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

Gut Microbes, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 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

Language: Английский

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Focusing on Ischemic Reperfusion Injury in the New Era of Dynamic Machine Perfusion in Liver Transplantation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1117 - 1117

Published: Jan. 17, 2024

Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between supply and demand of optimal organs. In this context, use extended criteria donor grafts has gained importance, even though these are more susceptible to ischemic reperfusion injury (IRI). Hepatic IRI an inherent inevitable consequence all transplants; it involves ischemia-mediated cellular damage exacerbated upon its severity directly affects graft function post-transplant complications. Strategies organ preservation constantly improving since they first emerged. The current gold standard perfusion solutions static cold storage. However, novel approaches that allow times, evaluation, their treatment, which could increase number viable organs transplantation, currently under investigation. This review discusses mechanisms associated IRI, describes existing strategies preservation, emphasizes developments challenges optimization.

Language: Английский

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Validation of a Pretransplant Risk Prediction Model for Early Allograft Dysfunction After Living-donor Liver Transplantation

Transplantation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Early allograft dysfunction (EAD) affects outcomes in liver transplantation (LT). Existing risk models developed for deceased-donor LT depend on posttransplant factors and fall short living-donor (LDLT), where pretransplant evaluations are crucial preventing EAD justifying the donor's risks. This retrospective study analyzed data from 2944 adult patients who underwent LDLT at 17 centers between 2016 2020. We a logistic regression model to predict based this development cohort. used 1020 King Faisal Transplant Center external validation. In cohort, 321 (10.9%) experienced EAD. These had poorer health status, more decompensation, higher requirements of hospitalization than those without Multivariable identified independent predictors EAD: laboratory Model End-Stage Liver Disease score (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.06-1.09), necessity time transplant (OR, 2.58; CI, 2.00-3.30), graft weight kilogram 0.27; 0.17-0.45). Using these predictors, we after LDLT, which demonstrated strong discriminative ability cohort with an area under curve (AUC) 0.71 (95% 0.68-0.74). The maintained high discrimination during internal validation (AUC, 0.70; 0.67-0.73) showed modest reduction power 0.65; 0.61-0.68). post-LDLT is influenced by recipient's condition weight. Integrating into process pairing donors recipients can enhance safety efficacy LDLT.

Language: Английский

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Circadian Control of Hepatic Ischemia/Reperfusion Injury via HSD17B13-Mediated Autophagy in Hepatocytes

Journal of Hepatology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Insights into the Role of Glutathione Peroxidase 3 in Non-Neoplastic Diseases

Biomolecules, Journal Year: 2024, Volume and Issue: 14(6), P. 689 - 689

Published: June 13, 2024

Reactive oxygen species (ROSs) are byproducts of normal cellular metabolism and play pivotal roles in various physiological processes. Disruptions the balance between ROS levels body’s antioxidant defenses can lead to development numerous diseases. Glutathione peroxidase 3 (GPX3), a key component system, is an oxidoreductase enzyme. GPX3 mitigates oxidative damage by catalyzing conversion hydrogen peroxide into water. Beyond its function, vital regulating metabolism, modulating cell growth, inducing apoptosis facilitating signal transduction. It also serves as significant tumor suppressor cancers. Recent studies have revealed aberrant expression several non-neoplastic diseases, associating it with multiple pathological This review synthesizes current understanding regulation, highlighting extensive noncancerous Additionally, this paper evaluates potential diagnostic biomarker explores emerging therapeutic strategies targeting enzyme, offering avenues for future clinical treatment conditions.

Language: Английский

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Dexmedetomidine alleviates ferroptosis following hepatic ischemia-reperfusion injury by upregulating Nrf2/GPx4-dependent antioxidant responses

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 169, P. 115915 - 115915

Published: Nov. 24, 2023

Hepatic ischemia-reperfusion injury (HIRI) adversely affects liver transplant and resection outcomes. Recently, ferroptosis has been associated with HIRI. Dexmedetomidine (Dex), a potent sedative anti-inflammatory, antioxidant, anti-apoptotic properties, protects organs from hypoxic or (I/R) injuries. However, the mechanisms underlying this protective effect against I/R-induced remain unclear. This study evaluated of Dex on HIRI in mouse models oxygen-glucose deprivation/reperfusion (OGD/R) AML12 cell model. We examined ferroptosis-related markers, including Fe2+ levels, reactive oxygen species (ROS) content, mitochondrial morphology, GPX4 protein expression, 4-hydroxynonenal (4-HNE), Nrf2. The Nrf2 inhibitor ML385 was used combination to treat mice OGD/R-induced cellular explore pathways by which counteracts ferroptosis. Our results showed that treatment significantly ameliorated cells, reduced Fe2+, ROS, malondialdehyde (MDA), 4-HNE levels. also tissue damage serum AST, ALT, inflammatory factor levels mice. Additionally, increased GSH, an antioxidative stress marker, expression Mechanistically, nuclear translocation were inhibited both OGD/R-treated cells. restored inhibition translocation. Dex-promoted aggregation Gpx4 hindering efficacy Dex. In conclusion, ameliorates positively regulating Nrf2/GPx4 axis, potentially presenting therapeutic avenue for addressing

Language: Английский

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New therapeutic concepts against ischemia-reperfusion injury in organ transplantation

Expert Review of Clinical Immunology, Journal Year: 2023, Volume and Issue: 19(10), P. 1205 - 1224

Published: July 25, 2023

Ischemia-reperfusion injury (IRI) involves a positive amplification feedback loop that stimulates innate immune-driven tissue damage associated with organ procurement from deceased donors and during transplantation surgery. As our appreciation of its basic immune mechanisms has improved in recent years, translating putative biomarkers into therapeutic interventions clinical remains challenging.

Language: Английский

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Effects of remote ischemic preconditioning in hepatectomy: a systematic review and meta-analysis

BMC Anesthesiology, Journal Year: 2024, Volume and Issue: 24(1)

Published: March 26, 2024

Abstract Background Animal experiments have confirmed that remote ischemic preconditioning (RIPC) can reduce hepatic ischemia-reperfusion injuries (HIRIs), significantly improving early tissue perfusion and oxygenation of the residual liver after resections, accelerating surgical prognoses, survival rates. However, there is still controversy over role RIPC in relieving HIRI clinical studies, which warrants clarification. This study aimed to evaluate beneficial effects applicability hepatectomy provide evidence-based information for decision-making. Methods Randomized controlled trials (RCTs) evaluating efficacy safety interventions were collected, comparing no patients undergoing hepatectomies. search spanned from database inception January 2024. Data extracted independently by two researchers according PRISMA guidelines. The primary outcomes assessed postoperative alanine transaminase (ALT), aspartate (AST), total bilirubin (TBIL), albumin (ALB) levels. secondary included duration surgery Pringle, length hospital stay, intraoperative blood loss transfusion, indocyanine green (ICG) clearance, hepatocyte apoptosis index, complications, others. Results Ten RCTs this meta-analysis, with a 865 (428 group 437 control group). ALT levels lower than those on day (POD) 1 (WMD = − 59.24, 95% CI: 115.04 3.45; P 0.04) POD 3 27.47, 52.26 2.68; 0.03). heterogeneities significant ( I 2 89% 78%), unstable based sensitivity analysis. AST 50.03, - 94.35 5.71; 0.03), but heterogeneity was also 81%). A subgroup analysis showed differences between groups, regardless whether Pringle maneuver or propofol used anesthesia (induction only induction maintenance, > 0.05). remaining outcome indicators not statistically could be analyzed due lack sufficient data. Conclusion has some short-term protective HIRIs during insufficient evidence encourage its routine use improve outcomes. Trial registration protocol registered PROSPERO (CRD42022333383).

Language: Английский

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Exosomes Derived from Adipose Mesenchymal Stem Cells Promote Regeneration of Injured Liver in Minipigs

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6604 - 6604

Published: June 15, 2024

Hepatic ischemia/reperfusion injury (IRI) is an important factor affecting liver regeneration and functional recovery postoperatively. Many studies have suggested that mesenchymal stem cells (MSCs) contribute to hepatic tissue repair through paracrine mechanisms mediated by exosomes. Minipigs exhibit much more similar characteristics of the those humans than rodents. This study aimed explore whether exosomes from adipose-derived MSCs (ADSCs-exo) could actively promote after hepatectomy combined with HIRI in minipigs role they play cell proliferation process. also compared effects differences ADSCs ADSCs-exo inflammatory response regeneration. The results showed suppressed histopathological changes reduced infiltration liver; significantly decreased levels ALT, TBIL, HA, pro-inflammatory cytokines TNF-α, IL-6, CRP; increased anti-inflammatory cytokine IL-10 pro-regeneration factors Ki67, PCNA, CyclinD1, HGF, STAT3, VEGF, ANG1, ANG2; anti-regeneration SOCS3 TGF-β. These indicators above intervention group. Indicating can exert same as regulating responses promoting Our findings provide experimental evidence for possibility be considered a safe effective cell-free therapy injured livers.

Language: Английский

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Neutrophil gelatinase–associated lipocalin for predicting acute kidney injury in orthotopic liver transplantation: a systematic review and meta-analysis

European Journal of Gastroenterology & Hepatology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Acute kidney injury (AKI) is associated with poor prognosis. New biomarkers, like neutrophil gelatinase–associated lipocalin (NGAL), are helpful for early warning of AKI. This study aims to investigate the accuracy NGAL in evaluating perioperative AKI liver transplantation. The four databases, PubMed, Web Science, Embase, and Cochrane Library, were searched relevant studies published from database inception August 2023. Results pooled using random-effects models, heterogeneity was examined. A total 16 case–control 1271 patients included. results showed that both preoperative [standardized mean difference (SMD) = 0.53; 95% confidence interval (CI): 0.15, 0.91; P < 0.001] postoperative levels (SMD 0.63; CI: 0.24, 1.03; 0.001) higher group compared non-AKI group. Subgroup analysis by continents European population 1.63; 0.55, 0.27; 0.003), but no differences Asian, African, North American, South American. revealed 0.002) Asian populations 0.42; 0.04, 0.81; 0.039). Higher plasma urine observed [plasma 1.29; 0.21, 2.38; 0.011), 0.88; 0.18, 1.59; 0.035)], while there serum NGAL. level may be an important biomarker detection period

Language: Английский

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