The protective role of curcumin in myocardial ischemia–reperfusion injury

Coronary artery disease (CAD) is a well-known pathological condition that is characterized by high morbidity and mortality. The main pathological manifestation of CAD is myocardial injury due to ischemia–reperfusion (I–R). Currently, no efficacious treatment of protecting the heart against myocardial I–R exists. Hence, it is necessary to discover or develop novel strategies to prevent myocardial-reperfusion injury to improve clinical outcomes in patients with CAD. A large body of experimental evidence supports cardioprotective properties of curcumin and the ability of this phytochemical to modify some cardiovascular risk factors. However, the detailed effects of curcumin in myocardial I–R injury are still unclear and there is a lack of evidence concerning which curcumin regimen may be ideal for myocardial I–R injury. This paper presents a brief review of the pathophysiology of myocardial I–R injury and the mechanisms of action of curcumin in reducing myocardial I–R injury.     

DNA damage response in renal ischemia–reperfusion and ATP-depletion injury of renal tubular cells

Renal ischemia–reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia–reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or “reperfusion” of renal proximal tubular cells (RPTCs) after ATP depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP depletion. The results suggest that DDR occurs during renal ischemia–reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death.     

Ebselen ameliorates renal ischemia–reperfusion injury via enhancing autophagy in rats

Renal ischemia–reperfusion (I/R) injury is one of the most common causes of chronic kidney disease (CKD). It brings unfavorable outcomes to the patients and leads to a considerable socioeconomic burden. The study of renal I/R injury is still one of the hot topics in the medical field. Ebselen is an organic selenide that attenuates I/R injury in various organs. However, its effect and related mechanism underlying renal I/R injury remains unclear. In this study, we established a rat model of renal I/R injury to study the preventive effect of ebselen on renal I/R injury and further explore the potential mechanism of its action. We found that ebselen pretreatment reduced renal dysfunction and tissue damage caused by renal I/R. In addition, ebselen enhanced autophagy and inhibited oxidative stress. Additionally, ebselen pretreatment activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effect of ebselen was suppressed by autophagy inhibitor wortmannin. In conclusion, ebselen could ameliorate renal I/R injury, probably by enhancing autophagy, activating the Nrf2 signaling pathway, and reducing oxidative stress.

     

The protective effect of cannabinoid type 2 receptor activation on renal ischemia–reperfusion injury

Natural products from medicinal plants have always attracted a lot of attention due to their diverse and interesting therapeutic properties. We have employed the principles of green chemistry involving isomerization, coupling and condensation reaction to synthesize a class of compounds derived from eugenol, a naturally occurring bioactive phytophenol. The compounds were characterized structurally by ¹H-, ¹³C-NMR, FT-IR spectroscopy and mass spectrometry analysis. The purity of compounds was detected by HPLC. The synthesized compounds exhibited anti-cancer activity. A 10–12-fold enhancement in efficiency of drug molecules (~?1 µM) was observed when delivered with graphene oxide (GO) as a nanovehicle. Our data suggest cell death via apoptosis in a dose-dependent manner due to increase in calcium levels in specific cancer cell lines. Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells. In addition to anti-cancer effect, we also observed significant role of these derivatives on parasite suggesting its multi-pharmacological capability.

     

Sphingolipid therapy in myocardial ischemia–reperfusion injury

Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia–reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia–reperfusion injury in clinically relevant in vivo murine models of ischemia–reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggest that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia–reperfusion injury and their possible mechanisms of cardioprotection.     

Effect of taurine on ischemia–reperfusion injury

Taurine is an abundant β-amino acid that regulates several events that dramatically influence the development of ischemia–reperfusion injury. One of these events is the extrusion of taurine and Na⁺ from the cell via the taurine/Na⁺ symport. The loss of Na⁺ during the ischemia–reperfusion insult limits the amount of available Na⁺ for Na⁺/Ca²⁺ exchange, an important process in the development of Ca²⁺ overload and the activation of the mitochondrial permeability transition, a key process in ischemia–reperfusion mediated cell death. Taurine also prevents excessive generation of reactive oxygen species by the respiratory chain, an event that also limits the activation of the MPT. Because taurine is an osmoregulator, changes in taurine concentration trigger “osmotic preconditioning,” a process that activates an Akt-dependent cytoprotective signaling pathway that inhibits MPT pore formation. These effects of taurine have clinical implications, as experimental evidence reveals potential promise of taurine therapy in preventing cardiac damage during bypass surgery, heart transplantation and myocardial infarction. Moreover, severe loss of taurine from the heart during an ischemia–reperfusion insult may increase the risk of ventricular remodeling and development of heart failure.     

Macrophages are involved in the protective role of human umbilical cord-derived stromal cells in renal ischemia–reperfusion injury

Administration of fibroblastic cells derived from a number of tissues (collectively called “mesenchymal stem cells”) has been suggested to be beneficial for renal repair and mortality reduction in renal ischemia–reperfusion injury (IRI), but the underlying mechanism is not fully understood. In the present study, our objective was to investigate the involvement of macrophages in the therapeutic effect of human umbilical cord-derived stromal cells (hUCSCs) on renal IRI. Twenty-four hours after reperfusion, hUCSCs were injected intravenously and resulted in significant improvements in renal function, with a lower tubular injury score together with more proliferative and fewer apoptotic tubular cells in kidney tissue. Moreover, hUCSCs reduced the infiltration of macrophages into renal interstitium especially at 5 days post-reperfusion, while the proportion of anti-inflammatory M2 macrophages was markedly increased. HUCSCs also alleviated the local inflammatory response in kidneys. The absence of macrophages during the early phase of reperfusion enhanced the therapeutic effect of hUCSCs, whereas macrophage depletion during the late repair phase eliminated the renoprotective role of hUCSCs. In vitro, macrophages cocultured with hUCSCs were switched to the alternatively activated M2 phenotype. Our data indicate that hUCSCs are capable of promoting the M2 polarization of macrophages at injury sites, suggesting a new mechanism for hUCSC-mediated protection in renal IRI.     

Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia–reperfusion injury

Kidney ischemia–reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress. We designed a P-selectin targeted CD39 molecule (rsol.CD39-PSGL-1) consisting of recombinant soluble CD39 that incorporates 20 residues of PSGL-1 that bind P-selectin. We hypothesised that rsol.CD39-PSGL-1 would maintain endothelial integrity by focusing the ectonucleotidase platelet-inhibitory activity and reducing leukocyte adhesion at the injury site. The rsol.CD39-PSGL-1 displayed ADPase activity and inhibited platelet aggregation ex vivo, as well as bound with high specificity to soluble P-selectin and platelet surface P-selectin. Importantly, mice injected with rsol.CD39-PSGL-1 and subjected to renal IRI showed significantly less kidney damage both biochemically and histologically, compared to those injected with solCD39. Furthermore, the equivalent dose of rsol.CD39-PSGL-1 had no effect on tail template bleeding times. Hence, targeting recombinant CD39 to the injured vessel wall via PSGL-1 binding resulted in substantial preservation of renal function and morphology after IRI without toxicity. These studies indicate potential translational importance to clinical transplantation and nephrology.     

NDUFV1 attenuates renal ischemia–reperfusion injury by improving mitochondrial homeostasis

Impaired mitochondrial function and dysregulated energy metabolism have been shown to be involved in the pathological progression of kidney diseases such as acute kidney injury (AKI) and diabetic nephropathy. Hence, improving mitochondrial function is a promising strategy for treating renal dysfunction. NADH: ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an important subunit of mitochondrial complex I. In the present study, we found that NDUFV1 was reduced in kidneys of renal ischemia/reperfusion (I/R) mice. Meanwhile, renal I/R induced kidney dysfunction as evidenced by increases in BUN and serum creatinine, severe injury of proximal renal tubules, oxidative stress, and cell apoptosis. All these detrimental outcomes were attenuated by increased expression of NDUFV1 in kidneys. Moreover, knockdown of Ndufv1 aggravated cell insults induced by H₂O₂ in TCMK-1 cells, which further confirmed the renoprotective roles of NDUFV1. Mechanistically, NDUFV1 improved the integrity and function of mitochondria, leading to reduced oxidative stress and cell apoptosis. Overall, our data indicate that NDUFV1 has an ability to maintain mitochondrial homeostasis in AKI, suggesting therapies by targeting mitochondria are useful approaches for dealing with mitochondrial dysfunction associated renal diseases such as AKI.     

The HMGB1–TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis

Toll-like receptor 4 (TLR4) and its ligand high mobility group box 1 (HMGB1), are known for playing central roles in ischemia–reperfusion injury in myocardium. However, the detailed mechanisms of TLR4 and HMGB1 are not fully understood. The aim of this study was to investigate the effects and possible mechanisms of the HMGB1–TLR4 axis and cardiomyocyte apoptosis on myocardial ischemic damage. Artificial oxygen ventilated anesthetized C3H/HeN mice and C3H/HeJ mice were subjected to 30 min of left anterior descending coronary artery occlusion followed by 6 h of reperfusion. The myocardial infarct size, HMGB1 levels, apoptosis index, Bax, Bcl-2 and TNF-α mRNA levels were assessed. The results showed that a lowered amount of cardiomyocyte apoptosis and infarct size in the myocardium of TLR4-mutant mice after myocardial I/R and that TLR4 deficiency notably inhibited the expression of HMGB1 and TNF-a, both of which were up-regulated by ischemia/reperfusion. These findings suggest that the HMGB1–TLR4 axis plays a pathogenic role in triggering cardiomyocyte apoptosis during myocardial I/R injury and that the possible mechanism for this process is the result of released cytokines and inflammatory response involved in the HMGB1/TLR4-related pathway.     

Pharmacological preconditioning with erythropoietin reduces ischemia–reperfusion injury in the small intestine of rats

AimsConsidering the implications that arose from several recent experimental studies using recombinant human erythropoietin in rodents, erythropoietin has been regarded as a pharmacological preconditioning agent. The purpose of the present study was to evaluate whether erythropoietin has a preconditioning effect against ischemia and reperfusion injury in the small intestine of the rat.Main methodsIntestinal ischemia was induced in male Wistar rats by clamping the superior mesenteric artery for 30 min, followed by reperfusion for 180 min. Recombinant human erythropoietin (1000 or 3000 U/kg) or vehicle was administered intraperitoneally 24 h prior to ischemia. After collection of ileal tissue, evaluation of damage was based on measurements of the accumulation of polymorphonuclear neutrophils by technetium-99m-labeled leukocyte uptake, content of malondialdehyde, reduced glutathione, contractile responses to agonists, and an evaluation of histopathological features in intestinal tissue.Key findingsTreatment with erythropoietin 24 h before ischemia significantly reduced the tissue content of malondialdehyde and increased that of reduced glutathione. Pretreatment also significantly suppressed leukocyte infiltration into the postischemic tissue, as evidenced by the lower content of myeloperoxidase and technetium-99m-labeled leukocytes. Physiological and histopathological improvements were also significant with the rHuEpo treatment.SignificanceResults of the present study indicate that rHuEpo is an effective preconditioning agent in ischemic injury of the small intestine. Protection provided by recombinant human erythropoietin is closely related to the inhibition of oxidative stress and leukocyte infiltration, which might be among the possible protective mechanisms of erythropoietin in intestinal ischemia and reperfusion.     

Curcumin reduces the cardiac ischemia–reperfusion injury: involvement of the toll-like receptor 2 in cardiomyocytes

Curcumin, a polyphenolic compound derived from turmeric, has protective effects on myocardial injury through attenuation of oxidative stress and inflammation. Toll-like receptor 2 (TLR2), a key mediator of the innate immune system, is involved in myocardial infarction and examined if controlled by curcumin. Rat cardiomyocytes (CMs) were stimulated with tumor necrosis factor (TNF)-α, peptidoglycan (PGN) or hypoxia/reoxygenation (H/R) with or without curcumin pretreatment. Sprague–Dawley rats were fed curcumin (300 mg/kg/day) 1 week before cardiac ischemia/reperfusion (I/R) injury. The expression level of TLR2 and cardiac function were assessed. Both mRNA and protein of TLR2 were up-regulated in infarcted myocardium, while TLR4 remained unchanged. In CMs, TLR2 and monocyte chemoattractant protein (MCP)-1 mRNAs were increased by TNF-α, PGN or H/R, whereas they were blunted by curcumin. Immunofluorescence staining of CMs also showed that TLR2 and MCP-1 were increased after H/R, whereas curcumin-pretreated CMs were not. In animal study, 2 weeks after I/R, TLR2 was increased in the infarct zone, whereas it stayed unchanged in the Cur+I/R group. Macrophage infiltration (CD68), high-mobility group box 1 and fibrosis were increased in the I/R group, whereas they were decreased in the Cur+I/R group. Connexin 43 was reduced in the I/R group, while it recovered significantly in the Cur+I/R group. Cardiac contractility in the Cur+I/R group was also improved compared with that in the I/R group (max dp/dt in Cur+I/R group: 9660±612 vs. I/R group: 8119±366, P<.05). These results suggest that selective inhibition of TLR2 by curcumin could be preventive and therapeutic for myocardial infarction.     

Role of CC-chemokine receptor 5 on myocardial ischemia–reperfusion injury in rats

The expression level of CC-chemokine receptor 5 (CCR5) is enhanced post inflammatory stimulations and might play a crucial role on inflammatory cells infiltration post myocardial ischemia. The purpose of this study was to evaluate the role of CCR5 on myocardial ischemia–reperfusion (I/R) injury in rats. Adult male rats were randomized to sham group, I/R group (I/R, 30 min coronary artery occlusion followed by 2-h reperfusion), ischemic preconditioning (I/R + Pre), CCR5 antibody group [I/R + CCR5Ab (0.2 mg/kg)], and CCR5 agonist group [I/R + CCR5Ago, RNATES (0.1 mg/kg)], n = 12 each group. The serum level of creatine kinase (CK) and tumor necrosis factor α (TNF-α) were measured by ELISA. Myocardial infarction size and myeloperoxidase (MPO) activity were determined. Myocardial protein expression of CCR5 and intercellular adhesion molecule-1 (ICAM-1) were evaluated by Western blotting and immunohistochemistry staining, respectively. Myocardial nuclear factor-kappa B (NF-κB) activity was assayed by electrophoretic mobility shift assay. Myocardial CCR5 protein expression was significantly reduced in I/R + Pre group (P < 0.05 vs. I/R) and further reduced in I/R + CCR5Ab group (P < 0.05 vs. I/R + Pre). LVSP and ±dP/dt _max were significantly lower while serum CK and TNF-α as well as myocardial MPO activity, ICAM-1 expression, and NF-κB activity were significantly higher in I/R group than in sham group (all P < 0.05), which were significantly reversed by I/R + Pre (all P < 0.05 vs. I/R) and I/R + CCR5Ab (all P < 0.05 vs. I/R + Pre) while aggravated by I/R + CCR5Ago (all P < 0.05 vs. I/R). Our results suggest that blocking CCR5 attenuates while enhancing CCR5 aggravates myocardial I/R injury through modulating inflammatory responses in rat heart.     

Akt1 is involved in tubular apoptosis and inflammatory response during renal ischemia–reperfusion injury

Molecular Biology Reports - Renal ischemia–reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI). Although Akt is involved in renal IRI, it is unclear as to which...     

Ablation of cereblon attenuates myocardial ischemia–reperfusion injury

Cereblon (CRBN) was originally identified as a target protein for a mild type of mental retardation in humans. However, recent studies showed that CRBN acts as a negative regulator of AMP-activated protein kinase (AMPK) by binding directly to the AMPK catalytic subunit. Because AMPK is implicated in myocardial ischemia–reperfusion (I–R) injury, we reasoned that CRBN might play a role in the pathology of myocardial I–R through regulation of AMPK activity. To test this hypothesis, wild-type (WT) and crbn knockout (KO) mice were subjected to I–R (complete ligation of the coronary artery for 30 min followed by 24 h of reperfusion). We found significantly smaller infarct sizes and less fibrosis in the hearts of KO mice than in those of WT mice. Apoptosis was also significantly reduced in the KO mice compared with that in WT mice, as shown by the reduced numbers of TUNEL-positive cells. In parallel, AMPK activity remained at normal levels in KO mice undergoing I–R, whereas it was significantly reduced in WT mice under the same conditions. In rat neonatal cardiomyocytes, overexpression of CRBN significantly reduced AMPK activity, as demonstrated by reductions in both phosphorylation levels of AMPK and the expression of its downstream target genes. Collectively, these data demonstrate that CRBN plays an important role in myocardial I–R injury through modulation of AMPK activity.     

Temporal activation of Nrf2 in the penumbra and Nrf2 activator-mediated neuroprotection in ischemia–reperfusion injury

Oxidative stress plays a critical role in mediating tissue injury and neuron death during ischemia–reperfusion injury (IRI). The Keap1–Nrf2 defense pathway serves as a master regulator of endogenous antioxidant defense, and Nrf2 has been attracting attention as a target for the treatment of IRI. In this study, we evaluated Nrf2 expression in IRI using OKD (Keap1-dependent oxidative stress detector) mice and investigated the neuroprotective ability of an Nrf2 activator. We demonstrated temporal changes in Nrf2 expression in the same mice with luciferase assays and an Nrf2 activity time course using Western blotting. We also visualized Nrf2 expression in the ischemic penumbra and investigated Nrf2 expression in mice and humans using immunohistochemistry. Endogenous Nrf2 upregulation was not detected early in IRI, but expression peaked 24 h after ischemia. Nrf2 expression was mainly detected in the penumbra, and it was found in neurons and astrocytes in both mice and humans. Intravenous administration of the Nrf2 activator bardoxolone methyl (BARD) resulted in earlier upregulation of Nrf2 and heme oxygenase-1. Furthermore, BARD decreased infarction volume and improved neurological symptoms after IRI. These findings indicate that earlier Nrf2 activation protects neurons, possibly via effects on astrocytes.     

Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia–reperfusion injury in rats

The aim of the present study was to evaluate the protective effects of the NF-кB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia–reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-кB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p < 0.05). The TBARS levels were significantly decreased in group III compared with the group II (p < 0.05). CAT, SOD and GST activities were decreased in group II, but these enzymes levels were significantly increased in group III according to the group II (p < 0.05). Under microscopic evaluation NF-кB expression increased significantly in group II compared to the group I (p < 0.05) and then decreased in group III (p < 0.05). HSP60 and p53 expression in group II was increased significantly compared with group I. Under microscopic evaluation we detected that HSP60 and p53 expression was increased significantly in group II compared with group I. In group III PDTC administration was decreased the HSP60 and p53 expression, this difference was statistically significant (p < 0.05). The results of the present study have demonstrated that NF-кB inhibition with PDTC protects and provides beneficial effects on ischemia/reperfusion stress related bladder tissue destruction.     

Osteopontin deficiency aggravates hepatic injury induced by ischemia–reperfusion in mice

Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia–reperfusion (I–R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the upregulation of the hepatic and systemic level of OPN in mice. Plasma aspartate aminotransferase and alanine aminotransferase levels were strongly increased in Opn^−/− mice compared with wild-type (Wt) mice after I–R, and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNFα), interleukin 6 (IL6) and interferon-γ were strongly upregulated in Opn^−/− mice versus Wt mice after I–R. One explanation for these responses could be the vulnerability of the OPN-deficient hepatocyte. Indeed, the downregulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen–glucose deprivation and TNFα. Further, the downregulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn^−/− mice versus Wt mice livers after I–R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the downregulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the upregulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I–R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.     

Emerging roles of microRNAs in intestinal ischemia/reperfusion–induced injury: a review

Journal of Physiology and Biochemistry - Intestinal ischemia/reperfusion (II/R) injury is a serious pathological phenomenon in underlying hemorrhagic shock, trauma, strangulated intestinal...