. Herein, we investigated whether, in addition to ATP, extracellular cAMP might be an alternative source of adenosine, influencing the contraction of vas deferens smooth muscle.</p></div><div><h3>Main methods</h3><p>The effects of cAMP, 8-Br-cAMP and adenosine were analyzed in the isometric contractions of rat vas deferens. cAMP efflux was analyzed by measuring extracellular cAMP levels after exposure of vas deferens segments to isoproterenol and forskolin in the presence or absence of MK-571, an inhibitor of MRP/ABCC transporters.</p></div><div><h3>Key findings</h3><p>While 8-Br-cAMP, a cell-permeable cAMP analog, induced relaxation of KCl-precontracted vas deferens, the non-permeant cAMP increased the KCl-induced contractile response, which was mimicked by adenosine, but prevented by inhibitors of ecto-5′-nucleotidase or A<sub>1</sub> receptors. Our results also showed that isoproterenol and forskolin increases cAMP efflux via an MRP/ABCC transporter-dependent mechanism, since it is inhibited by MK-571.</p></div><div><h3>Significance</h3><p>Our data show that activation of β-adrenoceptors and adenylyl cyclase increases cAMP efflux from vas deferens tissue, which modulates the vas deferens contractile response via activation of adenosine A<sub>1</sub> receptors. Assuming that inhibition of vas deferens contractility has been proposed as a strategy for male contraception, the extracellular cAMP-adenosine pathway emerges as a potential pharmacological target that should be considered in studies of male fertility.</p></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996553","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}

引用次数: 0