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Arachidonic acid: reconciling the dichotomy of its oxidative cascade through specific deuteration. 花生四烯酸:通过特定的重复来协调其氧化级联的二分性。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2023-11-05 DOI: 10.1080/10715762.2023.2277145
J Thomas Brenna, Marina G Sergeeva, Nikolay B Pestov, Tatyana V Korneenko, Mikhail S Shchepinov
{"title":"Arachidonic acid: reconciling the dichotomy of its oxidative cascade through specific deuteration.","authors":"J Thomas Brenna, Marina G Sergeeva, Nikolay B Pestov, Tatyana V Korneenko, Mikhail S Shchepinov","doi":"10.1080/10715762.2023.2277145","DOIUrl":"10.1080/10715762.2023.2277145","url":null,"abstract":"<p><p>A new approach to attenuating pathological inflammatory reactions by buffering the eicosanoid pathways with oxidation-resistant hexadeuterated arachidonic acid (D-ARA) is discussed. Enzymatic processing of ARA, released by phospholipase A2, by lipoxygenases, cyclooxygenases, and cytochromes yields a wide range of bioactive eicosanoids, including pro-inflammation, pro-angiogenesis and pro-thrombosis species that, when produced in excess, are an underlying cause of pathology. Conversely, some products of ARA oxidation possess pro-resolving properties. Non-enzymatic free radical oxidation of ARA generates another large group of products such as isoprostanes and their metabolites, associated with inflammation, ischemia-reperfusion stress, and atherosclerosis. A separate group comprises reactive carbonyl derivatives that irreversibly damage diverse biomolecules. Being resistant to both enzymatic and non-enzymatic oxidation pathways due to large kinetic isotope effects, D-ARA may play a role in mitigating inflammation-related disorders and conditions, including inflammaging.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"583-593"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66783751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Epoxides: an underestimated lipid oxidation product. 环氧化物:一种被低估的脂质氧化产物。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2023-12-20 DOI: 10.1080/10715762.2023.2277142
Karen M Schaich
{"title":"Epoxides: an underestimated lipid oxidation product.","authors":"Karen M Schaich","doi":"10.1080/10715762.2023.2277142","DOIUrl":"10.1080/10715762.2023.2277142","url":null,"abstract":"<p><p>Immense gains in understanding of mechanisms and effects of lipid oxidation have been achieved in the nearly 90 years over which lipid oxidation has been an active research focus. Even so, the substantial questions still being raised about lipid oxidation in this special issue show clearly that missing pieces remain and must be considered for full accounting of this important reaction in any system. In this context, epoxides are spotlighted as a critical overlooked product of lipid autoxidation - underestimated in analysis, underestimated in presence as a functionally active and competitive intermediate and product of lipid oxidation, and underestimated in potential contributions to impact of lipid oxidation on other molecules and cell functions. Logical reasons for ignoring or not finding epoxides are offered in historical development of lipid oxidation knowledge. Reactions generating lipid epoxides in autoxidation are reviewed, limitations in detecting and tracking epoxides are outlined to explain why epoxides may not be detected when they should be present, and justifications for increased research and analysis of epoxides are argued. The main goal is to provide a context for recognizing epoxides as critical products that must be accounted for in determining the state rather than extent of lipid oxidation and in tracking its consequences in oils, foods, personal care products, and tissues. A secondary goal is to stimulate new research using contemporary analyses to fill in the gaps of knowledge about epoxide formation, structure, and reactions in lipid autoxidation.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"517-564"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138829142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhanced anticancer activity of (-)-epigallocatechin-3-gallate (EGCG) encapsulated NPs toward colon cancer cell lines. 增强(-)-表没食子儿茶素-3-棓酸盐(EGCG)包裹的 NPs 对结肠癌细胞株的抗癌活性。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2024-06-22 DOI: 10.1080/10715762.2024.2360013
Tanushree Das, Sanchaita Mondal, Sujata Das, Sanjib Das, Krishna Das Saha
{"title":"Enhanced anticancer activity of (-)-epigallocatechin-3-gallate (EGCG) encapsulated NPs toward colon cancer cell lines.","authors":"Tanushree Das, Sanchaita Mondal, Sujata Das, Sanjib Das, Krishna Das Saha","doi":"10.1080/10715762.2024.2360013","DOIUrl":"10.1080/10715762.2024.2360013","url":null,"abstract":"<p><p>(-)-Epigallocatechin-3-gallate (EGCG), a bioactive polyphenol of green tea, has chemo-preventive effects against various cancer cells. Nanoparticles (NPs) carrying different ligands are able to specifically interact with their receptors on different cancer cells that can provide effective release of cytotoxic drugs. In the present study, we have prepared EGCG entrapped NPs using PLGA (poly(d,l-lactide-co-glycolide)). Polyethylene glycol (PEG) and folic acid (FA) via double emulsion solvent evaporation (DESE) method obtained PLGA-EGCG (P-E), PLGA-PEG-EGCG (PP-E), and PLGA-PEG-FA-EGCG (PPF-E). Nanoformulations had been characterized with <sup>1</sup>H NMR and FT-IR techniques, AFM, and DLS. PPF-E NPs showed an average size of 220 nm. Analysis of zeta potential confirmed the stability of NPs. HCT-116, HT-29, HCT-15, and HEK 293 cells were treated with both the prepared NPs and free EGCG (0-140 μM). Result showed PPF-E NPs had improved delivery, uptake and cell cytotoxicity toward human folic acid receptor-positive (FR+) colorectal cancer (CRC) cells as mainly on HCT-116 compared to HT-29, but not on the folic acid-negative cells (FR-) as HCT-15. PPF-E NPs enhanced intracellular reactive oxygen species (ROS) level in absence of N-acetyl-l-cysteine (NAC), elevated DNA fragmentation level, and increased apoptotic cell death at higher doses compared to other two NPs and free EGCG. In conclusion, PPF-E NPs exerted greater efficacy than PP-E, P-E, and free EGCG in HCT-116 cells.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"565-582"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Low-temperature plasma as a strategy to achieve SDGs. 将低温等离子体作为实现可持续发展目标的战略。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2024-11-28 DOI: 10.1080/10715762.2023.2297343
Hiromasa Tanaka, Kenji Ishikawa, Shinya Toyokuni
{"title":"Low-temperature plasma as a strategy to achieve SDGs.","authors":"Hiromasa Tanaka, Kenji Ishikawa, Shinya Toyokuni","doi":"10.1080/10715762.2023.2297343","DOIUrl":"https://doi.org/10.1080/10715762.2023.2297343","url":null,"abstract":"","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":"58 10","pages":"594-595"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Protective effect of alpha-tocopherol on lipogenesis and oxysterol production in hypercholesterolemia-induced nonalcoholic steatohepatitis. α-生育酚对高胆固醇血症诱发的非酒精性脂肪性肝炎的脂肪生成和氧杂环醇产生的保护作用
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2024-10-30 DOI: 10.1080/10715762.2024.2421173
Ali Sahin, Tugce Demirel-Yalciner, Erdi Sozen, Nesrin Kartal Ozer
{"title":"Protective effect of alpha-tocopherol on lipogenesis and oxysterol production in hypercholesterolemia-induced nonalcoholic steatohepatitis.","authors":"Ali Sahin, Tugce Demirel-Yalciner, Erdi Sozen, Nesrin Kartal Ozer","doi":"10.1080/10715762.2024.2421173","DOIUrl":"10.1080/10715762.2024.2421173","url":null,"abstract":"<p><p>Despite limited number of studies, oxysterols are known to contribute to the progression of nonalcoholic steatohepatitis (NASH) by affecting lipid/cholesterol metabolism and elevating proinflammatory and profibrotic processes. Accordingly, we used a high cholesterol-mediated in vivo NASH model and aimed to determine alterations in fatty acid content and oxysterol levels together with their effects on cholesterol/lipid metabolism during the progression of the disease. We further investigated the beneficial role of α-tocopherol. To this end, in our hypercholesterolemic rabbit model, we determined fatty acid profile by GC-MS while 25-, 27-, 4β-, 7α, and 24(S)-Hydroxycholesterol levels by means of LC-MS/MS. Additionally, lipid (SREBP-1c, PPARα, PPARγ) and cholesterol metabolism-related proteins (LXRα, SREBP2 and ABCA1) were determined by immunoblotting. In conclusion, the present findings provide a complete analysis of the hepatic alterations in lipid and oxysterol profiles mediated by a high-cholesterol diet. In addition, this study explains the protective effect of α-tocopherol on lipogenesis and oxysterol production in hypercholesterolemia-induced NASH. We believe that present study will guide to novel theories in the progression and therapeutic targeting of fatty liver diseases.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"630-640"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction. 中枢代谢的氧化还原重塑是细胞保护、增殖、分化和功能障碍的驱动力。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2024-09-24 DOI: 10.1080/10715762.2024.2407147
Junichi Fujii
{"title":"Redox remodeling of central metabolism as a driving force for cellular protection, proliferation, differentiation, and dysfunction.","authors":"Junichi Fujii","doi":"10.1080/10715762.2024.2407147","DOIUrl":"10.1080/10715762.2024.2407147","url":null,"abstract":"<p><p>The production of reactive oxygen species (ROS) is elevated <i>via</i> metabolic hyperactivation in response to a variety of stimuli such as growth factors and inflammation. Tolerable amounts of ROS moderately inactivate enzymes <i>via</i> oxidative modification, which can be reversed back to the native form in a redox-dependent manner. The excessive production of ROS, however, causes cell dysfunction and death. Redox-reactive enzymes are present in primary metabolic pathways such as glycolysis and the tricarboxylic acid cycle, and these act as floodgates for carbon flux. Oxidation of a specific form of cysteine inhibits glyceraldehyde-3-phosphate dehydrogenase, which is reversible, and causes an accumulation of upstream intermediary compounds that increases the flux of glucose-6-phosphate to the pentose phosphate pathway. These reactions increase the NADPH and ribose-5-phosphate that are available for reductive reactions and nucleotide synthesis, respectively. On the other hand, oxidative inactivation of mitochondrial aconitase increases citrate, which is then recruited to synthesize fatty acids in the cytoplasm. Decreases in the use of carbohydrate for ATP production can be compensated <i>via</i> amino acid catabolism, and this metabolic change makes nitrogen available for nucleic acid synthesis. Coupling of the urea cycle also converts nitrogen to urea and polyamine, the latter of which supports cell growth. This metabolic remodeling stimulates the proliferation of tumor cells and fibrosis in oxidatively damaged tissues. Oxidative modification of these enzymes is generally reversible in the early stages of oxidizing reactions, which suggests that early treatment with appropriate antioxidants promotes the maintenance of natural metabolism.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"606-629"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142344616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
NRF2 signaling and amino acid metabolism in cancer. 癌症中的 NRF2 信号传导和氨基酸代谢。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2024-11-14 DOI: 10.1080/10715762.2024.2423690
Suji Ham, Bo-Hyun Choi, Mi-Kyoung Kwak
{"title":"NRF2 signaling and amino acid metabolism in cancer.","authors":"Suji Ham, Bo-Hyun Choi, Mi-Kyoung Kwak","doi":"10.1080/10715762.2024.2423690","DOIUrl":"10.1080/10715762.2024.2423690","url":null,"abstract":"<p><p>Alterations in amino acid metabolism have emerged as a critical component in cancer biology, influencing various aspects of tumor initiation, progression, and metastasis. This review explores how amino acids, beyond their role as protein building blocks, are essential for redox balance, cell proliferation, metastasis, signaling/epigenetic regulation, and tumor microenvironment modulation in cancer. We particularly focus on the intricate relationship between amino acid metabolism and nuclear factor erythroid 2-related factor 2 (NRF2) signaling, a master regulator of oxidative stress response that frequently hyperactivated in cancer. Increasing evidence indicates that NRF2 is a key player in amino acid metabolism, orchestrating metabolism of cysteine, glutamine, and serine/glycine to promote cancer cell survival and growth. This comprehensive analysis provides insights into potential therapeutic strategies targeting the NRF2-amino acid metabolism axis, offering new avenues for cancer treatment that address multiple aspects of tumor biology.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"648-661"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Redox system and ROS-related disorders in peroxisomes. 过氧物酶体中的氧化还原系统和 ROS 相关紊乱。
IF 3.6 3区 生物学
Free Radical Research Pub Date : 2024-10-01 Epub Date: 2024-11-17 DOI: 10.1080/10715762.2024.2427088
Hyunsoo Kim, Jaetaek Hwang, Channy Park, Raekil Park
{"title":"Redox system and ROS-related disorders in peroxisomes.","authors":"Hyunsoo Kim, Jaetaek Hwang, Channy Park, Raekil Park","doi":"10.1080/10715762.2024.2427088","DOIUrl":"10.1080/10715762.2024.2427088","url":null,"abstract":"<p><p>Peroxisomes are essential organelles that help mitigate the oxidative damage caused by reactive oxygen species (ROS) through their antioxidant systems. They perform functions such as α-oxidation, β-oxidation, and the synthesis of cholesterol and ether phospholipids. During the breakdown of specific metabolites, peroxisomes generate ROS as byproducts, which can either be neutralized or contribute to oxidative stress. The relationship between peroxisomal metabolism and ROS-related disorders, including neurodegenerative diseases and cancers, has been studied for decades; however, the exact mechanisms remain unclear. Our review will provide recent insights into the peroxisomal redox system and its association with oxidative stress-related diseases.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"662-675"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The inhibitory potential of 4,7-dihydroxycoumarin derivatives on ROS-producing enzymes and direct HOO•/o2• - radical scavenging activity - a comprehensive kinetic DFT study. 4,7-二羟基香豆素衍生物对产生 ROS 的酶的抑制潜力和直接清除 HOO-/o2- 自由基的活性--一项全面的动力学 DFT 研究。
IF 3.3 3区 生物学
Free Radical Research Pub Date : 2024-09-12 DOI: 10.1080/10715762.2024.2400674
Žiko Milanović,Svetlana Jeremić,Marko Antonijević,Dušan Dimić,Đura Nakarada,Edina Avdović,Zoran Marković
{"title":"The inhibitory potential of 4,7-dihydroxycoumarin derivatives on ROS-producing enzymes and direct HOO•/o2• - radical scavenging activity - a comprehensive kinetic DFT study.","authors":"Žiko Milanović,Svetlana Jeremić,Marko Antonijević,Dušan Dimić,Đura Nakarada,Edina Avdović,Zoran Marković","doi":"10.1080/10715762.2024.2400674","DOIUrl":"https://doi.org/10.1080/10715762.2024.2400674","url":null,"abstract":"This study examined the antiradical activity of three synthesized coumarin derivatives: (E)-3-(1-((2-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A1-OH), (E)-3-(1-((3-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A2-OH), and (E)-3-(1-((4-hydroxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (A3-OH) against HOO•/O2•- radical species. The investigation included electron spin resonance (ESR) measurements and a DFT kinetic study. Thermodynamic and kinetic parameters of antiradical mechanisms-Formal Hydrogen Atom Transfer (f-HAT), Radical Adduct Formation (RAF), Sequential Proton Loss followed by Electron Transfer (SPLET), and Single-Electron Transfer followed by Proton Transfer (SET-PT)-were evaluated using the Quantum Mechanics-based test for Overall Free Radical Scavenging Activity (QM-ORSA) under physiological conditions. ESR results indicated antiradical activity decreased in the sequence A1-OH (58.7%) > A2-OH (57.5%) > A3-OH (53.1%). Kinetic analysis revealed the f-HAT mechanism dominated HOO• inactivation. A newly formulated Sequential Proton Loss followed by Radical Adduct Formation (SPL-RAF) mechanism described interactions with O2•-. The activity toward O2•- was A2-OH (1.26 × 106 M-1s-1) > A3-OH (7.71 × 105 M-1s-1) > A1-OH (4.22 × 105 M-1s-1). Molecular docking and dynamics studies tested inhibitory capability against enzymes producing reactive species: Lipoxygenase (LOX), Myeloperoxidase (MPO), NAD(P)H oxidase (NOX), and Xanthine Oxidase (XOD). Affinity to enzymes decreased in the order: XOD > LOX > NOX > MPO.","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":"27 1","pages":"1-16"},"PeriodicalIF":3.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells. EP4受体激动剂CAY10598能上调结直肠癌细胞中依赖于ROS的Hsp90裂解。
IF 3.3 3区 生物学
Free Radical Research Pub Date : 2024-09-11 DOI: 10.1080/10715762.2024.2396909
In Gyung Chae,Joohee Jung,Do-Hee Kim,Joon-Seok Choi,Kyung-Soo Chun
{"title":"EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells.","authors":"In Gyung Chae,Joohee Jung,Do-Hee Kim,Joon-Seok Choi,Kyung-Soo Chun","doi":"10.1080/10715762.2024.2396909","DOIUrl":"https://doi.org/10.1080/10715762.2024.2396909","url":null,"abstract":"Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and β isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":"6 1","pages":"1-10"},"PeriodicalIF":3.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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