Robin A Faber, Victor M Baart, Mark W Bordo, Taryn L March, Adrianus R P M Valentijn, Stefan Harmsen, Martin Pool, Jacobus Burggraaf, John V Frangioni, Alexander L Vahrmeijer
{"title":"Cardiac inotropy and cardiac calcium sensitization of PanLN800(-Forte), a cationic heptamethine indocyanine fluorescent contrast agent for intraoperative pan lymph node imaging.","authors":"Robin A Faber, Victor M Baart, Mark W Bordo, Taryn L March, Adrianus R P M Valentijn, Stefan Harmsen, Martin Pool, Jacobus Burggraaf, John V Frangioni, Alexander L Vahrmeijer","doi":"10.1016/j.taap.2024.117222","DOIUrl":"10.1016/j.taap.2024.117222","url":null,"abstract":"<p><strong>Introduction: </strong>Accurate staging of malignancies often requires comprehensive evaluation of lymph nodes. However, finding these lymph nodes during oncological surgery is a daunting and time-consuming task, which increases the risk of missed lymph nodes and complications. Near-infrared (NIR) fluorescence imaging with the experimental fluorescent contrast agent PanLN800(-Forte) could provide real-time identification of lymph nodes and may solve this longstanding problem. In the current study we performed the preclinical toxicology evaluation of PanLN800(-Forte) towards its clinical translation for intraoperative pan lymph node imaging in thoracic surgery.</p><p><strong>Methods: </strong>A single extended dose toxicology study was conducted to determine the safety and potential toxicity of PanLN800(-Forte) after administration of a single intravenous dose to Wistar Han rats. The study included a control group and two treatment groups (5.0 mg/kg and 15.0 mg/kg PanLN800(-Forte)), each consisting of 10 male and 10 female rats. Experimental endpoints included moribundity/mortality, clinical signs, body weights, body weight gains, clinical pathology, toxicity, and gross necropsy observations.</p><p><strong>Results: </strong>Unexpected acute mortality was observed after administration of 5.0 mg/kg PanLN800(-Forte) to rats. No clear cause of sudden death was found after gross necropsy and pathology observations. To understand the mechanism of toxicity of PanLN800(-Forte), several additional tests were performed. By elimination, acute cardiac toxicity appears to be the cause of acute mortality in rats, in which PanLN800(-Forte) was found to be a potent inotrope acting as a cardiac calcium sensitizer.</p><p><strong>Conclusion: </strong>PanLN800(-Forte) is not a viable fluorescent contrast agent for lymph node imaging in surgery because of cardiac calcium sensitization but may be a novel treatment for heart failure.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117222"},"PeriodicalIF":3.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915645","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}
Zhexuan Li, Juan Nie, Runyu Zhou, Hui Huang, Xuemei Li, Li Wang, Lin Lv, Sichong Ren, Ming Zhao
{"title":"Thiostrepton suppresses colorectal cancer progression through reactive oxygen species related endoplasmic reticulum stress.","authors":"Zhexuan Li, Juan Nie, Runyu Zhou, Hui Huang, Xuemei Li, Li Wang, Lin Lv, Sichong Ren, Ming Zhao","doi":"10.1016/j.taap.2024.117221","DOIUrl":"10.1016/j.taap.2024.117221","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Due to the poor therapeutic efficacy of CRC treatments and poor prognosis of the disease, effective treatment strategies are urgently needed. As long-term proteotoxic stress is a major cause of cell death, agents that induce proteotoxic stress offer a promising strategy for cancer intervention. Thiostrepton is a natural antibiotic derived from the Streptomyces genus. In the present study, we found that thiostrepton triggered apoptosis, reduced the migration of CRC cells, and inhibited xenograft tumour growth in vivo. Mechanistically, thiostrepton reduced proteasome activity; induced the aggregation of ubiquitinated proteins; caused endoplasmic reticulum (ER) stress, which was characterized by increased protein levels of GRP78, ATF4, P-eIF2α, and CHOP and cytosolic calcium release; and ultimately resulted in cell death. Thiostrepton-related changes in cell survival and cell migration, as well as mechanistical processes, were almost completely reversed by treatment with the antioxidant N-acetylcysteine (NAC), suggesting that the mechanism is dependent on reactive oxygen species (ROS). These results demonstrated that thiostrepton induced apoptosis and inhibited migration through ROS-induced ER stress and proteotoxic stress in colorectal cancer.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117221"},"PeriodicalIF":3.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902857","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}
Bo Cai, Zelin He, Dandan Liu, Yuping Zhang, Zikang Yin, Weijia Bao, Qiaoyi Le, Ju Shao, Hongyan Du, Ligang Jie
{"title":"Thymidine phosphorylase participates in platelet activation and promotes inflammation in rheumatoid arthritis.","authors":"Bo Cai, Zelin He, Dandan Liu, Yuping Zhang, Zikang Yin, Weijia Bao, Qiaoyi Le, Ju Shao, Hongyan Du, Ligang Jie","doi":"10.1016/j.taap.2024.117217","DOIUrl":"10.1016/j.taap.2024.117217","url":null,"abstract":"<p><p>The elevated risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) have a higher mortality rate compared to the general population due to abnormal platelet activation. Thymidine phosphorylase (TYMP) plays a crucial role in platelet activation and thrombosis, following bridging the link between RA and CVD. Data from Gene Expression Omnibus (GEO) database exhibited that TYMP levels were highly expressed in synovial tissues, immune cells, and whole blood of RA patients especially those with high levels of inflammation. Platelet count (PLT) and plateletcrit (PCT) were positively correlated with the severity of inflammation in rheumatoid arthritis while platelet distribution width (PDW) and mean platelet volume (MPV) were adverse. Levels of CD62P and TYMP in platelets of patients with active RA were significantly elevated compared to patients in the inactive phase. In vivo experiments showed that reducing TYMP expression levels of platelets could relieve inflammation in Adjuvant-Induced Arthritis (AIA) mice. Platelet activation was significantly elevated in AIA model mice, along with increased levels of intracellular calcium (Ca<sup>2+</sup>), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of Tymp<sup>-/-</sup> mice reversed these effects. In vitro stimulation of wild type (WT) mouse platelets with tumor necrosis factor-alpha (TNF-α) promoted platelet activation, elevated levels of intracellular Ca<sup>2+</sup>as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of Tymp<sup>-/-</sup> mice exhibited the adverse results. Our study illustrates the vital role of TYMP in promoting RA inflammation and platelet activation, suggesting that TYMP may be a potential therapeutic target for RA.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117217"},"PeriodicalIF":3.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898147","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}
Hyun Kil Shin, Se-Myo Park, Mi-Sun Choi, Jung-Hwa Oh, Sang Kyum Kim, Seokjoo Yoon, Hae-Ryung Park, Hyoung-Yun Han
{"title":"Enhancing toxicity prediction for natural products in herbal medicine and dietary supplements: Integrating (Q)STR models and in vitro assays.","authors":"Hyun Kil Shin, Se-Myo Park, Mi-Sun Choi, Jung-Hwa Oh, Sang Kyum Kim, Seokjoo Yoon, Hae-Ryung Park, Hyoung-Yun Han","doi":"10.1016/j.taap.2024.117220","DOIUrl":"10.1016/j.taap.2024.117220","url":null,"abstract":"<p><p>New approach methods (NAMs) are required to predict human toxicity effectively, particularly due to limitations in conducting in vivo studies. While NAMs have been established for various industries, such as cosmetics, pesticides, and drugs, their applications in natural products (NPs) are lacking. NPs' complexity (multiple ingredients and structural differences from synthetic compounds) complicates NAM development. In this study, we devised NAMs for NPs using (quantitative) structure-toxicity relationship (Q)STR models and in vitro assays. Validation involved testing each method with single compounds isolated from NPs. A linear regression model was developed for (Q)STR prediction (R<sup>2</sup> on test set: 0.52), with an applicability domain analysis demonstrating its reliability across NPs. This model was applied to predict the LD<sub>50</sub> range of species, aiding in the development of herbal medicine and dietary supplements. In vitro screening employed three reporter cell lines (AP-1, P53, and Nrf2), with Tox scores derived by integrating in silico and in vitro data. Nimbolide exhibited the highest Tox score, with experimental studies corroborating the accuracy and reliability of the predictions made via Tox score analysis. The findings of the study align well with the purpose, as the suggested NAMs, utilizing (Q)STR models and in vitro assays, provide a Tox score to efficiently prioritize NPs for herbal medicine and dietary supplements.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117220"},"PeriodicalIF":3.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896785","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}
Jan Dehner, Hana Holcova Polanska, Katerina Petrlakova, Sanja Cavar Zeljkovic, Tibor Beres, Michal Hendrych, Jan Storch, Petr Tarkowski, Michal Masarik, Petr Babula, Jan Vacek
{"title":"Safety assessment on CBD-rich hemp extract in sub-chronic cross-sex study with rats.","authors":"Jan Dehner, Hana Holcova Polanska, Katerina Petrlakova, Sanja Cavar Zeljkovic, Tibor Beres, Michal Hendrych, Jan Storch, Petr Tarkowski, Michal Masarik, Petr Babula, Jan Vacek","doi":"10.1016/j.taap.2024.117218","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117218","url":null,"abstract":"<p><p>Cannabidiol (CBD) is a phytocannabinoid from Cannabis sativa L., in which there is currently growing interest for medicinal use. Here, we focused on the safety and pharmacokinetics of a CBD-rich (77 %, w/w) full-spectrum hemp extract in male and female rats. A 90-day sub-chronic toxicity assay was conducted with doses of 0.5, 5, 10, and 35 mg CBD extract/kg/day administered orogastrically. No adverse effects or disruption in organ or body weight, behaviour, locomotion, food intake, or impact on morbidity/mortality were observed. Pathomorphological examination showed no gastrointestinal or liver changes. Blood cell analysis showed a significant (p < 0.05) decrease in the number of leukocytes for both sexes, and a significant difference (p < 0.01 or 0.05) between the control and treated animals for mean corpuscular haemoglobin concentration, mean corpuscular volume of erythrocytes, and number of neutrophils and monocytes. However, blood cell analysis revealed significant (p < 0.05) sex-dependent differences, such as haematocrit and erythrocyte count. The levels of ions (Ca<sup>2+</sup>, Na<sup>+</sup>, K<sup>+</sup> and Cl<sup>-</sup>), alkaline phosphatase, and creatinine in treated animals were also observed for both sexes. Males exhibited decreased alanine transaminase levels, and females exhibited hyperalbuminemia (p < 0.01). CBD was quantified in treated animals in a dose-dependent manner, with statistical significance varying from p < 0.05 to 0.0001. The accumulation of CBD in the individual tissues increased in the order: brain < serum < liver < heart << kidney <<< muscle and skin. The results indicated sex-dependent latent disruption of kidney and liver homeostasis, most likely reversible in nature.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117218"},"PeriodicalIF":3.3,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142897828","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":"Cadmium biphasically impacts the adaptive immune system via regulating mitochondrial activation of hematopoietic stem cells in mice.","authors":"Yifan Zhao, Chuanxuan Wang, Jun Du, Wei Wang, Jiaojiao Wu, Ting Liu, Peng Xue, Yingzi Ju, Xinyu Hong, Jianheng Zheng, Weidong Qu, Yubin Zhang","doi":"10.1016/j.taap.2024.117216","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117216","url":null,"abstract":"<p><p>Cadmium (Cd) is a highly toxic metal in human body, and therefore understanding the immunotoxicity of Cd is significant for public health. The aim of this study was to investigate the role of hematopoietic stem cells (HSC) in regulating the immunotoxicity of Cd. After exposure to 10 ppm Cd via drinking water for up to 9 months, C57BL/6 mice had a suppressed adaptive immune system at day 135 but had an enhanced adaptive immune system at day 270 during Cd exposure. The biphasic impacts of Cd on the adaptive immune system were correlated to the mitochondrial (MT) activation of HSC. Mechanistically, a direct action of Cd activated the non-canonical Wnt signaling to increase MT activation in HSC in the bone marrow (BM) at day 90, thus resulting in an impaired adaptive immune system in mice at day 135 during Cd exposure; conversely, Cd reduced the production of thrombopoietin (TPO) by osteoblasts in the BM to suppress MT activation in HSC at day 180, which in turn caused an enhanced adaptive immune system in mice at day 270 during Cd exposure. Thus, Cd biphasically impacts the adaptive immune system via regulating MT activation of HSC, providing a novel angle for understanding the immunotoxicology of metals.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"117216"},"PeriodicalIF":3.3,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898156","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":"Fucoxanthin ameliorates ulcerative colitis by maintaining the epithelial barrier via blocking JAK2/STAT3 signaling pathway.","authors":"Jingjing Ma, Simei Yue, Yinghui Liu, Lingjiao Gong, Pengzhan He, Yingjie Yang, Zhengxin Fu, Danxiang Han, Qiang Hu, Fei Liao, Lin Xu","doi":"10.1016/j.taap.2024.117213","DOIUrl":"10.1016/j.taap.2024.117213","url":null,"abstract":"<p><strong>Background: </strong>The clinical efficacies of Ulcerative colitis (UC) are far from satisfactory. Fucoxanthin (FUC) is a marine carotenoid that is abundant in seaweed and microalgae. It has been reported that FUC can possess anti-inflammatory and antioxidant. However, its mechanism and role in UC is yet to be clarified. This study aimed to investigate the protective effect and potential mechanism of FUC extracted from the diatom Phaeodactylum tricornutm on dextran sodium sulfate (DSS) -induced colitis.</p><p><strong>Methods: </strong>Animal UC model was induced by DSS and cellular model was established by TNF-α. Immunohistochemical staining, Western blot, RT-qPCR, and immunofluorescence were used to assess the inflammatory responses and epithelial barrier in vivo and in vitro models.</p><p><strong>Results: </strong>The results showed that FUC attenuates DSS-induced colitis by ameliorating the epithelial mucosal barrier. Moreover, FUC possessed antioxidant and anti-inflammatory effects on NCM460 cells. JAK/STAT activator RO8191 could reverse these changes.</p><p><strong>Conclusion: </strong>FUC exerted anti-inflammatory and antioxidant effects via the JAK2/STAT3 signaling pathway, and served as a potential therapeutic agent for the treatment of UC.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117213"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885468","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}
Shishun Xie, Jianjun Zhao, Fan Zhang, Xiangjun Li, Xiaoyan Yu, Zhiyun Shu, Hongyuan Cheng, Siyao Liu, Shaomin Shi
{"title":"Dehydrodiisoeugenol inhibits PDGF-BB-induced proliferation and migration of human pulmonary artery smooth muscle cells via the mTOR/HIF1-α/HK2 signaling pathway.","authors":"Shishun Xie, Jianjun Zhao, Fan Zhang, Xiangjun Li, Xiaoyan Yu, Zhiyun Shu, Hongyuan Cheng, Siyao Liu, Shaomin Shi","doi":"10.1016/j.taap.2024.117212","DOIUrl":"10.1016/j.taap.2024.117212","url":null,"abstract":"<p><p>Abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling are critical factors in the development of pulmonary hypertension (pH). Dehydrodiisoeugenol (DEH), a natural phenolic compound, is renowned for its antioxidant and anti-inflammatory properties. However, the precise role and mechanisms of DEH in PH remain unclear. In this study, human PASMCs were exposed to PDGF-BB for 48 h to establish an in vitro model. Subsequently, cells were treated with DEH, and assessments of cell proliferation, migration, and apoptosis were performed using CCK-8/EdU assays, scratch/transwell assays, and flow cytometry. The results showed that PDGF-BB induced phenotypic modulation, proliferation, and migration of PASMCs while reducing apoptosis. Treatment with DEH effectively reversed these effects. Bioinformatics analysis identified mTOR as a target of DEH action. Western blot experiments were conducted to evaluate the expression of proteins involved in the mTOR/HIF1-α/HK2 signaling pathway, suggesting that DEH modulates this pathway by targeting and inhibiting mTOR. After treating cells with mTOR inhibitors, cellular glycolysis was assessed using the extracellular acidification rate (ECAR) assay. The results indicated that inhibition of mTOR phosphorylation decreased aerobic glycolysis in PASMCs and suppressed cell proliferation, migration, and apoptosis resistance, regardless of PDGF-BB treatment. Activation of mTOR reversed the inhibition of PDGF-BB-induced PASMC-related protein expression by DEH. These findings suggest that DEH inhibits aerobic glycolysis in PDGF-BB-induced PASMCs through the mTOR/HIF1-α/HK2 signaling pathway, thereby suppressing cell proliferation, migration, and resistance to apoptosis. Consequently, DEH holds promise as a novel therapeutic agent for treating pulmonary arterial hypertension.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117212"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884846","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}
Christine Li Mei Lee, Claire J Brabander, Yoko Nomura, Yasunari Kanda, Sachiko Yoshida
{"title":"Embryonic exposure to acetamiprid insecticide induces CD68-positive microglia and Purkinje cell arrangement abnormalities in the cerebellum of neonatal rats.","authors":"Christine Li Mei Lee, Claire J Brabander, Yoko Nomura, Yasunari Kanda, Sachiko Yoshida","doi":"10.1016/j.taap.2024.117215","DOIUrl":"10.1016/j.taap.2024.117215","url":null,"abstract":"<p><p>Concerns have been raised regarding acetamiprid (ACE), a neonicotinoid insecticide, due to its potential neurodevelopmental toxicity. ACE, which is structurally similar to nicotine, acts as an agonist of nicotinic acetylcholine receptors (nAChRs) and resists degradation by acetylcholinesterase. Furthermore, ACE has been reported to disrupt neuronal transmission and induce developmental neurotoxicity and ataxia in animal models. However, the prenatal ACE exposure and its pathological changes, including impacts on motor control, remains unclear. In this study, we investigated the effects of ACE exposure, focusing on the development of cerebellar neurons and glia, which are linked to motor impairment. ACE at doses of 20, 40-, and 60 mg/kg body weight was administered to Pregnant Wistar rats via feed on gestational day (G) 15. The developing cerebellum of the pups was examined on postnatal days (P) 7, 14, and 18, corresponding to the critical periods of cerebellar maturation in rodents. Our data revealed that ACE exposure at 40 and 60 mg/kg induced abnormal neuronal alignment on P14, and neuronal cell loss on P18. Additionally, ACE altered microglial behavior, with an increase in the number of CD68-positive microglia, suggesting that the exposure results in an increase in phagocytic microglia in response to neuronal abnormalities, ultimately leading to neuronal cell loss. Pups exposed to 60 mg/kg ACE exhibited hindlimb clasping during the hindlimb suspension test, indicating motor impairment. These findings suggest that ACE exposure causes neuronal cell loss of developing Purkinje cells and promotes a phase shift to the activate mode of microglia. This study further highlights the crucial role of neuron-glia interactions in ACE-induced motor impairment, thus contributing to our understanding of the potential risks associated with prenatal ACE exposure.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117215"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885365","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}
Ye Peng, Long Hu, Huilei Xu, Jian Fang, Hongliang Zhong
{"title":"Resveratrol alleviates reactive oxygen species and inflammation in diabetic retinopathy via SIRT1/HMGB1 pathway-mediated ferroptosis.","authors":"Ye Peng, Long Hu, Huilei Xu, Jian Fang, Hongliang Zhong","doi":"10.1016/j.taap.2024.117214","DOIUrl":"10.1016/j.taap.2024.117214","url":null,"abstract":"<p><p>This study aims to explore the potential of using resveratrol (RES) to treat diabetic retinopathy (DR), as well as the involved molecular mechanisms underlying RES-mediated protection against DR. High concentration of glucose (HG)-induced Human retinal capillary endothelial cells (HRCECs) cell model and streptozotocin (STZ)-induced DR mice model were established. Then, cell viability, apoptosis, reactive oxygen species (ROS) levels, pro-inflammatory factors, and expression of the related proteins SIRT1, HMGB1, VEGF, and CD31 were assayed by a series of cell biology methods. Also, the ferroptosis-related indicators were also explored, including contents of Fe<sup>2+</sup>, glutathione (GSH), malondialdehyde (MDA), SLC7A11 and GPX4 protein expression. Results showed that RES could alleviate inflammation and oxidative stress in HG-induced HRCECs. In addition, the mRNA and protein expression of SIRT1 and HMGB1 were significantly changed in HG-induced HRCECs and STZ-induced DR mice, while RES treatment could reverse this alteration. In addition, the HMGB1 acetylation level was enhanced after downregulation of SIRT1. Moreover, the ROS generation, expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α), CD31, and VEGF changed by RES administration were reversed by SIRT1-silence. Besides, HG implement could dramatically up-regulated the Fe<sup>2+</sup> and MDA contents, and down-regulated the content of GSH and SLC7A11 and GPX4 protein expression in HRCECs, as well as STZ-induced DR mice. RES implement could reverse the above alterations, while SIRT1-silence dramatically reversed these alterations changed by RES treatment. In conclusion, RES suppresses inflammation in DR, as well as inhibit retinal angiogenesis and oxidative stress, and inhibits ferroptosis to alleviate DR via SIRT1/HMGB1 pathway.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117214"},"PeriodicalIF":3.3,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885469","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}