miR-125b-5p in adipose derived stem cells exosome alleviates pulmonary microvascular endothelial cells ferroptosis via Keap1/Nrf2/GPX4 in sepsis lung injury

Redox Biology, Год журнала: 2023, Номер 62, С. 102655 - 102655

Опубликована: Март 9, 2023

Sepsis is a fatal disease with high rate of morbidity and mortality, during which acute lung injury the earliest most serious complication. Injury pulmonary microvascular endothelial cells (PMVECs) induced by excessive inflammation plays an important role in sepsis injury. This study meant to explore protective effect mechanism ADSCs exosomes on PMVECs injury.We successfully isolated exosomes, characteristic were confirmed. reduced inflammatory response ROS accumulation cell PMVECs. Besides, inhibited ferroptosis while upregulated expression GPX4 And further inhibition experiments revealed that alleviated via upregulating GPX4. Meanwhile, could increase nucleus translocation Nrf2, decrease Keap1. miRNA analysis verified specific delivery miR-125b-5p Keap1 ferroptosis. In CLP model, relieve tissue death rate. oxidative stress tissue, remarkably Nrf2 GPX4.Collectively, we illustrated novel potentially therapeutic alleviate regulating Keap1/Nrf2/GPX4 expression, hence improve sepsis.

Язык: Английский

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Ferroptosis: a promising candidate for exosome-mediated regulation in different diseases

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 2, 2024

Ferroptosis is a newly discovered form of cell death that featured in wide range diseases. Exosome therapy promising therapeutic option has attracted much attention due to its low immunogenicity, toxicity, and ability penetrate biological barriers. In addition, emerging evidence indicates exosomes possess the modulate progression diverse diseases by regulating ferroptosis damaged cells. Hence, mechanism which cell-derived noncellular-derived target different through system Xc

Язык: Английский

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Lachnospiraceae-bacterium alleviates ischemia-reperfusion injury in steatotic donor liver by inhibiting ferroptosis via the Foxo3-Alox15 signaling pathway

Gut Microbes, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 30, 2025

Ischemia-reperfusion injury (IRI) is a major obstacle in liver transplantation, especially with steatotic donor livers. Dysbiosis of the gut microbiota has been implicated modulating IRI, and Lachnospiraceae plays pivotal role regulating host inflammatory immune responses, but its specific transplantation IRI remains unclear. This study explores whether can mitigate underlying mechanisms. We found Lachnospiraceae-bacterium (Lachn.) abundance was significantly reduced rats cirrhosis. Lachn.-treated exhibited improved intestinal permeability, severity both normal livers, decreased levels neutrophil macrophage infiltration, cytokines. Multi-omics analysis revealed elevated pyruvate transplanted livers after Lachn. treatment, alongside Alox15 Foxo3 expression. Mechanistically, Lachn.-derived inhibited expression ferroptosis Furthermore, nuclear translocation further suppressed expression, alleviating Clinical samples confirmed cirrhotic recipients high transplantation. In conclusion, alleviates by inhibiting via Foxo3-Alox15 axis, providing potential therapeutic strategy to modulate alleviate following

Язык: Английский

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The crosstalk between exosomal miRNA and ferroptosis: A narrative review

Biology of the Cell, Год журнала: 2025, Номер 117(1)

Опубликована: Янв. 1, 2025

Ferroptosis is a type of cell death that multiple mechanisms and pathways contribute to the positive negative regulation it. For example, increased levels reactive oxygen species (ROS) induce ferroptosis. ferroptosis unlike apoptosis, it not dependent on caspases, but iron. Exosomes are membrane-bound vesicles with size about 30 150 nm, contain various cellular components, including DNA, RNA, microRNAs (miRNAs), lipids, proteins, which genetically similar their cells origin. found in all bodily fluids, blood, saliva, urine. Cells often release exosomes after fusion membrane. They play an important role immune cell-cell communication. miRNAs, noncoding RNAs length 18 24 nucleotides, involved regulating gene expression transcription. Emerging data suggests exosomal miRNAs implicated pathophysiological cells, metastasis, drug resistance, death. In addition, functional studies have indicated can key modulation by Therefore, this review, given importance ferroptosis, we decided elucidate relationship between diseases.

Язык: Английский

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Mechanistic Insight and Clinical Implications of Ischemia/Reperfusion Injury Post Liver Transplantation

Cellular and Molecular Gastroenterology and Hepatology, Год журнала: 2023, Номер 15(6), С. 1463 - 1474

Опубликована: Янв. 1, 2023

Ischemia/reperfusion injury is an inevitable process during liver transplantation and can lead to a high incidence of early allograft dysfunction graft failure. The mechanism hepatic ischemia/reperfusion has been elucidated as the sequelae microcirculation dysfunction, hypoxia, oxidative stress, cell death. In addition, essential role innate adaptive immune response in its deleterious outcomes have discovered. Furthermore, mechanistic studies living donor distinct features mitochondrial metabolic steatotic small-for-size injury. findings laid foundation for exploring new biomarkers; however, they are yet be validated large cohorts. Moreover, molecular cellular analysis promoted development potential therapeutics preclinical clinical trials. This review summarizes most up date evidence puts forward importance spatiotemporal microenvironment that results from immunologic response, immunity, death signaling. SummaryHepatic post characterized microenvironmental disturbance including microcirculatory dysregulation, understanding enables novel biomarkers models Hepatic subjected ischemia reperfusion hepatectomy, transplantation, systemic shock. With improvement surgical techniques medical treatment, mostly occurs setting transplantation. Liver provides curative treatment end-stage disease superior any other modality. However, may (EAD), primary nonfunction, or even failure acute phase after transplantation.1Lee D.D. Croome K.P. Shalev J.A. et al.Early transplantation: intermediate outcome measure targeted improvements.Ann Hepatol. 2016; 15: 53-60Crossref PubMed Scopus (76) Google Scholar,2Ito T. Naini B.V. Markovic D. al.Ischemia-reperfusion relationship with transplant patients.Am J Transplant. 2021; 21: 614-625Abstract Full Text PDF (0) Scholar it suggested also renders more susceptible recurrent diseases, such cancer, viral hepatitis, fibrosis, nonalcoholic fatty disease.3Burra P. Becchetti C. Germani G. NAFLD burden, current management future challenges.JHEP Rep. 2020; 2100192PubMed Scholar, 4Liu J. Lo C.M. Man K. Role intrahepatic regional immunity post-transplant cancer recurrence.Eng Proc. 2022; 10: 57-64Google 5Liu X.B. Cheng Q. al.Oval cells contribute fibrogenesis marginal grafts under stepwise regulation aldose reductase notch signaling.Theranostics. 2017; 7: 4879-4893Crossref (6) Clinically, several developed alleviate through rapid procurement, shortened transportation, continuing machine perfusion, remote situ ischemic preconditioning, ischemia-free transplantation.6Belon A.R. Tannuri A.C.A. de Albuquerque Rangel Moreira al.Impact three methods preconditioning on ischemia-reperfusion pig model transplantation.J Invest Surg. 35: 900-909Crossref (2) 7Hessheimer A.J. Polak W. Antoine al.Regulations procurement surgery DCD expert consensus guidance International Transplantation Society.Transplantation. 105: 945-951Crossref 8Tang Y. Wang Ju al.Ischemic-free reduces recurrence hepatocellular carcinoma transplantation.Front Oncol. 11773535Crossref (3) 9van Rijn R. Schurink I.J. Vries al.Hypothermic perfusion randomized trial.N Engl Med. 384: 1391-1401Crossref (49) EAD still ranges 2%–23%.10Deschenes M. Early dysfunction: causes, recognition, management.Liver Transpl. 2013; 19: S6-8Crossref (61) Unfortunately, situation worse when using extended-criteria donors. use grafts, steatotic, aged, reduced-size graft, organs donors cardiac HBcAb-positive individuals greatly expanded pool; all these conditions independent risk factors loss.11Liu Pang L. Ng K.T.P. al.Compromised AMPK-PGCIα axis exacerbated by dysregulating homeostasis transplantation.Ann 276: e483-e492Crossref Scholar,12Zhang Dunson Kanwal F. al.Trends allografts transplant.JAMA 155: 926-932Crossref (5) Among them, predominant because prevalence throughout world. To minimize loss, acceptable cutoff steatosis deceased organ less than 30%. When degree between 30% 60% used, caution should taken organs' increases nonfunction 4%–13%.13Kulik U. Lehner Klempnauer al.Primary non-function frequently associated mortality re-transplantation.Liver Int. 37: 1219-1228Crossref Scholar,14Mikolasevic I. Milic S. Filipec-Kanizaj Fatty transplantation.Liver 1113-1115Crossref (7) higher syndrome, long-term Mechanistically, underlying mechanism,11Liu although further investigation necessary. arise hypoxic injury, intracellular responses, signaling.15Hirao H. Nakamura Kupiec-Weglinski J.W. ischaemia-reperfusion injury: immunity.Nat Rev Gastroenterol 239-256Crossref (29) A better mechanisms processes will lay result precise selection criteria. Here, we summarize recent progress their implications practice indicated initiated hemodynamic change (Figure 1). preservation, which warm cold damage hepatocytes, cholangiocytes, sinusoidal endothelial hypoxia-induced dysfunction.16Zhai Petrowsky Hong J.C. al.Ischaemia-reperfusion transplantation--from bench bedside.Nat 79-89Crossref (530) Reperfusion, exacerbates transient portal hypertension hyperdynamic stress. Transient initial event causes stress lining. Portal pressure increase 30–35 cm H2O 60–70 immediately reperfusion.17Man Fan S.T. al.Graft relation size right lobe live study correlation hemodynamics intragraft gene expression.Ann 2003; 237: 256-264Crossref shearing force direct exposes vessel wall circulating platelets leukocytes adhesion. Platelet aggregation then narrows venule, platelet activation releases amounts cytokines, chemokines, vasoactive molecules.18Esch J.S. Jurk Knoefel W.T. al.Platelet increased tissue factor expression monocytes following orthotopic transplantation.Platelets. 2010; 348-359Crossref (32) 19Himmelreich Hundt Neuhaus al.Evidence intraoperative prostaglandin E1 infusion impaired transplantation.Transplantation. 1993; 55: 819-826Crossref 20Nishiyama Suzuki al.Platelet-activating effects PAF antagonist combined I2 analogue.Transplantation. 1261-1265Crossref 21Sindram Porte R.J. Hoffman M.R. al.Platelets induce apoptosis upon rat liver.Gastroenterology. 2000; 118: 183-191Abstract 22Miyashita Nakanuma Ahmed A.K. al.Ischemia reperfusion-facilitated resulting impact extravasated aggregation.Eur 48: 92-98Crossref (40) imbalance vasocontraction vasodilation microcirculation. Levels vasoconstricting peptide endothelin-1 were found 1.6-fold, whereas nitric oxide synthase, produces oxide, decreased 17.4 μmol/L, respectively.17Man Collectively, this decrease worsens return, congestion sinusoids collapse space Disse thereby prolonging hypoxia.23Man Lee T.K. al.Intragraft profiles cDNA microarray grafts.Liver 9: 425-432Crossref (58) Microcirculatory often grafts. inflow lasts longer normal large-sized cases, syndrome small-for-flow Scholar,24Ikegami Onda Furukawa al.Small-for-size modulation Hepatobiliary Pancreat Sci. 27: 799-809Crossref (13) interpreted unmatched simultaneous splenectomy demonstrated reduce syndrome.25Sanchez-Cabus Cherqui Rashidian N. al.Left-liver adult-to-adult improved? retrospective multicenter European study.Ann 2018; 268: 876-884Crossref Scholar,26Yoshizumi Itoh Shimokawa al.Simultaneous improves adult 74: 372-379Abstract (15) Reperfusion production reactive oxygen species (ROS), mainly come neutrophils Kupffer cells.27Amersi Buelow Kato al.Upregulation heme oxygenase-1 protects genetically fat Zucker livers injury.J Clin Invest. 1999; 104: 1631-1639Crossref Scholar,28Lemasters J.J. Peng X.X. Bachmann al.Dual stored surgery.J 1995; S84-87Crossref Increased ROS primarily caused respiratory diminished activity endogenous antioxidants, oxygenase 1 superoxide dismutase (SOD) Mitochondrial involves reversal electron transition complex II I injury.29Chouchani E.T. Pell V.R. Gaude E. al.Ischaemic accumulation succinate controls ROS.Nature. 2014; 515: 431-435Crossref (1583) inactivation IV production.11Liu severe multifaceted, impairments biogenesis, membrane depolarization, calcium overload, enhanced glycolysis.11Liu Inadequate metabolism accumulated acids lipid superoxide, key enzymes beta-oxidation.30Xue Liu Yang al.Inhibition carnitine palmitoyltransferase 1A aggravates via promoting permeability transition.Transplantation. 550-560Crossref (1) Additionally, downregulation SOD vulnerable attack.31Nakamura Zhang Kageyama al.Macrophage oxygenase-1-SIRT1-p53 regulates sterile inflammation 67: 1232-1242Abstract (118) Scholar,32Zwacka R.M. Zhou al.Redox therapy AP1 NF-kappaB activation.Nat 1998; 4: 698-704Crossref (250) Many reported delivering increasing levels protect injury.27Amersi Scholar,33Fondevila Shen X.D. Tsuchiyashi al.Biliverdin injury.Hepatology. 2004; 40: 1333-1341Crossref (146) 34Ke B. Gao al.Adoptive transfer ex vivo HO-1 modified bone marrow-derived macrophages prevents injury.Mol Ther. 18: 1019-1025Abstract (34) 35Lehmann T.G. Wheeler M.D. Schwabe R.F. al.Gene delivery Cu/Zn-superoxide function rat.Hepatology. 32: 1255-1264Crossref Consequently, peaks around 2–6 hours reperfusion, leading swelling, hepatocytes.17Man As damage-associated patterns released into circulation activate response. accompanied activated residential 2). remodeled recurrence, steatosis, malignancies.5Liu Scholar,36Li C.X. Ling C.C. Shao al.CXCL10/CXCR3 signaling mobilized-regulatory T promote tumor 65: 944-952Abstract (73) Scholar,37Yeung O.W. al.Alternatively (M2) tumour growth invasiveness carcinoma.J 2015; 62: 607-616Abstract (251) release (eg, nucleic acids, heat shock protein, high-mobility group protein 1) activates first wave adhesive binding pattern recognition receptors surface.38Corbitt Kimura Isse al.Gut bacteria drive expansion MAMP-mediated ICAM-1 induction endothelium influence preservation-reperfusion transplantation.Am Pathol. 182: 180-191Abstract (66) 39Kadono Uchida Hirao al.Thrombomodulin attenuates inflammatory due mice toll-like receptor 4-dependent manner.Am 17: 69-80Abstract 40Wang Birch S.E. He al.Remote hindlimb occlusion ischemic/reperfusion High Mobility Group-Box 1.Ann 251: 292-299Crossref 41Yang M.Q. Du Goswami al.Interferon regulatory 1-Rab27a regulated extracellular vesicles 1056-1070Crossref (31) 4 (TLR4) expressed almost cells. Our previous shown pathogenic involvement TLR4 inducing graft.36Li Scholar,42Liu Yeung W.H.O. al.Monocytic MDSC mobilization promotes CXCL10/TLR4/MMP14 signaling.Cell Death Dis. 12: 489Crossref (16) not only enhances proinflammatory macrophages, but recruits polymorphonuclear circulation.39Kadono Scholar,41Yang Scholar,43Kuriyama Duarte Hamada al.Tenascin-C: mediator 2011; 54: 2125-2136Crossref (43) Recently, involved macrophage Activation DNA-sensing STING pathway induced become proinflammatory,44Jiao Jiang Qian al.Expression monocyte-derived contributes injury.Am 192: 1745-1762Abstract Scholar,45Zhong Rao Z. al.Aging aggravated STING-mediated NLRP3 macrophages.Aging Cell. 19e13186Crossref (47) DNA stimulatory factor. On activation, neutrophils, along injured cells, secret cytokines chemokines sinusoid, exacerbating reaction, recruiting graft. cytokine storm observed 2 at 6–24 Within microenvironment, are, interleukin (IL)1β, IL2, IL6, IL15, interferon-γ (IFNγ), necrosis factor-α;and CCL2, CXCL8, CXCL10, among others.16Zhai Scholar,17Man severe. Additional pathways lipocalin-2, NLR 3, reductase, repressor activator 1.46Cheng K.T. Xu A. al.The roles lipocalin-2 injury.Ann 260: 1062-1072Crossref (11) Scholar,47Liu O.W.H. al.NLRP3 inflammasome telomere-independent RAP1/KC axis.J 242: 284-296Crossref (24) Their system recruit CXCL10 CXCL2 secretion.46Cheng 47Liu 48Li inhibition reducing response.Ann 317-328Crossref (42) Other myeloid blood-borne dendritic play bidirectional mediating injury.49Zhang Ueki al.Roles murine transplantation-induced 57: 1585-1596Crossref (36) Dendritic antigen-presenting immunity. mouse showed costimulatory molecule B7-H1 exaggerating CD8+ T-cell proliferation infiltration.50Ueki Castellaneta Yoshida O. al.Hepatic B7 homolog controlling transplantation.Hepatology. 216-228Crossref (35) Regulatory molecules, DAP12-TREM2 YAP-CD47-CD172α, inhibit maturation and/or activation.51Nakao Ono Dai al.DNAX activating 12 kDa/triggering human cells: functional 2019; 70: 696-710Crossref Scholar,52Yuan Ye Feng X. al.YAP-dependent CD47-enriched inhibits ameliorates injury.Oxid Med Cell Longev. 20216617345Crossref (4) upregulation CD39 hydrolyzing ATP recognition.53Yoshida Jackson E.K. al.CD39 mice.Hepatology. 58: 2163-2175Crossref (55) Conversely, ischemia/r

Язык: Английский

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Targeting ferroptosis by poly(acrylic) acid coated Mn3O4 nanoparticles alleviates acute liver injury

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 21, 2023

Ferroptosis, a newly characterized form of regulated cell death, is induced by excessive accumulation lipid peroxidation catalyzed intracellular bioactive iron. Increasing evidence has suggested that ferroptosis involved in the pathogenesis several human diseases, including acute liver injury. Targeted inhibition holds great promise for clinical treatment these diseases. Herein, we report simple and one-pot synthesis ultrasmall poly(acrylic) acid coated Mn3O4 nanoparticles (PAA@Mn3O4-NPs, PMO), which perform multiple antioxidant enzyme-mimicking activities can scavenge broad-spectrum reactive oxygen species. PMO could potently suppress ferroptosis. Mechanistically, after being absorbed mainly through macropinocytosis, are largely enriched lysosomes, where detoxify ROS, inhibit ferritinophagy-mediated iron mobilization preserve mTOR activation, collectively confer prominent Additionally, injection counteracts alleviates acetaminophen- ischaemia/reperfusion-induced injury mice. Collectively, our results reveal biocompatible act as potent inhibitors multifaceted mechanisms, ensures have translational potential ferroptosis-related

Язык: Английский

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Ferroptosis Regulated by Hypoxia in Cells

Cells, Год журнала: 2023, Номер 12(7), С. 1050 - 1050

Опубликована: Март 30, 2023

Ferroptosis is an oxidative damage-related, iron-dependent regulated cell death with intracellular lipid peroxide accumulation, which associated many physiological and pathological processes. It exhibits unique features that are morphologically, biochemically, immunologically distinct from other forms. by iron metabolism, anti-oxidant defense systems, as well various signal pathways. Hypoxia, found in a group of conditions, can affect multiple cellular functions activation the hypoxia-inducible factor (HIF) signaling mechanisms. Emerging evidence demonstrated hypoxia regulates ferroptosis certain types conditions. In this review, we summarize basic mechanisms regulations hypoxia, regulation may contribute to numerous diseases therapies.

Язык: Английский

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Total Flavonoids of Rhizoma Drynariae Mitigates Aflatoxin B1-Induced Liver Toxicity in Chickens via Microbiota-Gut-Liver Axis Interaction Mechanisms

Antioxidants, Год журнала: 2023, Номер 12(4), С. 819 - 819

Опубликована: Март 28, 2023

Aflatoxin B1 (AFB1) is a common mycotoxin that widely occurs in feed and has severe hepatotoxic effects both humans animals. Total flavonoids of Rhizoma Drynaria (TFRD), traditional Chinese medicinal herb, have multiple biological activities potential hepatoprotective activity. This study investigated the protective mechanisms TFRD against AFB1-induced liver injury. The results revealed supplementation with markedly lessened broiler intestinal permeability by increasing expression tight junction proteins, as well correcting changes gut microbiota damage induced AFB1. Metabolomics analysis alterations plasma metabolites, especially taurolithocholic acid, were significantly improved treatment AFB1-exposed chickens. In addition, these metabolites closely associated [Ruminococcus], ACC, GPX1, indicating AFB1 may cause injury inducing bile acid metabolism involving microbiota-gut-liver axis. We further found suppressed oxidative stress hepatic lipid deposition, increased glutathione (GSH) concentrations, reversed ferroptosis gene expression. Collectively, findings indicate might contribute to hepatotoxicity chickens through axis interaction mechanisms; furthermore, was confirmed an herbal extract could potentially antagonize mycotoxins detrimental effects.

Язык: Английский

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Current Status and Prospect of Delivery Vehicle Based on Mesenchymal Stem Cell-Derived Exosomes in Liver Diseases

International Journal of Nanomedicine, Год журнала: 2023, Номер Volume 18, С. 2873 - 2890

Опубликована: Май 1, 2023

Abstract: With the improvement of average life expectancy and increasing incidence obesity, burden liver disease is increasing. Liver a serious threat to human health. Currently, transplantation only effective treatment for end-stage disease. However, still faces unavoidable difficulties. Mesenchymal stem cells (MSCs) can be used as an alternative therapy disease, especially cirrhosis, failure, complications. MSCs may have potential tumorigenic effects. Exosomes derived from (MSC-Exos), important intercellular communication mode MSCs, contain various proteins, nucleic acids, DNA. MSC-Exos delivery system treat diseases through immune regulation, apoptosis inhibition, regeneration promotion, drug delivery, other ways. Good histocompatibility material exchangeability make new diseases. This review summarizes latest research on vehicles in different diseases, including injury, fibrosis, hepatocellular carcinoma (HCC), ischemia reperfusion injury. In addition, we discuss advantages, disadvantages, clinical application prospects MSC-Exos-based vectors Keywords: exosomes, mesenchymal cells, nanocarriers

Язык: Английский

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Cellular and molecular mechanisms of cell damage and cell death in ischemia–reperfusion injury in organ transplantation

Molecular Biology Reports, Год журнала: 2024, Номер 51(1)

Опубликована: Март 29, 2024

Ischemia-reperfusion injury (IRI) is a critical pathological condition in which cell death plays major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs metabolism decreases bioenergetics through dysfunction of mitochondrial electron transport chain, causing switch from respiration anaerobic metabolism, subsequent cascades events that lead increased intracellular concentrations Na

Язык: Английский

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