Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 8, 2024

Abstract Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of intricate mechanisms underlying I/R hinders development effective therapeutic interventions. Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system pathways involved in injury. This review article elucidates signaling, as well complex interplay between and including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca 2+ -Activin A, Hippo-Yes-associated toll-like receptor 4/toll-interleukine-1 domain-containing adapter-inducing interferon-β, hepatocyte factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, apoptosis, inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, blood-brain barrier damage Our comprehensive analysis reveals that activation canonical promotes organ recovery, while non-canonical exacerbates Moreover, explore novel approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, clinical trials. objective this is provide deeper insights roles its I/R-mediated processes dysfunction, facilitate innovative agents for

Language: Английский

---

Dexmedetomidine Attenuates Ferroptosis-Mediated Renal Ischemia/Reperfusion Injury and Inflammation by Inhibiting ACSL4 via α2-AR

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 14, 2022

Ischemia-reperfusion (I/R) injury is a serious clinical pathology associated with acute kidney (AKI). Ferroptosis non-apoptotic cell death that known to contribute renal I/R injury. Dexmedetomidine (Dex) has been shown exert anti-inflammatory and organ protective effects. This study aimed investigate the detailed molecular mechanism of Dex protects kidneys against through inhibiting ferroptosis. We established I/R-induced model in mice, OGD/R induced HEK293T cells damage vitro. RNA-seq analysis was performed for identifying potential therapeutic targets. differentially expressed genes (DEGs) reported Acyl-CoA synthetase long-chain family member 4 (ACSL4) related ferroptosis inflammation mice renal, which validated rodent renal. Liproxstatin-1, specific small-molecule inhibitor ferroptosis, significantly attenuated ferroptosis-mediated decreased LPO, MDA, LDH levels, increased GSH level. Inhibiting activity ACSL4 by Rosiglitazone (ROSI) resulted inflammation, as well reduced tissue damage, decreasing MDA level, increasing reducing COX2 GPx4 protein expression, suppressing TNF-α mRNA IL-6 levels. α2-adrenergic receptor (α2-AR) agonist effects Our results also revealed administration mitigated inhibited downregulated response following injury, were suppression ACSL4. In addition, overexpression abolishes Dex-mediated on cells, promotion expression α2-AR reversed role Dex. present indicated attenuates via α2-AR.

Language: Английский

---

The mechanism of ferroptosis and its related diseases

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 16, 2023

Abstract Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation lipid peroxides, provides novel avenue for delving into intersection metabolism, oxidative stress, and disease pathology. We have witnessed mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, traumatic tissue injuries. By unraveling intricate underpinnings molecular machinery, contributors, signaling conduits, regulatory networks governing researchers aim bridge gap between intricacies this unique mode multifaceted implications health disease. In light rapidly advancing landscape ferroptosis research, we present comprehensive review aiming at extensive in origins progress human diseases. This concludes careful analysis potential treatment approaches carefully designed either inhibit or promote ferroptosis. Additionally, succinctly summarized therapeutic targets compounds that hold promise targeting within various facet underscores burgeoning possibilities manipulating as strategy. summary, enriched insights both investigators practitioners, while fostering an elevated comprehension latent translational utilities. revealing basic processes investigating possibilities, crucial resource scientists medical aiding deep understanding effects situations.

Language: Английский

---

Frailty and Kidney Transplantation: A Systematic Review and Meta-analysis

Transplantation Direct, Journal Year: 2021, Volume and Issue: 7(6), P. e701 - e701

Published: May 18, 2021

Frailty is a multidimensional condition and the result of body's age-associated decline in physical, cognitive, physiological, immune reserves. The aim this systematic review to assess quality evidence included studies, determine prevalence frailty among kidney transplant candidates, evaluate relationship between associated patient characteristics outcomes after transplantation.A search was performed for relevant literature on transplantation. This followed by meta-analysis reported minimum 2 studies including mean age, gender, body mass index, type transplantation, dialysis, previous comorbidities, hypertension, race, preemptive delayed graft function, length stay.A total 18 were 14 those suitable meta-analysis. overall pooled before transplantation estimated at 17.1% (95% confidence interval [CI], 15.4-18.7). significantly with higher age (mean difference, 3.6; 95% CI, 1.4-5.9), lower rate (relative risk, 0.60; 0.4-0.9), longer duration function 1.80; 1.1-3.0), stay than wk (odds ratio, 1.64; 1.2-2.3).One 6 recipients frail presence rates older recipient stay. Future research required explore association other adverse effects intervention programs improve different domains.

Language: Английский

---

Dipeptidase-1 governs renal inflammation during ischemia reperfusion injury

Science Advances, Journal Year: 2022, Volume and Issue: 8(5)

Published: Feb. 2, 2022

The mechanisms that drive leukocyte recruitment to the kidney are incompletely understood. Dipeptidase-1 (DPEP1) is a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of kidney. Renal ischemia reperfusion injury (IRI) induces robust monocyte causes acute (AKI). inflammation AKI phenotype were attenuated in Dpep1-/- mice or pretreated with DPEP1 antagonists, including LSALT peptide, nonenzymatic inhibitor. deficiency inhibition primarily blocked reduced inflammatory after IRI. CD44 but not ICAM-1 blockade also decreased during IRI was additive effects. DPEP1, CD44, all contributed monocyte/macrophages following These results identify as potential therapeutic target for AKI.

Language: Английский

---

Macrophage Ontogeny, Phenotype, and Function in Ischemia Reperfusion-Induced Injury and Repair

Kidney360, Journal Year: 2024, Volume and Issue: 5(3), P. 459 - 470

Published: Feb. 1, 2024

AKI is characterized by a sudden, and usually reversible, decline in kidney function. In mice, ischemia-reperfusion injury (IRI) commonly used to model the pathophysiologic features of clinical AKI. Macrophages are unifying feature IRI as they regulate both initial response well long-term outcome following resolution injury. Initially, macrophages take on proinflammatory phenotype production inflammatory cytokines, such CCL2 (monocyte chemoattractant protein 1), IL-6, IL-1 β , TNF- α . Release these cytokines leads tissue damage. After injury, reparative role, aiding repair restoration By contrast, failure resolve results prolonged macrophage accumulation increased damage, fibrosis, eventual development CKD. Despite extensive amount literature that has ascribed functions M1/M2 macrophages, recent paradigm shift field now defines basis their ontological origin, namely monocyte-derived tissue-resident macrophages. this review, we focus function during IRI-induced repair, transition CKD using classic (M1/M2) novel (ontological origin) definition

Language: Английский

---

Cellular dynamics in pig-to-human kidney xenotransplantation

Med, Journal Year: 2024, Volume and Issue: 5(8), P. 1016 - 1029.e4

Published: May 21, 2024

Xenotransplantation of genetically engineered porcine organs has the potential to address challenge organ donor shortage. Two cases porcine-to-human kidney xenotransplantation were performed, yet physiological effects on xenografts and recipients' immune responses remain largely uncharacterized.

Language: Английский

---

Неімуноопосередковані детермінанти тривалості функціонування трансплантованої нирки

Ukrainian Journal of Nephrology and Dialysis, Journal Year: 2025, Volume and Issue: 1(85), P. 81 - 96

Published: Feb. 18, 2025

Незважаючи на успіхи щодо подовження тривалості функціонування трансплантованої нирки, вона складає, у середньому, лише 10-12 років. При цьому тривалість нирки прогресивно знижується вже після першого року трансплантації. Прогресуюче зниження функціональної здатності обумовлюється двома основними групами причин: неімуноопосередкованими та імуноопосередкованими. Відстрочена функція трансплантата (ВФТ) є кількісним і якісним інтегральним проявом як імуноопосередкованих так неімуноопосередкованих механізмів, котра суттєво впливає короткострокові довгострокові результати Питома вага кожної складової конкретного реципієнта індивідуальна змінюється протягом усього післятрансплантаційного періоду. Робіт, присвячених визначенню детермінант трансплантату загалом виникнення ВФТ тому числі, небагато. У огляді систематизовані ключові неімуноопосередковані детермінанти можливі терапевтичні мішені, що визначальним для своєчасного початку лікування терміну нирки. Очевидно, сьогодні максимального результату можна досягти встановивши мішені ефективні способи впливу імуно складові донора реціпієнта. Мета аналітичного огляду – визначити ретро проспективне вивчення яких дозволить запропонувати

---

Recent Advances and Clinical Outcomes of Kidney Transplantation

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(4), P. 1193 - 1193

Published: April 22, 2020

Recent advances in surgical, immunosuppressive and monitoring protocols have led to the significant improvement of overall one-year kidney allograft outcomes. Nonetheless, there has not been a change long-term In fact, chronic acute antibody-mediated rejection (ABMR) non-immunological complications following transplantation, including multiple incidences primary disease, as well such cardiovascular diseases, infections, malignancy are major factors that contributed failure allografts. The use molecular techniques enhance histological diagnostics noninvasive surveillance what latest studies field clinical transplant seem mainly focus upon. Increasingly innovative approaches being used discover methods overcome critical sensitization, prevent development anti-human leukocyte antigen (HLA) antibodies, treat active ABMR, reduce recurrence disease other complications, malignancy. present era utilizing electronic health records (EHRs), it is strongly believed big data artificial intelligence will reshape research done on transplantation near future. addition, utilization telemedicine increasing, providing benefits reaching out patients remote areas helping make scarce healthcare resources more accessible for transplantation. this article, we discuss recent developments transplants may affect allografts, survival patient. living donation also explored.

Language: Английский

---

Naringenin Alleviates Renal Ischemia Reperfusion Injury by Suppressing ER Stress-Induced Pyroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling Pathway

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 24

Published: Oct. 10, 2022

Endoplasmic reticulum (ER) stress, pyroptosis, and apoptosis are critical molecular events in the occurrence progress of renal ischemia reperfusion (I/R) injury. Naringenin (4 ′ ,5,7-trihydroxyflavanone) is one most widely consumed flavonoids with powerful antioxidant anti-inflammatory activities. However, whether naringenin able to relieve I/R injury corresponding mechanisms have not been fully clarified. This study was aimed at exploring its role relevant The C57Bl/6 mice were randomly assigned receive administration (50 mg/kg/d) or sterile saline (1.0 mL/d) for 3 d by gavage suffered from surgery. One specific ER stress inhibitor, 4-phenylbutyric acid (4-PBA, 100 mg/kg/d), intraperitoneally administered validate regulation on pyroptosis apoptosis. Cultured HK-2 cells went through process hypoxia/reoxygenation (H/R) perform cellular experiments incubation (200 μM), 4-PBA (5 mM), brusatol (400 nM). animal results verified that obviously relieved injury, while it refined function attenuated tissue structural damage. Furthermore, treatment inhibited I/R-induced as well indicated decreased levels biomarkers such GRP78, CHOP, caspase-12, NLRP3, ASC, caspase-11, caspase-4, caspase-1, IL-1β, GSDMD-N, BAX, cleaved caspase-3 animals cells. Besides, upregulated expression Nrf2 HO-1 proteins after suggested activated Nrf2/HO-1 signaling pathway, which again authenticated usage (Bru), unique inhibitor pathway. Importantly, application showed I/R-generated be regulated vivo vitro. In conclusion, suppressed activating pathway further alleviated protect against

Language: Английский

---