Chemico-Biological Interactions最新文献

{"title":"Sorafenib-induced cardiovascular toxicity: A cause for concern","authors":"Zheng Deng ,&nbsp;Shuang Xiao ,&nbsp;Ying-Ying He ,&nbsp;Yu Guo ,&nbsp;Li-Jing Tang","doi":"10.1016/j.cbi.2025.111388","DOIUrl":"10.1016/j.cbi.2025.111388","url":null,"abstract":"<div><div>Sorafenib, a multi-target tyrosine kinase inhibitor, is primarily used to manage hepatocellular carcinoma, advanced renal cell carcinoma, and differentiated thyroid cancer. Although this drug extends patient survival and slows tumor progression, its cardiovascular toxicity substantially impacts of quality of life. Effective the prevention and treatment of the resulting complications are needed. The mechanisms underlying of sorafenib-induced cardiovascular toxicity are complex, and remain incompletely understood despite extensive research. In this review, we discuss the incidence of sorafenib-induced cardiovascular toxicity, including hypertension, thromboembolism, and heart failure in clinical settings. We also summarize current research on the underlying mechanisms, such as ferroptosis, necroptosis, autophagy, mitochondrial damage, and endoplasmic reticulum stress. Additionally, we explore studies regarding the protective effects of various drugs against sorafenib-induced cardiovascular toxicity. This in-depth synthesis of data regarding the clinical manifestations and mechanisms of sorafenib-induced cardiotoxicity provides a valuable scientific foundation for developing therapeutic drugs to combat these adverse effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"410 ","pages":"Article 111388"},"PeriodicalIF":4.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076193","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}

{"title":"A novel PDE4 inhibitor ZX21011 alleviates neuronal apoptosis by decreasing GSK3β-mediated Drp1 Ser616 phosphorylation in cerebral ischemia reperfusion","authors":"Huizhen Wen ,&nbsp;Xingxing Tu ,&nbsp;Fulan Luo ,&nbsp;Chunyuan Zeng ,&nbsp;Chuang Xia ,&nbsp;Qian Zhao ,&nbsp;Zihong Xian ,&nbsp;Zhongzhen Zhou ,&nbsp;Jiangping Xu ,&nbsp;Haitao Wang","doi":"10.1016/j.cbi.2025.111405","DOIUrl":"10.1016/j.cbi.2025.111405","url":null,"abstract":"<div><div>Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and participates in neuronal apoptosis during the pathology of cerebral ischemia. We have previously shown that inhibition of phosphodiesterase-4 (PDE4) protects against neuronal apoptosis in models of ischemic stroke. However, it remains unclear whether PDE4 inhibition affects Drp1-mediated mitochondrial dysfunction and apoptosis under cerebral ischemia conditions. This study aimed to determine whether ZX21011, a novel PDE4 inhibitor synthesized in our laboratory, can act on Drp1 to counteract ischemic brain injury and to elucidate its mechanism of action. We demonstrated that ZX21011 effectively reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells and ameliorated neurological deficits caused by middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. ZX21011 enhanced glycogen synthase kinase-3β (GSK3β) phosphorylation (Ser9), GSK3β(S9A) mutation blocked the protective effects of ZX21011. Simultaneously, ZX21011 reduced the levels of reactive oxygen species (ROS), restored the morphology of mitochondria, and inhibited the phosphorylation of Drp1(Ser616). The Drp1(S616E) mutation blocked the protective effects of ZX21011 on ROS production and mitochondrial morphology function after cerebral ischemia. What's more, co-immunoprecipitation analysis revealed that ZX21011 decreased the binding of GSK3β to Drp1, and GSK3β(S9A) mutation reversed the effects of ZX21011 on Drp1 phosphorylation and cell viability. Moreover, ZX21011 decreased Drp1(Ser616) phosphorylation within the ischemic penumbra of rats following cerebral ischemia/reperfusion. In summary, ZX21011 counteracts ischemic stroke-induced oxidative stress and neuronal death, and its action is related to decreased Drp1 phosphorylation at Ser616. Thus, ZX21011 is a potential compound for the intervention of stroke.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111405"},"PeriodicalIF":4.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076044","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}

{"title":"Toxicological profile of Acovenoside A as an active pharmaceutical ingredient – prediction of missing key toxicological endpoints using in silico toxicology methodology","authors":"Kamil Jurowski ,&nbsp;Łukasz Niżnik ,&nbsp;Adrian Frydrych ,&nbsp;Damian Kobylarz ,&nbsp;Maciej Noga ,&nbsp;Alicja Krośniak ,&nbsp;Oktawia Fijałkowska ,&nbsp;Agnieszka Świdniak ,&nbsp;Varun Ahuja","doi":"10.1016/j.cbi.2025.111404","DOIUrl":"10.1016/j.cbi.2025.111404","url":null,"abstract":"<div><div>Acovenoside A, a cardenolide glycoside from <em>Acokanthera oppositifolia</em>, demonstrates significant therapeutic potential in cardioprotection and oncology, particularly against non-small cell lung cancer (NSCLC). However, its toxicological profile requires thorough evaluation for safe pharmaceutical application. For this purpose a comprehensive <em>in silico</em> methods were applied, including ACD/Labs Percepta, STopTox, admetSAR 3.0, ADMETlab 3.0, ProTox 3.0, TEST 5.1.2, and VEGA QSAR, for prediction of a key toxicological endpoints (acute toxicity, potential health effects, skin and eye irritation, as well as endocrine disruption). These different methods and models were applied to build a comprehensive toxicological profile for Acovenoside A, synthesizing predictions to inform its potential risks and guide future research. The qualitative toxicity predictions using <em>in silico</em> tools (STopTox, admetSAR 3.0) shows specific structural fragments responsible for toxicity (toxicophores) and high probabilities (89.3–90 %) of acute toxicity depending on route of exposure. Quantitative acute toxicity predictions (Percepta, ProTox 3.0, Test 5.1.2, VEGA QSAR) indicated moderate to high toxicity, with LD₅₀ values ranging from 6.2 mg/kg (intravenous, mice) to 51 mg/kg (subcutaneous, mice), and oral administration LD₅₀ values of 5–49 mg/kg. The digoxigenin scaffold present in Acovenoside A was associated with increased toxicity, consistent with similar compounds exhibiting a median LD₅₀ of 9.2 mg/kg. Health effects assessments highlighted substantial risks of multiorgan toxicity, with high probabilities of adverse effects on the cardiovascular, gastrointestinal, respiratory, renal, hematologic, and hepatic systems. Prediction for eye irritation (Percepta, STopTox, admetSAR 3.0, ADMETlab 3.0, VEGA QSAR) suggested minimal risk, with probabilities ranging from 0 % to 39 %, though some results fell outside the domain of applicability. For skin irritation (Percepta, STopTox, admetSAR 3.0, ADMETlab 3.0, VEGA QSAR), moderate potential was predicted (30–37 %), but reliability varied across models, underscoring the need for experimental confirmation. Endocrine disruption (Percepta, admetSAR 3.0, VEGA QSAR) risk appears low, with minimal predicted binding affinity to estrogen receptors (LogRBA &gt; −3) and inactivity in some models. This integrative analysis of multiple <em>in silico</em> tools provides valuable insights into the toxicological profile of Acovenoside A. While the compound holds therapeutic promise, its toxicological risks necessitate careful dosing and further experimental validation to ensure safety across various applications.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111404"},"PeriodicalIF":4.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070284","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}

{"title":"Resveratrol loaded microglia-derived exosomes attenuate astrogliasis by restoring mitochondrial function to reduce spinal cord injury","authors":"Jingwen Cui ,&nbsp;Sen Lin ,&nbsp;Mingyuan Zhang","doi":"10.1016/j.cbi.2025.111407","DOIUrl":"10.1016/j.cbi.2025.111407","url":null,"abstract":"<div><div>The activation of astrocytes in the injured lesion induces the progression of spinal cord injury (SCI). However, adverse side-effects during systemic administration have limited applications. Exosomes (Exos) are an emerging clinical treatment method that exerts anti-inflammatory effects by reducing pro-inflammatory factors and promoting functional recovery. Exosomes exhibit great potential as carriers of traditional Chinese medicine, attributed to their high delivery efficiency to internalized and targeted accumulation in inflammatory tissues. Herein, We synthesized resveratrol loaded microglia-derived exosomes (R-MDEs) for highly efficient accumulation and infiltration in the injured spinal cord. In vitro and in vivo experiments suggested that R-MDEs effectively accumulated in A1 astrocytes, inhibited reactive oxygen species (ROS) and glial scar formation by reprogramming the metabolic astrocytes. R-MDEs achieve a synergistic therapeutic effect of immunomodulation and neuroprotection, thereby shedding new light on the application of Exos and provides great potential for SCI.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"408 ","pages":"Article 111407"},"PeriodicalIF":4.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070279","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}

{"title":"Urolithin A attenuates Doxorubicin-induced cardiotoxicity by enhancing PINK1-regulated mitophagy via Ambra1","authors":"Xiaoyan Wang ,&nbsp;Chao Ma ,&nbsp;Keying Mi ,&nbsp;Xinran Cao ,&nbsp;Yinghua Tan ,&nbsp;Haitao Yuan ,&nbsp;Jun Ren ,&nbsp;Xinyue Liang","doi":"10.1016/j.cbi.2024.111363","DOIUrl":"10.1016/j.cbi.2024.111363","url":null,"abstract":"<div><div>Doxorubicin (Dox) is a widely used antineoplastics although its clinical usage is greatly limited by its cardiotoxicity. Several studies have depicted an essential role for dampened mitophagy and mitochondrial injury in Dox cardiotoxicity. However, preventative measure to alleviate Dox-evoked cardiotoxicity via targeting mitophagy and mitochondrial integrity remains elusive. Urolithin A (UA) is a newly identified mitophagy inducer with antioxidant and anti-apoptotic properties although its effect on Dox-induced cardiotoxicity is unknown. This study was designed to explore the effect of UA on Dox cardiotoxicity and mechanisms involved. Our results indicated that UA alleviated Dox-induced cardiac dysfunction exhibited by echocardiographic parameters and histological analyses, and partially relieved Dox-induced apoptosis in vitro and in vivo, and mitochondrial dysfunction including ΔΨm dissipation and ROS production in vitro. The ability of UA to facilitate restoration of mitophagy in mice and H9C2s underscored its advantageous effects, manifested as upregulation of mitophagy-related proteins, including p62, LC3, PINK1 and Parkin, as well as the co-location between LC3 and mitochondria. Incubation with 3 -MA nearly reversed the UA-evoked rise of mitophagy-related proteins, and inhibition of apoptosis. Given that knockdown of Ambra1 almost abolished UA-induced protective effect, the enhanced expression of Ambra1 owing to UA increased PINK1 levels by inhibiting its degradation via LONP1. Collectively, our results suggest that the cardioprotective properties of UA depend on the stimulation of PINK1-dependent mitophagy through promoting Ambra1 expression to inhibit PINK1 degradation by LONP1. This highlights UA's potential as a valuable treatment option and its importance in cardioprotective strategies against Dox-induced cardiotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"406 ","pages":"Article 111363"},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900598","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}

{"title":"Obeticholic acid aggravates liver fibrosis by activating hepatic farnesoid X receptor-induced apoptosis in cholestatic mice","authors":"Qian Lu ,&nbsp;Jingyi Yu ,&nbsp;Ninglin Xia ,&nbsp;Ming Jin ,&nbsp;Wen Zhao ,&nbsp;Xue Fan ,&nbsp;Rongmi Zhang ,&nbsp;Jie Wang ,&nbsp;Zhenzhou Jiang ,&nbsp;Qinwei Yu","doi":"10.1016/j.cbi.2024.111364","DOIUrl":"10.1016/j.cbi.2024.111364","url":null,"abstract":"<div><div>Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients. However, it can cause severe drug-induced liver injury (DILI), which may put PBC patients at risk of acute-on-chronic liver failure (ACLF) and even death. Farnesoid X receptor (FXR) is considered as the target of OCA for cholestasis, but there is still a lack of research on whether hepatic and ileal FXR have different effects after OCA treatment. The aim of this study was to investigate the mechanism of OCA aggravating liver fibrosis in cholestasis. The results showed that 40 mg/kg OCA elevated serum AST, ALT, ALP and γ-GT levels in bile duct ligation (BDL) mice. Besides, severe fibrosis and necrosis were observed in the OCA-treated BDL mice, which was related to hepatic apoptosis pathway activation. Both hepatic and ileal FXR signaling could be significantly activated by OCA. However, ileum-specific knockout of <em>Fxr</em> aggravated OCA-induced liver injury in BDL mice. On the contrary, hepatic-specific knockout of <em>Fxr</em> structurally and functionally ameliorated liver pathological processes in the OCA-treated BDL mice, which was due to the blockade of hepatic FXR-induced apoptosis. In conclusion, the mechanism of OCA aggravating liver fibrosis in cholestasis was based on the activation of hepatic FXR-induced apoptosis. It was also indicated ileal FXR might be a safer pharmacological target for bile acids regulation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"406 ","pages":"Article 111364"},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900637","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}

{"title":"Squaric acid derivatives with cytotoxic activity-a review","authors":"Georgi Tirolski ,&nbsp;Georgi Momekov ,&nbsp;Emiliya Cherneva","doi":"10.1016/j.cbi.2024.111344","DOIUrl":"10.1016/j.cbi.2024.111344","url":null,"abstract":"<div><div>3,4-Dihydroxycyclobut-3-ene-1,2-dione (squaric acid, SQ) is the most important representative of the oxocarbon acids family. Squaric acid derivatives can be promising pharmaceutical agents, due to their unique structural properties, from which novel drugs benefit: a planar aromatic ring, the ability to form hydrogen bonds, good reactivity and similarity with carboxylate, phosphate and amide groups. These properties make it suitable for three major applications in cancer treatment. Firstly, due to their excellent ion binding ability, the halogenated squaramides can be used as artificial ion transporters or mobile carriers to disrupt Na⁺/Cl⁻ gradients in cancer cells, thus hindering lysosomal function and inducing apoptosis. Another advantage of this class is their bioisosteric properties. Such molecules have been reported to be selective inhibitors of HDACs, FAK, SNM1A, MMP and kinases, involved in tumor growth and metastasis. Finally, the cyclobutenedione moiety proves to be a great linker in complex radiopharmaceuticals, used in theranostics. Its aromaticity and good reactivity make the generation and stability of these drugs easy and efficient. Multiple derivatives containing the squamide motif have been the subject of <em>in-vitro</em> investigations and have demonstrated anti-cancer activity in the nanomolar range against tumor cell lines, including colorectal adenocarcinoma, breast cancer, gastric carcinoma and cervical cancer. On the other hand, squaric acid derivative-Navarixin, has already been evaluated in Phase II clinical trials for its potential efficacy in the treatment of solid tumors. In this context this review is the first looking into the potential applications of squaric acid derivatives as anticancer therapies. It analyzes experimental studies presented in articles published between 2000 and 2024.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"406 ","pages":"Article 111344"},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomics with gut microbiota analysis of podophyllotoxin-mediated cardiotoxicity in mice based on the toxicological evidence chain (TEC) concept","authors":"Lu Sun ,&nbsp;Jiaojiao Liu ,&nbsp;Yangyang Cheng ,&nbsp;Yikang Wu ,&nbsp;Tao He ,&nbsp;Yingyue Zhang ,&nbsp;Xiaorui Bai ,&nbsp;Zixin Zhou ,&nbsp;Xiayu Xu ,&nbsp;Yuxin Yao ,&nbsp;Yafei Tan ,&nbsp;Qiang Qiu ,&nbsp;Chuanxin Liu","doi":"10.1016/j.cbi.2024.111360","DOIUrl":"10.1016/j.cbi.2024.111360","url":null,"abstract":"<div><div>Podophyllotoxin (PPT) is a lignan isolated from the traditional Chinese medicine <em>Dysosma Versipellis</em>, with significant anti-tumor activity. However, its cardiotoxicity restricts its clinical application. This study aims to investigate the cardiotoxicity of PPT in mice and its underlying mechanisms based on the concept of toxicological evidence chain (TEC). In this study, alterations in body weight, behavior, and the levels of myocardial enzymes and histopathology in mice were observed. Additionally, microbiome and metabolome were integrated to identify potential microorganisms, metabolic markers and major pathways with correlation analysis. The results indicated that PPT induced pathological changes in mice, including weight loss, diarrhea, alopecia and dehydration accompanied by increased levels of serum myocardial enzymes. The results of microbiome showed that PPT altered the gut microbiota composition, changing the abundance of microbial community. The results of metabolome studies indicated total of 55 differential metabolites were involved in glycine, serine, and threonine metabolism, alanine, glutamate, and aspartate metabolism, purine, pyrimidine metabolism, and steroid hormone metabolism. Integrating the results of microbiome and metabolome, it was concluded that PPT remodeled the gut microbiota composition, which in turn modified the gut microbiota metabolism, affecting amino acid metabolisms, nucleotide metabolism, and steroid hormone metabolism in the heart, potentially leading to energy metabolism disorders, apoptosis, and oxidative stress, ultimately inducing cardiotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"406 ","pages":"Article 111360"},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873783","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}

{"title":"The role of HIF-1α/BNIP3/mitophagy in acrylonitrile-induced neuronal death in HT22 cells and mice: A potential neuroprotection target","authors":"Jing Hu ,&nbsp;Bobo Yang ,&nbsp;Zehua Tao ,&nbsp;Jian Chen ,&nbsp;Xinyu Zhang ,&nbsp;Suhua Wang ,&nbsp;Guangwei Xing ,&nbsp;Ngwa Adeline Ngeng ,&nbsp;Abdul Malik ,&nbsp;Kwaku Appiah-Kubi ,&nbsp;Marcelo Farina ,&nbsp;Anatoly V. Skalny ,&nbsp;Alexey A. Tinkov ,&nbsp;Michael Aschner ,&nbsp;Rongzhu Lu","doi":"10.1016/j.cbi.2024.111327","DOIUrl":"10.1016/j.cbi.2024.111327","url":null,"abstract":"<div><div>Acrylonitrile (AN) is a widely utilized organic compound in the production of diverse industrial synthetic materials. While acute exposure to AN can cause neurotoxicity, the precise mechanism remains unclear. Hypoxia-inducible factor 1 alpha (HIF-1α) is a pivotal transcription factor that coordinates and orchestrates multiple physiological processes to adapt to hypoxic conditions, ensuring cellular survival and homeostasis. In this study, we used <em>in vitro</em> (cultured mouse hippocampal neuronal cell line, HT22) and <em>in vivo</em> (AN exposed mice) approaches to investigate the potential modulator effects of HIF-1α in AN-induced neurotoxicity. <em>In vitro,</em> AN exposure caused concentration-dependent toxicity in HT22 cells, which was paralleled by increased Bax levels while decreasing Bcl-2. Exposure to AN resulted in reduced protein levels of HIF-1α, Bcl-2 19-kDa interacting protein 3 (BNIP3), microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1, while increased the protein levels of the translocase of outer mitochondrial membrane 20 (TOM20). Furthermore, mitochondrial morphology and function were compromised, suggesting that AN impaired HIF-1α/BNIP3-mediated mitochondrial autophagy and promoted apoptosis. Treatment with a HIF-1α activator, cobalt chloride (CoCl₂), reversed these effects, while pretreatment with a HIF-1α inhibitor, 2-methoxyestradiol (2-MeOE2), augmented them. In BNIP3 overexpressing HT22 cells, enhanced cell viability and reduced apoptosis rates were observed. Furthermore, the HIF-1α/BNIP3 pathway was activated by the prolyl hydroxylase (PHD2) inhibitor, deferoxamine (DFO), which increased HT22 cell viability. Similarly, the activation of HIF-1α by administering 20 mg/kg of CoCl₂ was found to alleviate neurotoxicity in mice. This treatment enhanced elevations of autophagy protein expression and co-localization of BNIP3 and LC3B. In summary, under normoxia, AN induced neurotoxicity by promoting PHD2-mediated HIF-1α degradation, disrupted the BNIP3-mediated mitophagy pathway, and enhanced apoptosis. Our findings underscore the effect of the HIF-1α/BNIP3-mediated mitochondrial autophagy in AN-induced neurotoxicity and suggest potential therapeutic strategies involving HIF-1α activation or BNIP3 overexpression for AN poisoning treatment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"406 ","pages":"Article 111327"},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775451","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}

{"title":"Do the hormetic effects of chlorogenic acid mediate some of the beneficial effects of coffee?","authors":"Edward J. Calabrese ,&nbsp;Peter Pressman ,&nbsp;A. Wallace Hayes ,&nbsp;Linda Baldwin ,&nbsp;Evgenios Agathokleous ,&nbsp;Gaurav Dhawan ,&nbsp;Rachna Kapoor ,&nbsp;Vittorio Calabrese","doi":"10.1016/j.cbi.2024.111343","DOIUrl":"10.1016/j.cbi.2024.111343","url":null,"abstract":"<div><div>The present paper provides the first documentation and assessment of the capacity of chlorogenic acid to induce hormetic dose-response relationships. The findings suggest that chlorogenic acid may induce anabolic (i.e., growth) and catabolic (i.e., protective) hormetic dose responses in several cell types via a range of complementary and cross-talking pathways, affecting a spectrum of endpoints of biomedical and therapeutic importance. This paper also addresses the issue of whether the widely recognized beneficial effects of coffee consumption, as reported in multiple epidemiological studies, may be related to the hormetic effects of chlorogenic acid and its metabolites and their interactions. The present analysis suggests that some beneficial effects of coffee consumption may be due to the effects of chlorogenic acid and/or its metabolites on the gastrointestinal tract via their capacity to impact gastrointestinal integrity, structure, and functionality. These effects collectively contribute to the attenuation of the gastrointestinal tract and concurrent systemic oxidative stress, positively affecting a range of organ-specific effects.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"406 ","pages":"Article 111343"},"PeriodicalIF":4.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808719","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}