Antioxidants & redox signaling最新文献

{"title":"Lipotoxicity Induces Cardiomyocyte Ferroptosis via Activating the STING Pathway.","authors":"Qian Chen, Yina Wang, Jiafu Wang, Xiaolan Ouyang, Junlin Zhong, Yao Huang, Zhuoshan Huang, Benrong Zheng, Long Peng, Xixiang Tang, Suhua Li","doi":"10.1089/ars.2023.0510","DOIUrl":"10.1089/ars.2023.0510","url":null,"abstract":"<p><p><b><i>Objective:</i></b> Lipotoxicity is a well-established contributor to cardiomyocyte death and heart damage, with ferroptosis being identified as a crucial death mode in cardiomyocyte disease. This study aims to explore the potential role and mechanism of ferroptosis in lipotoxicity-induced myocardial injury. <b><i>Methods:</i></b> Eight-week high-fat diet (HFD) Sprague-Dawley rat and H9c2 cardiomyocytes treated with palmitic acid (PA) were established for an <i>in vivo</i> and <i>in vitro</i> lipotoxic model. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were used to inhibit ferroptosis. Myocardial-specific stimulator of interferon genes (STING) knockdown rat (<i>Sting</i>^myo-KD) with HFD was further introduced. Rat cardiac structure and function, cell viability, the level of lipid peroxidation, malondialdehyde (MDA), glutathione (GSH), mitochondrial function, ferroptosis-related proteins, and STING pathway-related proteins in H9c2 cells/myocardium were detected. <b><i>Results:</i></b> HFD rats with a ferroptosis inhibitor showed improved cardiac structure and function, reduced lipid peroxidation, and restored GSH, which was further confirmed in H9c2 cell. The time-dependent activation of the STING pathway following PA stimulation was observed. Knockdown of the expression of STING could reduce PA-induced cell death, lipid peroxidation, and MDA levels while restoring the GSH. In addition, both HFD <i>Sting</i>^myo-KD rats and HFD rats with systematic inhibition by the STING inhibitor exhibited mitigating lipotoxicity-induced myocardial ferroptosis and reducing myocardial injury. <b><i>Innovation and Conclusion:</i></b> These findings suggest that lipotoxicity can induce ferroptosis in cardiomyocytes through the activation of the STING pathway, providing new targets and strategies for the treatment of lipotoxicity cardiomyopathy. <i>Antioxid. Redox Signal.</i> 42, 184-198.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"184-198"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCAAT/Enhancer-Binding Protein Beta Nitration Participates in Hyperhomocysteinemia-Induced Cardiomyocyte Autophagic Flux Blockage by Inhibiting Transcription Factor EB Transcription.","authors":"Jiayin Chai, Jiahui Xu, Shangyue Zhang, Wenjing Yan, Shuai Chen, Xinyu Zhu, Chenghua Luo, Wen Wang","doi":"10.1089/ars.2023.0517","DOIUrl":"10.1089/ars.2023.0517","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Autophagy is a protective mechanism of cardiomyocytes. Hyperhomocysteinemia (HHcy) elevates oxidative and nitrosative stress levels, leading to an abnormal increase in nitration protein, possibly leading to abnormal autophagy regulation in cardiomyocytes. However, the regulatory effect of HHcy on autophagy at the post-translational modification level is still unclear. Here, we aimed to explore the regulatory mechanism of HHcy on transcription factor EB (TFEB) and nitration of CCAAT/enhancer-binding protein beta (C/EBPβ), a transcriptional repressor of <i>Tfeb</i>, on autophagy in cardiomyocytes. <b><i>Results:</i></b> In this study, we established the HHcy rat model by feeding a 2.5% (w/w) methionine diet. The nitration level of C/EBPβ was increased in HHcy, which promoted the entry of C/EBPβ into the nucleus, enhanced the transcriptional suppressive effect of C/EBPβ on <i>Tfeb</i>, and induced insufficient autophagy in cardiomyocytes. Furthermore, we confirmed that the Tyr 274 site of C/EBPβ could undergo nitration induced by HHcy. Once C/EBPβ was nitrated on the Tyr 274 site, the nuclear translocation of C/EBPβ and transcription suppressor function of C/EBPβ on <i>Tfeb</i> were enhanced. <b><i>Innovation and Conclusion:</i></b> We find that C/EBPβ is a transcriptional repressor of <i>Tfeb</i>, and HHcy induces the nitration at the Tyr 274 site of C/EBPβ, leading to autophagic flux blockage in cardiomyocytes. These data indicated that nitrated C/EBPβ might be a potential therapeutic target against HHcy-induced autophagy insufficiency of cardiomyocytes. <i>Antioxid. Redox Signal.</i> 42, 165-183.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"165-183"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitric Oxide Is Required for Primary Nitrate Response in Arabidopsis: Evidence for S-Nitrosation of NLP7.","authors":"Andrés Nejamkin, Fiorella Del Castello, Lorenzo Lamattina, Natalia Correa-Aragunde, Noelia Foresi","doi":"10.1089/ars.2022.0210","DOIUrl":"10.1089/ars.2022.0210","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Nitrogen (N) is a necessary nutrient for plant development and seed production, with nitrate (NO₃^-) serving as the primary source of N in soils. Although several molecular players in plant responses to NO₃^- signaling were unraveled, it is still a complex process with gaps that require further investigation. The aim of our study is to analyze the role of nitric oxide (NO) in the primary nitrate response (PNR). <b><i>Results:</i></b> Using a combination of genetic and pharmacological approaches, we demonstrate that NO is required for the expression of the NO₃^--regulated genes nitrate reductase 1 (<i>NIA1</i>), nitrite reductase (<i>NIR</i>), and nitrate transporters (nitrate transporter 1.1 [<i>NRT1.1</i>] and nitrate transporter 2.1 [<i>NRT2.1</i>]) in Arabidopsis. The PNR is impaired in the Arabidopsis mutant <i>noa1</i>, defective in NO production. Our results also show that <i>PHYTOGLOBIN 1</i> (<i>PHYTOGLB1</i>), involved in NO homeostasis, is rapidly induced during PNR in wild type (wt) but not in the mutants of the nitrate transceptor NTR1.1 and the transcription factor nodule inception-like protein 7 (NLP7), suggesting that the NRT1.1-NLP7 cascade modulates <i>PHYTOGLB1</i> gene expression. Biotin switch experiments demonstrate that NLP7, the PNR-master regulator, is S-nitrosated <i>in vitro</i>. Depletion of NO during PNR intensifies the decrease in reactive oxygen species levels and the rise of catalase (CAT) and ascorbate peroxidase (APX) enzyme activity. <b><i>Conclusion and Innovation:</i></b> NO, a by-product of NO₃^- metabolism and a well-characterized signal molecule in plants, is an important player in the PNR.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"280-291"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10027101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does Deteriorating Antioxidant Defense and Impaired γ-Glutamyl Cycle Induce Oxidative Stress and Hemolysis in Individuals with Sickle Cell Disease?","authors":"Shruti Bhatt, Amit Kumar Mohapatra, Apratim Sai Rajesh, Satyabrata Meher, Alo Nag, Pradip Kumar Panda, Ranjan Kumar Nanda, Suman Kundu","doi":"10.1089/ars.2024.0594","DOIUrl":"10.1089/ars.2024.0594","url":null,"abstract":"<p><p>Sickle cell disease (SCD) affects two-thirds of African and Indian children. Understanding the molecular mechanisms contributing to oxidative stress may be useful for therapeutic development in SCD. We evaluated plasma elemental levels of Indian SCD patients, trait, and healthy controls (<i>n</i> = 10 per group) <i>via</i> inductively coupled plasma mass spectrometry. In addition, erythrocyte metabolomics of Indian SCD and healthy (<i>n</i> = 5 per group) was carried out using liquid chromatography-mass spectrometry. Followed by assessment of antioxidant defense enzymes namely glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) in erythrocytes and plasma of Indian SCD patients (<i>n</i> = 31) compared with trait (<i>n</i> = 10) and healthy (<i>n</i> = 10). In SCD plasma an elevated plasma ²⁴ Mg, ⁴⁴Ca, ⁶⁶Zn, ²⁰⁸Pb, ³⁹K and reduced ⁵⁷Fe, ⁷⁷Se, and ⁸⁵Rb levels indicated higher hemolysis and anemia. Erythrocyte metabolome of SCD patients clustered separately from healthy revealed 135 significantly deregulated metabolic features, including trimethyllysine, pyroglutamate, glutathione, aminolevulinate, and d-glutamine, indicating oxidative stress and membrane fragility. Repressed GR, SOD, and CAT activities were observed in SCD patients of which GR and CAT activities did not change under hypoxia. These findings lead to the hypothesis that SCD-associated metabolic deregulations and a shift to ATP-consuming aberrant γ-glutamyl cycle leads to anemia, dehydration, oxidative stress, and hemolysis driving the biomechanical pathophysiology of erythrocyte of SCD patients. <i>Antioxid. Redox Signal.</i> 42, 199-211.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"199-211"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nattokinase's Neuroprotective Mechanisms in Ischemic Stroke: Targeting Inflammation, Oxidative Stress, and Coagulation.","authors":"Xin-Ying Yang, Sheng-Lin Wang, Wen-Chi Xue, Yu-Peng Zhang, Liang-Liang Li, Zhao-Hu Luo, Feng-Jiao Zhang","doi":"10.1089/ars.2023.0527","DOIUrl":"10.1089/ars.2023.0527","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Nattokinase (NK), a potent serine endopeptidase, has exhibited a variety of pharmacological effects, including thrombolysis, anti-inflammation, and antioxidative stress. Building on previous research highlighting NK's promise in nerve regeneration, our study investigated whether NK exerted protective effects in transient middle cerebral artery occlusion (tMCAO)-induced cerebral ischemia-reperfusion injury and the underlying mechanisms. <b><i>Results:</i></b> The rats were administered NK (5000, 10000, 20000 FU/kg, i.g., 7 days before surgery, once daily). We showed that NK treatment dose dependently reduced the infarction volume and improved neurological symptoms, decreased the proinflammatory and coagulation cytokines levels, and attenuated reactive oxygen species (ROS) in the infarcted area of tMCAO rats. We also found that NK could exert neuroprotective effects in a variety of vitro models, including the microglia inflammation model and neuronal oxygen-glucose deprivation/reperfusion (OGD/R) model. Notably, NK effectively countered OGD/R-induced neuron death, modulating diverse pathways, including autophagy, apoptosis, PARP-dependent death, and endoplasmic reticulum stress. Furthermore, the neuroprotection of NK was blocked by phenylmethylsulfonyl fluoride (PMSF), a serine endopeptidase inhibitor. We revealed that heat-inactive NK was unable to protect against tMCAO injury and other vitro models, suggesting NK attenuated ischemic injury by its enzymatic activity. We conducted a proteomic analysis and found inflammation and coagulation were involved in the occurrence of tMCAO model and in the therapeutic effect of NK. <b><i>Innovation and Conclusion:</i></b> In conclusion, these data demonstrated that NK had multifaceted neuroprotection in ischemic brain injury, and the therapeutic effect of NK was related with serine endopeptidase activity. Antioxid. Redox Signal. 42, 228-248.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"228-248"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Emerging Role of Herbal Medicines in Cancer by Interfering with Posttranslational Modifications.","authors":"Rui Wang, Yu Li, Jiahui Ji, Lingwei Kong, Yukai Huang, Zhongqiu Liu, Linlin Lu","doi":"10.1089/ars.2023.0418","DOIUrl":"10.1089/ars.2023.0418","url":null,"abstract":"<p><p><b><i>Significance:</i></b> Herbal medicines have a long history of comprehensive cancer treatment through various posttranslational modifications (PTMs). Recently, emerging evidence revealed that dysregulation of reactive oxygen species (ROS) and ROS-regulated signaling pathways influence cancer initiation, growth, and progression in a paradoxical role with either low levels or increasing levels of basal ROS. However, ROS-triggered modifications of target proteins in the face of ROS-mediated signal transduction are not fully understood in the anticancer therapies of herbal medicines. In this review, we briefly introduce the PTM-dependent regulations of herbal medicines, and then focus on the current ideals that targeting ROS-dependent PTMs <i>via</i> antioxidant and redox signaling pathways can provide a promising strategy in herbal-based anticancer effects. <b><i>Recent Advances:</i></b> Advanced development in highly sensitive mass spectrometry-based techniques has helped utilize ROS-triggered protein modifications in numerous cancers. Accumulating evidence has been achieved in laboratory to extensively ascertain the biological mechanism of herbal medicines targeting ROS in cancer therapy. Two general mechanisms underlining ROS-induced cell signaling include redox state and oxidative modification of target protein, indicating a new perspective to comprehend the intricate dialogues between herbal medicines and cancer cellular contexts. <b><i>Critical Issues:</i></b> Complex components of herbal medicines limit the benefits of herbal-based cancer therapies. In this review, we address that ROS-dependent PTMs add a layer of proteomic complexity to the cancer through altering the protein structure, expression, function, and localization. Elaborating ROS-triggered PTMs implicated in cell signaling, apoptosis, and transcriptional regulation function, and the possible cellular signaling, has provided important information about the contribution of many ROS targeting herbal therapies in anticancer effects. Continued optimization of proteomic strategies for PTM analysis in herbal medicines is also briefly discussed. <b><i>Future Directions:</i></b> Rigorous evaluations of herbal medicines and proteomic strategies are necessary to explore the aberrant regulation of ROS-triggered antioxidant and redox signaling contributing to the novel protein targets and herbal-associated pharmacological issues. These efforts will eventually help develop more herbal drugs as modern therapeutic agents. <i>Antioxid. Redox Signal.</i> 42, 150-164.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"150-164"},"PeriodicalIF":5.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asperuloside as a Novel NRF2 Activator to Ameliorate Endothelial Dysfunction in High Fat Diet-Induced Obese Mice.","authors":"Chufeng He, Ruiwen Zhu, Lei He, Chui Yiu Bamboo Chook, Huixian Li, Fung Ping Leung, Gary Tse, Zhen-Yu Chen, Yu Huang, Wing Tak Wong","doi":"10.1089/ars.2024.0593","DOIUrl":"10.1089/ars.2024.0593","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Current treatments are inadequate in alleviating obesity-associated vascular diseases. The development of effective therapies to ameliorate endothelial dysfunction and attenuate oxidative stress is of utmost importance. Asperuloside (ASP), a bioactive compound extracted from <i>Eucommia species</i>, exhibits antiobesity properties. However, the effects of ASP on vasculopathy have not been investigated. Therefore, the effects of ASP on vascular dysfunction and related mechanisms were elucidated. <b><i>Results:</i></b> ASP significantly reversed the impaired endothelium-dependent relaxations (EDRs) in obese mice and interleukin (IL)-1β-treated aortas. ASP suppressed endothelial activation in obese mice aortas and IL-1β-treated endothelial cells. ASP attenuated oxidative stress, scavenged mitochondrial reactive oxygen species (ROS), and upregulated heme oxygenase-1 (HO-1) expression in endothelium, independent of its anti-inflammatory properties. HO-1 knockdown diminished the protective effects of ASP against impaired EDRs, ROS overproduction, and endothelial activation. Endothelial cell-specific nuclear factor erythroid 2-related factor 2 (Nrf2) knockdown eliminated the ASP-mediated vascular protective effects and endothelial HO-1 upregulation, emphasizing that ASP improves endothelial function by activating Nrf2/HO-1 signaling. ASP facilitated Nrf2 nuclear translocation and the direct binding of Nrf2 to antioxidant response element, thereby enhancing HO-1 transcription and scavenging ROS. The cellular thermal shift assay results provide the first experimental characterization of the direct binding of ASP to Nrf2. <b><i>Conclusions:</i></b> These findings demonstrate that ASP ameliorates obesity-associated endothelial dysfunction by activating Nrf2/HO-1 signaling and thereby maintaining redox hemostasis, suggesting its potential as a novel Nrf2-targeted therapeutic agent and dietary supplement for vasculopathy. <i>Antioxid. Redox Signal.</i> 42, 77-96.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"77-96"},"PeriodicalIF":5.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Antioxidant Ergothioneine Alleviates Cisplatin-Induced Hearing Loss Through the Nrf2 Pathway.","authors":"Wenji Zhao, Fan Wu, Rui Hu, Jintao Lou, Guisheng Chen, Ziyi Cai, Suijun Chen","doi":"10.1089/ars.2024.0648","DOIUrl":"10.1089/ars.2024.0648","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Cisplatin (CDDP) is a commonly used chemotherapeutic agent for treating head and neck tumors. However, there is high incidence of ototoxicity in patients treated with CDDP, which may be caused by the excessive reactive oxygen species (ROS) generation in the inner ear. Many studies have demonstrated the strong antioxidant effects of ergothioneine (EGT). Therefore, we assumed that EGT could also attenuate cisplatin-induced hearing loss (CIHL) as well. However, the protective effect and mechanism of EGT on CIHL have not been elucidated as so far. In this study, we investigated whether EGT could treat CIHL and the mechanism. <b><i>Results:</i></b> In our study, we confirmed the protective effect of EGT on preventing CDDP-induced toxicity both <i>in vitro</i> and <i>in vivo</i>. The auditory brainstem response threshold shift in the EGT + CDDP treatment mice was 30 dB less than that in the CDDP treatment mice. EGT suppressed production of ROS and proapoptotic proteins both in tissue and cells. By silencing nuclear factor erythroid 2-related factor 2 (Nrf2), we confirmed that EGT protected against CIHL <i>via</i> the Nrf2 pathway. We also found that SLC22A4 (OCTN1), an important molecule involved in transporting EGT, was expressed in the cochlea. <b><i>Innovation:</i></b> Our results revealed the role of EGT in the prevention of CIHL by activating Nrf2/HO-1/NQO-1 pathway, and broadened a new perspective therapeutic target of EGT. <b><i>Conclusion:</i></b> EGT decreased ROS production and promoted the expression of antioxidative enzymes to maintain redox homeostasis in sensory hair cells. Overall, our results indicated that EGT may serve as a novel treatment drug to attenuate CIHL. <i>Antioxid. Redox Signal.</i> 42, 97-114.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"97-114"},"PeriodicalIF":5.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disturbance of Fetal Growth by Azithromycin Through Induction of ER Stress in the Placenta.","authors":"Fan Pan, Fan Zhang, Meng-Die Li, YaKun Liang, Wang-Sheng Wang, Kang Sun","doi":"10.1089/ars.2024.0592","DOIUrl":"10.1089/ars.2024.0592","url":null,"abstract":"<p><p><b><i>Aim:</i></b> Azithromycin (AZM) is widely used to treat mycoplasma infection in pregnancy. However, there is no adequate evaluation of its side effect on the placenta. In this study, using human placental syncytiotrophoblasts and a mouse model, we investigated whether AZM use in pregnancy might adversely affect placental function and pregnancy outcome. <b><i>Results:</i></b> Transcriptomic analysis of AZM-treated human placental syncytiotrophoblasts showed increased expression of endoplasmic reticulum (ER) stress-related genes and decreased expression of genes for hormone production and growth factor processing. Verification studies showed that AZM increased the abundance of ER stress mediators (phosphorylated eIF2α, activating transcription factor 4 [ATF4], and C/EBP Homologous Protein [CHOP]) and decreased the abundance of enzymes involved in progesterone and estradiol synthesis (<i>STS</i>, <i>CYP11A1</i>, and <i>CYP19A1</i>) and insulin-like growth factor binding protein (IGFBP) cleavage (<i>PAPPA</i> and <i>ADAM12</i>) in human placental syncytiotrophoblasts. Inhibition of ER stress blocked AZM-induced decreases in the expression of CYP19A1, CYP11A1, PAPPA, and ADAM12, suggesting that the inhibition of AZM on those genes' expression was secondary to AZM-induced ER stress. Further mechanism study showed that increased ATF4 in ER stress might repressively interact with C/EBPα to suppress the expression of those genes, including <i>CEBPA</i> itself. Mouse studies showed that AZM administration decreased fetal weights along with increased ER stress mediators and decreased levels of insulin-like growth factor, estrogen, and progesterone in the maternal blood, which could be alleviated by inhibition of ER stress. <b><i>Innovation and Conclusion:</i></b> These findings first support the fact that AZM, often used during pregnancy, may affect fetal growth by inhibiting crucial enzymes for estrogen and progesterone synthesis and disrupting crucial proteases for IGFBP cleavage <i>via</i> inducing ER stress in placental syncytiotrophoblasts. <i>Antioxid. Redox Signal.</i> 42, 16-35.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"16-35"},"PeriodicalIF":5.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baicalin Attenuates Diabetic Cardiomyopathy <i>In Vivo</i> and <i>In Vitro</i> by Inhibiting Autophagy and Cell Death Through SENP1/SIRT3 Signaling Pathway Activation.","authors":"Peipei Zhang, Haowei Wu, Haifei Lou, Jiedong Zhou, Jinjin Hao, Hui Lin, Songqing Hu, Zuoquan Zhong, Juntao Yang, Hangyuan Guo, Jufang Chi","doi":"10.1089/ars.2023.0457","DOIUrl":"10.1089/ars.2023.0457","url":null,"abstract":"<p><p><b><i>Aims:</i></b> Diabetic heart damage can lead to cardiomyocyte death, which endangers human health. Baicalin (BAI) is a bioactive compound that plays an important role in cardiovascular diseases. Sentrin/SUMO-specific protease 1 (<i>SENP1</i>) regulates the de-small ubiquitin-like modifier (deSUMOylation) process of Sirtuin 3 (<i>SIRT3</i>) and plays a crucial role in regulating mitochondrial mass and preventing cell injury. Our hypothesis is that BAI regulates the deSUMOylation level of <i>SIRT3</i> through <i>SENP1</i> to enhance mitochondrial quality control and prevent cell death, ultimately improving diabetic cardiomyopathy (DCM). <b><i>Results:</i></b> The protein expression of <i>SENP1</i> decreased in cardiomyocytes induced by high glucose and in db/db mice. The cardioprotective effects of BAI were eliminated by silencing endogenous <i>SENP1</i>, whereas overexpression of <i>SENP1</i> showed similar cardioprotective effects to those of BAI. Furthermore, co-immunoprecipitation experiments showed that BAI's cardioprotective effect was due to the inhibition of the SUMOylation modification level of <i>SIRT3</i> by <i>SENP1</i>. Inhibition of <i>SENP1</i> expression resulted in an increase in SUMOylation of <i>SIRT3</i>. This led to increased acetylation of mitochondrial protein, accumulation of reactive oxygen species, impaired autophagy, impaired mitochondrial oxidative phosphorylation, and increased cell death. None of these changes could be reversed by BAI. <b><i>Conclusion:</i></b> BAI improves DCM by promoting <i>SIRT3</i> deSUMOylation through <i>SENP1</i>, restoring mitochondrial stability, and preventing the cell death of cardiomyocytes. <b><i>Innovation:</i></b> This study proposes for the first time that <i>SIRT3</i> SUMOylation modification is involved in the development of DCM and provides <i>in vivo</i> and <i>in vitro</i> data support that BAI inhibits cardiomyocyte ferroptosis and apoptosis in DCM through <i>SENP1</i>. <i>Antioxid. Redox Signal.</i> 42, 53-76.</p>","PeriodicalId":8011,"journal":{"name":"Antioxidants & redox signaling","volume":" ","pages":"53-76"},"PeriodicalIF":5.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}