4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 159, P. 114301 - 114301

Published: Jan. 25, 2023

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas investigation, particularly in cancers. present study aimed explore the role colorectal cancer progression. genetic alterations colon were evaluated using database. MTT assays, colony formation, flow cytometry used examine effect elesclomol-Cu 4-Octyl itaconate (4-OI) on oxaliplatin-resistant viability. anti-tumor elesclomol with 4-OI was verified vivo assay. results showed that FDX1, SDHB, DLAT, DLST genes more highly expressed normal tissues than those primary tumor tissues. Patients high expressions these had better prognosis. Using assay formation analysis, pulse treatment significant inhibition viability HCT116, LoVo, HCT116-R cells. In addition, revealed significantly promoted apoptosis. Tetrathiomolybdate, copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, glucose metabolism inhibitor, sensitized Furthermore, galactose further Interestingly, enhanced which irrelevant ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis through GAPDH, one key enzymes glycolysis, sensitizing Meanwhile, FDX1 knockdown weakened ability promote experiments, effects. These indicated rapidly halted growth cells line. Importantly, aerobic targeting GAPDH

Language: Английский

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Hepatic TGFβr1 Deficiency Attenuates Lipopolysaccharide/D-Galactosamine–Induced Acute Liver Failure Through Inhibiting GSK3β–Nrf2–Mediated Hepatocyte Apoptosis and Ferroptosis

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2022, Volume and Issue: 13(6), P. 1649 - 1672

Published: Jan. 1, 2022

Background & AimsAcute liver failure (ALF) is a condition with high mortality and morbidity, characterized by glutathione depletion, oxidative stress, mitochondrial dysfunction. Ferroptosis may be involved in ALF. Indeed, emerging studies have shown that ferroptosis plays significant role However, the mechanism of hepatocytes during ALF remains unknown.MethodsHepatic-specific transforming growth factor β receptor 1 knockout (TGFβr1Δhep-CKO) mice nuclear erythroid 2-related 2 (Nrf2-/-) were generated subjected to Electron microscopy was used detect other cell substructure changes ALF.ResultsIn this study, we noticed lipopolysaccharide (LPS)/D-galactosamine (D-GalN) induced caspases-mediated apoptosis as current research reported, also found lipid peroxidation, reactive oxygen species accumulation, glutathione, co-enzyme Q10 system inhibition mediated LPS/D-GalN-induced Rescue ferrostatin-1 (Fer-1) deferoxamine mesylate (DFOM), inhibitor ferroptosis, could alleviate In addition, TGFβ1 increased ALF, while relieved TGFβr1Δhep-CKO mice. We TGFβr1 deficiency alleviated affecting phosphorylation glycogen synthase kinase 3β Nrf2, key antioxidant factor, up-regulating levels peroxidase 4 (GPX4), glutamine antiporter xCT (XCT), dihydroorotate dehydrogenase (DHODH), suppressor protein (FSP1), down-regulating transferrin (TFR), prostaglandin-endoperoxide (Ptgs2), chaC specific gamma-glutamylcyclotransferase (CHAC1), cytochrome P450 reductase (POR) expression. The further supplemental experiment showed aggravated significantly Nrf2-/- compared its wild-type controls reversed ferrostatin-1.ConclusionsThis study shows critical mediating promoting ferroptosis. Acute unknown. Hepatic-specific ferrostatin-1. This

Language: Английский

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Necrosulfonamide ameliorates intestinal inflammation via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis

Biochemical Pharmacology, Journal Year: 2022, Volume and Issue: 206, P. 115338 - 115338

Published: Nov. 5, 2022

Language: Английский

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The Role of the NLRP3 Inflammasome and Programmed Cell Death in Acute Liver Injury

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3067 - 3067

Published: Feb. 4, 2023

Acute liver injury (ALI) is a globally important public health issue that, when severe, rapidly progresses to acute failure, seriously compromising the life safety of patients. The pathogenesis ALI defined by massive cell death in liver, which triggers cascade immune responses. Studies have shown that aberrant activation nod-like receptor protein 3 (NLRP3) inflammasome plays an role various types and NLRP3 causes programmed (PCD), these effectors can turn regulate activation. This indicates inextricably linked PCD. In this review, we summarize PCD (APAP, ischemia reperfusion, CCl4, alcohol, Con A, LPS/D-GalN induced ALI) analyze underlying mechanisms provide references for future relevant studies.

Language: Английский

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4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 118, P. 110104 - 110104

Published: March 31, 2023

Language: Английский

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A cross-talk between sestrins, chronic inflammation and cellular senescence governs the development of age-associated sarcopenia and obesity

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 86, P. 101852 - 101852

Published: Jan. 13, 2023

Language: Английский

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Restoration of epigenetic impairment in the skeletal muscle and chronic inflammation resolution as a therapeutic approach in sarcopenia

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102267 - 102267

Published: March 9, 2024

Language: Английский

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Maresin‐1 ameliorates hypertensive vascular remodeling through its receptor LGR6

MedComm, Journal Year: 2024, Volume and Issue: 5(3)

Published: March 1, 2024

Abstract Hypertensive vascular remodeling is defined as the changes in function and structure induced by persistent hypertension. Maresin‐1 (MaR1), one of metabolites from Omega‐3 fatty acids, has been reported to promote inflammation resolution several inflammatory diseases. This study aims investigate effect MaR1 on hypertensive remodeling. Here, we found serum levels were reduced patients was negatively correlated with systolic blood pressure (SBP). The treatment elevation alleviated angiotensin II (AngII)‐infused mouse model. In addition, MaR1‐treated smooth muscle cells (VSMCs) exhibited excessive proliferation, migration, phenotype switching, well impaired pyroptosis. However, knockout receptor MaR1, leucine‐rich repeat‐containing G protein‐coupled 6 (LGR6), seen aggravate pathological remodeling, which could not be reversed additional treatment. mechanisms regulates through LGR6 involves Ca 2+ /calmodulin‐dependent protein kinase II/nuclear factor erythroid 2‐related 2/heme oxygenase‐1 signaling pathway. Overall, supplementing may a novel therapeutic strategy for prevention

Language: Английский

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Maresin-1 and Inflammatory Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(3), P. 1367 - 1367

Published: Jan. 25, 2022

Inflammation is an essential action to protect the host human body from external, harmful antigens and microorganisms. However, excessive inflammation reaction sometimes exceeds tissue damage can disrupt organ functions. Therefore, anti-inflammatory resolution mechanisms need be clarified. Dietary foods are daily lifestyle that influences various physiological processes pathological conditions. Especially, omega-3 fatty acids in diet ameliorate chronic inflammatory skin diseases. Recent studies have identified acid derivatives, such as resolvin series, showed strong actions Maresin-1 a derivative of one representative acids, i.e., docosahexaenoic (DHA), has shown beneficial disease models. In this review, we summarize detailed maresin-1 immune cells

Language: Английский

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The double sides of NLRP3 inflammasome activation in sepsis

Clinical Science, Journal Year: 2023, Volume and Issue: 137(5), P. 333 - 351

Published: March 1, 2023

Abstract Sepsis is defined as a life-threatening organ dysfunction induced by dysregulated host immune response to infection. Immune sepsis complex and dynamic. It schematically described an early systemic inflammatory leading failures deaths, followed the development of persistent alterations affecting both innate adaptive responses associated with increased risk secondary infections, viral reactivations, late mortality. In this review, we will focus on role NACHT, leucin-rich repeat pyrin-containing protein 3 (NLRP3) inflammasome in pathophysiology sepsis. NLRP3 multiproteic intracellular activated infectious pathogens through two-step process resulting release pro-inflammatory cytokines IL-1β IL-18 formation membrane pores gasdermin D, inducing form cell death called pyroptosis. The can be ambivalent. Indeed, although it might protect against when moderately after initial infection, excessive activation induce inflammation multiple failure during acute phase disease. Moreover, become exhausted contribute post-septic immunosuppression, driving impaired functions cells. Targeting could thus attractive option either antagonists or inhibition pathway downstream components. Available treatments results first clinical trials discussed.

Language: Английский

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