Ischemia Reperfusion-induced Injury Research Articles

Epigallocatechin gallate prevents cardiomyocytes from pyroptosis through lncRNA MEG3/TAF15/AIM2 axis in myocardial infarction

Background( −)-Epigallocatechin-3-gallate (EGCG), a bioactive polyphenol isolated from green tea, has recently garnered attention for its potential protective role against acute myocardial infarction (MI) via inhibiting inflammation. Herein, we tested whether EGCG participates in modulating cardiac ischemia reperfusion-induced injury and elucidate its potential mechanisms.MethodsTo induce MI in mice, we employed coronary artery ligation, while cell models utilized oxygen glucose deprivation/re-oxygenation (OGD/R)-treated HL-1 cells. TTC, HE and Massion staining evaluated the pathological changes of heart tissues. Besides, RNA-pull down and RIP assays analyzed the interactions of MEG3/TAF15 and AIM2 mRNA/TAF15. FISH associated with immunofiuorescence (IF) double staining was conducted to measure the co-localization of MEG3 and TAF15.ResultsIn vitro and in vivo evidence supported that EGCG treatment improved cardiomyocytes viability while inhibiting the expressions of AIM2, C-caspase-1, ASC, GSDMD-N, IL-18 and IL-1β. Knockdown of MEG3 intensified EGCG's therapeutic effects both in vitro and in vivo. LncRNA MEG3 and AIM2 mRNA interacted with TAF15, and MEG3, in turn, promoted the stability of AIM2 mRNA through regulating TAF15. Overexpression of TAF15 reversed the promoting effect of EGCG and MEG3 knockdown on cell viability, and the inhibiting effect on cell pyroptosis.ConclusionEGCG protected cardiomyocytes from pyroptosis by the MEG3/TAF15/AIM2 axis, indicating EGCG as a potential novel therapeutic strategy for managing MI.

β-caryophyllene ameliorates hepatic ischemia reperfusion-induced injury: the involvement of Keap1/Nrf2/HO 1/NQO 1 and TLR4/NF-κB/NLRP3 signaling pathways.

Hepatic ischemia-reperfusion (H I/R) injury is a frequent clinical event during which the leading contributing players are inflammation and oxidative stress responses. β-caryophyllene (BCP), a natural bicyclicsesquiterpene, is an essential oil component of different plant species and edibles. This study aims to identify whether BCP pretreatment could avert H I/R injury with inspections of the underlying mechanisms. Animals were devised into five groups; Sham and BCP + Sham; the animals were administered saline or BCP (200 mg/kg, orally) respectively; H I/R group, the animals were administered saline orally for 14 days before induction of H I/R; BCP100 and BCP200, the animals were administered BCP (100 and 200 mg/kg, respectively) for 14 days, followed by induction of H I/R. H I/R showed markedly increased ALT, AST, MDA, and lowered antioxidant enzyme activities, while the Nrf2/HO1/NQO1 pathway components were significantly augmented. The TLR4/NF-κB/NLRP3 elements were deterred, and subsequently, escalations in the inflammatory mediators (IL-1β, IL-6, and TNF-α), adhesion molecule ICAM-1, neutrophils infiltration (MPO), and apoptotic markers were observed. Pretreatment with BCP amplified the antioxidant enzyme activities and Keap1/Nrf2/HO1/NQO1 pathway components. BCP pretreatment lowered TLR4/NF-κB/NLRP3 pathway elements, which mitigated inflammatory mediators, ICAM-1, MPO, and apoptotic markers. The protective effect of BCP against hepatic I/R induced injury might be accomplished via mitigation of oxidative stress by regulating the Keap1/Nrf2/HO1/NQO1 pathway and inhibition of the inflammatory process via manipulating the TLR4/ NF-κB/ NLRP3, reflected by inflammatory markers, neutrophils recruitment, and adhesion molecules reduction. BCP might be a potential therapeutic agent for alleviating hepatic I/R-induced injury.

RBM3 interacts with Raptor to regulate autophagy and protect cardiomyocytes from ischemia-reperfusion-induced injury.

Acute myocardial infarction (AMI) is a common disease with high morbidity and mortality worldwide. However, postinfarction pathogenesis remains unclear, and it is particularly important to identify new therapeutic targets. The RNA-binding motif protein RBM3 (also known as cold-inducible protein) is known to promote translation and is associated with tumor proliferation and neuroprotection. However, little is known about the biological effects of RBM3 on myocardial infarction. In the present study, we found that RBM3 expression was significantly upregulated in ischemia-reperfusion (I/R) condition and downregulation of RBM3 inhibited autophagy and promoted apoptosis in cardiomyocytes. We confirmed that RBM3 interacts with Raptor to regulate the autophagy pathway. Taken together, these findings illustrate the protective effects of RBM3 against I/R-induced myocardial apoptosis through the autophagy pathway.

Neuroprotective Effect of Piclamilast-Induced Post-Ischemia Pharmacological Treatment in Mice

Various studies have evidenced the neuroprotective role of PDE4 inhibitors. However, whether PDE4 inhibitor, Piclamilast pharmacological post-treatment is protective during cerebral ischemia reperfusion-induced injury remains unknown. Therefore, this study design included testing the hypothesis that Piclamilast administered at the beginning of a reperfusion phase (Piclamilast pPost-trt) shows protective effects and explores & probes underlying downstream mechanisms. Swiss albino male mice were subjected to global ischemic and reperfusion injury for 17min. The animals examined cerebral infarct size, biochemical parameters, inflammatory mediators, and motor coordination. For memory, assessment mice were subjected to morris water maze (MWM) and elevated plus maze (EPM) test. Histological changes were assessed using HE staining. Piclamilast pPost-trt significantly reduced I/R injury-induced deleterious effects on biochemical parameters of oxidative stress, inflammatory parameters, infarct size, and histopathological changes, according to the findings. These neuroprotective effects of pPost-trt are significantly abolished by pre-treatment with selective CREB inhibitor, 666-15. Current study concluded that induced neuroprotective benefits of Piclamilast Post-trt, in all probability, maybe mediated through CREB activation. Hence, its neuroprotective effects can be further explored in clinical settings.

Inhibition of mitochondrial reactive oxygen species improves coronary endothelial function after cardioplegic hypoxia/reoxygenation

ObjectiveCardioplegic ischemia–reperfusion and diabetes mellitus are correlated with coronary endothelial dysfunction and inactivation of small conductance calcium-activated potassium channels. Increased reactive oxidative species, such as mitochondrial reactive oxidative species, may contribute to oxidative injury. Thus, we hypothesized that inhibition of mitochondrial reactive oxidative species may protect coronary small conductance calcium-activated potassium channels and endothelial function against cardioplegic ischemia–reperfusion-induced injury. MethodsSmall coronary arteries and endothelial cells from the hearts of mice with and without diabetes mellitus were isolated and examined by using a cardioplegic hypoxia and reoxygenation model to determine whether the mitochondria-targeted antioxidant Mito-Tempo could protect against coronary endothelial and small conductance calcium-activated potassium channel dysfunction. The microvessels or mouse heart endothelial cells were treated with or without Mito-Tempo (0-10 μM) 5 minutes before and during cardioplegic hypoxia and reoxygenation. Microvascular function was assessed in vitro by vessel myography. K+ currents of mouse heart endothelial cells were measured by whole-cell patch clamp. The levels of intracellular cytosolic free calcium (Ca2+) concentration, mitochondrial reactive oxidative species, and small conductance calcium-activated potassium protein expression of mouse heart endothelial cells were measured by Rhod-2 fluorescence staining, MitoSox, and Western blotting, respectively. ResultsCardioplegic hypoxia and reoxygenation significantly attenuated endothelial small conductance calcium-activated potassium channel activity, caused calcium overload, and increased mitochondrial reactive oxidative species of mouse heart endothelial cells in both the nondiabetic and diabetes mellitus groups. In addition, treating mouse heart endothelial cells with Mito-Tempo (10 μM) reduced cardioplegic hypoxia and reoxygenation-induced Ca2+ and mitochondrial reactive oxidative species overload in both the nondiabetic and diabetes mellitus groups, respectively (P < .05). Treatment with Mito-Tempo (10 μM) significantly enhanced coronary relaxation responses to adenosine 5′-diphosphate and NS309 (P < .05), and endothelial small conductance calcium-activated potassium channel currents in both the nondiabetic and diabetes mellitus groups (P < .05). ConclusionsAdministration of Mito-Tempo improves endothelial function and small conductance calcium-activated potassium channel activity, which may contribute to its enhancement of endothelium-dependent vasorelaxation after cardioplegic hypoxia and reoxygenation.

Telluric acid ameliorates hepatic ischemia reperfusion-induced injury in rats: Involvement of TLR4, Nrf2, and PI3K/Akt signaling pathways

In past tellurium-based compounds had limited use, however, their therapeutic potential have been target of interest recently due to antioxidant and anti-inflammatory capabilities in experimental endotoxemia. Nevertheless, their potential hepatoprotective effect against ischemia reperfusion (IR) injury is still obscure. This study examined the possible hepatoprotective effect of telluric acid (TELL), one of tellurium-based compound, against the deteriorating effect hepatic IR injury in rats through directing toll like receptor-4 (TLR4) cascade, phosphoinositide 3-kinase(PI3K)/Akt axis, and nuclear erythroid-related factor-2 (Nrf-2) pathway as possible mechanisms contributed to TELL’s effect. Indeed, male Wistar rats were randomized into 3 groups: sham-operated, control IR and TELL (50 µg/kg). TELL was administrated once daily for seven consecutive days prior to the IR induction. Pretreatment with TELL attenuated hepatic IR injury as manifested by hampered plasma aminotransaminases and lactate dehydrogenase activities. Also, TELL opposed IR induced elevation in tissue expression/activity of high-mobility group box protein-1 (HMGB1), TLR4, myeloid differentiation primary-response protein 88 (MyD88), phospho-nuclear factor-kappa B p65 (p-NF-κB p65), phospho-mitogen activated protein kinasep38 (p-MAPKp38) and tumor necrosis factor-alpha (TNF-α). Moreover, TELL reduced the elevated thiobarbituric acid reactive substances along with increased both Nrf-2 and endothelial nitric oxide synthase (eNOS) protein expression, beside replenishment of hepatic reduced glutathione. In addition, TELL induced obvious upregulation of p-PI3K and p-Akt protein expressions together with restoration of histopathological changes in IR injury. In conclusion, TELL purveyed conceivable novel hepatoprotective mechanisms and attenuated events associated with acute hepatic injury via inhibition of TLR4 downstream axis and activation of Nrf-2 and PI3K/Akt signaling cascades. Thus, TELL may provide a novel therapeutic potential for complications of hepatic IR injury.

The hepatoprotective effect of sitagliptin against hepatic ischemia reperfusion-induced injury in rats involves Nrf-2/HO-1 pathway.

Oxidative stress and inflammation play a key role in the development of hepatic ischemia reperfusion (HIR)-induced injury. Nuclear factor-erythroid 2-related factor-2 (Nrf-2) is a main regulator of numerous genes, encoding cytoprotective molecules including heme oxygenase-1 (HO-1). Sitagliptin (Sit) is an incretin enhancer acting via inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme. This study was undertaken to investigate the ability of Sit to prevent the hepatic pathological changes of HIR induced injury and to modify Nrf-2 and its target HO-1. Pringle's maneuver was used to induce total HIR in adult male rats that were randomly assigned into 4 groups. Group1 (sham-operated control), Group 2 (sham-operated + Sit-control group), Group 3 (HIR non-treated), and Group 4 (HIR + Sit). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities together with hepatic contents of malondialdhyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) and superoxide dismutase (SOD) activity were evaluated. Hepatic tissue mRNA of Nrf-2 and protein content of HO-1 along with histopathological examination and scoring of hepatic injury were performed. Sit caused a significant reduction in ALT and AST activities together with attenuation of HIR-induced histopathological liver injury. Effect of Sit was associated with decreased hepatic level of MDA and NO with increased GSH level and SOD activity. Non-treated rats with HIR showed an increase in Nrf-2 mRNA expression and HO-1 content in hepatic tissue which was further increased by Sit treatment. These results indicate that hepatoprotective activity of Sit against HIR is attributed at least in part to modulation of Nrf-2/ HO-1 signaling pathway.

Interleukin-33 Protects Ischemic Brain Injury by Regulating Specific Microglial Activities

Interleukin-33 (IL-33), a novel member of the IL-1 family, expressed in many tissue and cell types, is involved in inflammation and immune functions. Previous studies suggest that IL-33 may play a role in ischemic stroke. Here, we evaluated the effect of IL-33 in cerebral ischemia–reperfusion-induced injury and investigated its underlying mechanism. Our data indicated that IL-33 deficiency exacerbated the neurological dysfunction caused by cerebral ischemia–reperfusion injury in mice and led to the formation of larger cerebral infarct volume as shown by 2,3,5-triphenyltetrazolium chloride staining and magnetic resonance imaging. Furthermore, the M1 and M2 macrophage-like microglial immune responses with decreased expression of the corresponding cytokines were seen in IL-33-deficient mice. IL-33 deficiency led to more biased to M2-like activities. The aggravated cerebral ischemia–reperfusion injury in IL-33-deficient mice is partially restored by intracerebroventricular injection of IL-33. These data suggest that IL-33 promotes the amplification of macrophage polarization and cytokine production associated with M2 macrophage-like microglial immune phenotype, which may contribute to the protective effects in the ischemic stroke, and that IL-33 may be a potential therapeutic target for ischemic stroke.

Protective effect of salvianolic acid B against intestinal ischemia reperfusion-induced injury in a rat model

Purpose: To evaluate the gastro-protective efficacy of salvianolic acid B (SAB) against intestinal ischemic-reperfusion injury (IIRI) in a rat model.Methods: Forty-eight healthy male rats were randomly choosen and divided into 4 groups of 12 rats each. Control group rats underwent laparotomy without occlusion; IIRI group rats underwent laparotomy with occlusion for 60 min, followed by 24 h of reperfusion; SAB + IIRI group received 7 days of pretreatment with 40 mg/kg of SAB + IIRI; while the fourth group received only SAB. The antioxidant, inflammatory markers, intestinal permeability marker, as well as intestinal histopathological changes were assessed.Results: The activities of antioxidants including reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) were significantly ameliorated (p &lt; 0.01) in SAB-supplemented group (SAB + IIRI). The concentration of inflammatory markers, including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and nuclear factor p65 (NF-p65) as well as small intestinal permeability marker (FITC-Dextran), were significantly reduced (p &lt; 0.01) following administration of SAB for 7 days. In addition, pretreatment with SAB reverted intestinal (ileum) histopathological changes to almost normal architecture with significant reduction in Chiu score.Conclusion: The results of this study demonstrate that SAB may protect the intestine by attenuating oxidative stress and inflammatory response and hence, may be potentially for treating IIRI.Keywords: Salvianolic acid B, Intestinal Ischemia-reperfusion, Antioxidants, Inflammation, Intestinal permeability

Pentoxifylline exerts anti-inflammatory effects on cerebral ischemia reperfusion‑induced injury in a rat model via the p38 mitogen-activated protein kinase signaling pathway.

Pentoxifylline exhibits complex functions with extensive pharmacological effects and is used therapeutically due to its therapeutic effects and rapid metabolism in the body, with no cumulative effects and few side effects. The present study investigated the effects of pentoxifylline on cerebral ischemia reperfusion‑induced injury (IRI) through suppression of inflammation in rats. Hematoxylin and eosin staining was performed to evaluate the number of neurocytes, and ELISAs were applied to measure tumor necrosis factor‑α, interleukin‑6, malondialdehyde and superoxide dismutase activities. Treatment with pentoxifylline significantly recovered the cerebral ischemia reperfusion‑induced neurological deficit score and cerebral infarct volume in rats. In addition, pentoxifylline treatment significantly reversed the cerebral ischemia reperfusion‑induced interleukin‑6, tumor necrosis factor‑α, malondialdehyde and superoxide dismutase levels invivo. Furthermore, pentoxifylline significantly inhibited cyclooxygenase‑2 and inducible nitric oxide synthase mRNA and protein expression in cerebral IRI mice. Treatment with pentoxifylline also significantly suppressed the expression of cleaved caspase‑3 and p38 mitogen‑activated protein kinase(MAPK) protein in cerebral IRI mice. These results indicate that the protective effects of pentoxifylline on cerebral IRI may occur via the p38 MAPK signaling pathway.

Exploring the putative role of TRPV1 -dependent CGRP release in remote hind preconditioning-induced cardioprotection.

Remote ischemic preconditioning (RIPC) is a phenomenon whereby transient nonlethal ischemia and reperfusion episodes confer protection against prolonged ischemia reperfusion-induced injury. However, the underlying intracellular signaling has not been extensively explored. This study aimed to inspect the putative involvement of TRPV1 -dependent CGRP release in mediating remote hind limb preconditioning-induced cardioprotection. In this study, remote hind limb preconditioning stimulus was delivered (four consecutive episodes of 5minutes of ischemia reperfusion) using a blood pressure cuff tied at the inguinal level of the rat. The isolated rat hearts were perfused on the Langendorff's system and were subjected to 30-minutes global ischemia and 120-minutes reperfusion. Prolonged ischemia and subsequent reperfusion led to myocardial injury that was evaluated in terms of infarct size, LDH release, CK release, LVDP, +dp/dtmax , -dp/dtmin , and coronary flow rate. The pharmacological agents used in this study included capsaicin as TRPV1 channel activator, sumatriptan and CGRP8-37 as CGRP blockers. Remote hind limb and capsaicin preconditioning (10mg/kg-1 ) significantly reduced the infarct size, LDH release, CK release and significantly improved LVDP, +dp/dtmax , -dp/dtmin , and coronary flow rate. However, remote hind limb and capsaicin preconditioning-induced cardioprotective effects were remarkably reduced in the presence of sumatriptan (8mg/kg-1 ) and CGRP8-37 (1mg/kg-1 ). This indicates that remote hind limb preconditioning stimulus probably activates TRPV1 channels which subsequently induces CGRP release to produce cardioprotective effects.

NRG-1β exerts neuroprotective effects against ischemia reperfusion-induced injury in rats through the JNK signaling pathway

BackgroundNeuregulin-1β (NRG-1β) has great potential to be developed into therapeutics for neuroprotection. The aim of the current study was to analyze the effects and possible signaling pathway of NRG-1β on brain tissues in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). MethodsIn order to observe the protective effect of NRG-1β on MCAO/R, the neurological deficit and infarct volume were measured using a modified neurological severity score (mNSS) test and by triphenyl tetrazolium chloride (TTC) staining. In order to detect the antagonistic effect of NRG-1β on nerve cells and the blood–brain barrier (BBB), the morphology and structure of cortical brain tissues were observed by Evans Blue (EB) staining, hematoxylin–eosin (H&E) and Nissl staining, in situ cell death detection kit, and transmission electron microscopy (TEM). In order to investigate whether NRG-1β exhibited a significant neuroprotective effect via the JNK signaling pathway, the activity of JNK and the levels of phospho-MKK4, phospho-JNK, pan-JNK and phospho-c-Jun were tested using a JNK activity screening kit, immunofluorescent labeling, and western blot analysis, respectively. ResultsIn the NRG-1β treatment group, accompanied with a decrease in JNK activity, the protein levels of phospho-JNK, phospho-MKK4 and phospho-c-Jun decreased, the ischemia-induced apoptosis decreased, the abnormal morphological structures of nerve cells were ameliorated, the integrity of the BBB was restored, and infarct volume was reduced. At the same time, neurological function was significantly recovered. ConclusionNRG-1β exerts a neuroprotective effect through the JNK signaling pathway in MCAO/R rats.

Study of neuron-protective effect and mechanism of neuregulin1β against cerebral ischemia reperfusion-induced injury in rats

Objective: Thecurrent study is to explore the neuron-protective mechanism of neuregulin1β (NRG1β) in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) through inhibiting the c-Jun phosphorylation. Methods: After 24 h of MCAO/R (referring to Longa's method), neurobehavioral function was measured by modified neurological severity score (mNSS) test; the cerebral infarction volume was detected by triphenyltetrazolium chloride (TTC) staining; the blood brain barrier (BBB) permeability was measured by Evans Blue (EB); the neuron morphology of brain tissue was observed by Nissl stain; the ultra-structures of the neurons were observed by transmission electron microscopy (TEM); the apoptotic neurons were counted by in situ cell death detection kit colocalized with NeuN; the expressions of phospho-c-Jun was determined by immunofluorescent labeling and Western blot analysis. Results: Compared with the sham-operation rats, the rats receiving MCAO/R showed increased mNSS (9.7±1.2), cerebral infarction volume (41.4±3.0)%, permeability of BBB, deformation of neurons, ischemia-induced apoptosis (0.63±0.04), and enhanced expression of phospho-c-Jun protein (0.90±0.07) (all P<0.05). Our data indicated that NRG1β attenuated neurologic deficits (6.4±0.9), decreased the cerebral infarction volume (10.4±0.5), reduced EB extravasation (1.55±0.13) and the deformation of neurons, protected the ultra-structure of neurons, blocked ischemia-induced apoptosis (0.23±0.02), through down-regulated phospho-c-Jun expression (0.40±0.03) in MCAO/R rats (P<0.05). Conclusion: NRG1β exerts neuron-protective effects against ischemia reperfusion-induced injury in rats through inhibiting the c-Jun phosphorylation.

Neuroprotective effects of curdione against focal cerebral ischemia reperfusion injury in rats.

BackgroundCurdione is one of the most highly concentrated component of the active constituents in E-zhu, which has been reported to possess a variety of activities. However, the pharmacologic neuroprotective activity of curdione has not been evaluated. The present study aimed to investigate the protective effect of curdione on focal cerebral ischemia reperfusion-induced injury in rats and further exploring the underlying mechanisms.Materials and methodsAdult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO) surgery for 2 h, followed by reperfusion stage. All animals received treatment once a day for 7 days before surgery and 14 days from 4 h after the reperfusion started. The neurological deficit test and Morris water maze test were performed at 1, 4, 7 and 14 days after MCAO. The infarct size of animals was determined by the 2,3,5-triphenyltetrazolium chloride staining, and pathological brain damage was estimated by hematoxylin–eosin staining. The malonaldehyde (MDA) levels and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) were detected by enzyme-linked immunosorbent assay. Expression of apoptotic proteins was measured by Western blot.ResultsOur results showed that curdione could significantly reduce the infarct size and neurological deficits, promote cognitive function recovery and recover neuronal morphologic damages in MCAO rats. It also blocked the increase of MDA content and elevated the activities of SOD, CAT and GSH-PX. Moreover, curdione attenuated the expression of Cyt-C, c-caspase-3 and c-caspase-9 increased the Bcl-2/Bax ratio and hence decreased the cellular apoptosis.ConclusionCurdione possessed potential neuroprotective effect on rats in the MCAO model. The anti-oxidative and anti-apoptotic properties may be involved in the underlying mechanisms.

Pharmacological enrollment of aldehyde dehydrogenase modulators to assist treating ischemia reperfusion-induced intestinal injury: is there a gap to be bridged?

This commentary highlights the research presented by Zhu et al. [1]. In this issue of the Clinical Science, the authors evaluated the protective effect of Alda-1 (a novel class of small molecule aldehyde dehydrogenase (ALDH2) activators) in the intestinal ischemia reperfusion (IR) injury. Remarkably, enhancing the ADLH2 activity by the use of Alda-1 can ameliorate several deleterious effects related to aldehydes, and may provide a better protection against an injury preestablished by IR. Together, an innovative metabolic strategy for treating patients with IR injury could be the use of ALDH modulators in a near future.

A Review on Potential Involvement of TRPV1 Channels in Ischemia-Reperfusion Injury.

Besides functioning as thermosensors, transient receptor potential vanilloid 1 (TRPV1) channels play a pivotal role in ischemia-reperfusion injury. Transient receptor potential vanilloid 1 channel activation attenuates ischemia-reperfusion-induced injury in various organs including the heart, lungs, kidneys, and the brain. Transient receptor potential vanilloid 1 channels are expressed on the sensory neurons innervating the myocardium, ventricles of the heart, epicardial surface of the heart, endothelial cells, and the vascular smooth muscle cells. During ischemic conditions, activation of TRPV1 channels on the perivascular nerves stimulates the release of calcitonin gene-related peptide and substance P to produce cardioprotection. Furthermore, TRPV1 channel activation reduces the generation of free radicals and inflammatory cytokines, inhibits neutrophil infiltration, and enhances the production of anti-inflammatory cytokines to reduce ischemia-reperfusion-induced tissue injury. The present review describes the potential involvement of TRPV1 channels and the signaling cascade in attenuating ischemia-reperfusion injury in various organs.

Ischemic Colitis Complicated by Consumptive Coagulopathy

Colonic ischemia-induced reperfusion injury can lead to multisystem organ failure, regardless of ischemic colitis etiology. However, it rarely leads to consumptive coagulopathy. A review of the current literature shows that there have been limited reported cases of colonic ischemia-induced consumptive coagulopathy. Known etiologies of disseminated intravascular coagulopathy (DIC) include sepsis, malignancy, trauma, and intravascular hemolysis. Ischemic colitis is not a known cause of disseminated intravascular coagulopathy; however, we can relate it to the mechanism of sepsis-induced disseminated intravascular coagulopathy as sepsis is frequently complicated by disseminated intravascular coagulopathy. Disseminating intravascular coagulopathy is the activation of intravascular coagulation culminating in intravascular fibrin formation and deposition into the microvasculature. Secondary fibrinolysis accompanies coagulation activation. Intravascular deposition of fibrin in sepsis leads to a diffuse obstruction of the microvascular bed resulting in progressive organ dysfunction, such as in acute respiratory distress syndrome, acute kidney injury, hypotension, and shock liver. Both the coagulation activation and the consumption of coagulation inhibitors leading to anticoagulation pathways are activated in sepsis, leading to consumptive coagulopathy. Consumptive coagulopathy was an unexpected response to ischemic colitis. We present a case of a 71 year old Hispanic female with past medical history significant for hypertension presented to our facility with sudden onset diffuse abdominal pain and bright red blood per rectum. Work up revealed hematologic profile significant for DIC in addition to acute kidney injury and ischemic hepatitis, negative for schistocytes on peripheral blood smear. Colonoscopy revealed severe ischemic colitis with submucosal hemorrhage and necrosis involving descending colon. Biopsy from colonoscopy was consistent with observation, revealing acute colitis with focal ischemic changes, granulation tissue, and acute inflammatory exudate of descending colon. We believe that the intense inflammatory reaction of ischemic colitis led to this consumptive coagulopathy. While the known etiologies of disseminated intravascular coagulopathy are numerous, ischemic colitis is rarely presented as one.Table 1: Initial labsTable 2: Resolution of disseminated intravascular coagulopathy in a case of ischemic colitisFigure 1Figure 2

Donor pretreatment with carbon monoxide prevents ischemia/reperfusion injury following heart transplantation in rats.

Because inhaled carbon monoxide (CO) provides potent anti-inflammatory and antioxidant effects against ischemia reperfusion injury, we hypothesized that treatment of organ donors with inhaled CO would decrease graft injury after heart transplantation. Hearts were heterotopically transplanted into syngeneic Lewis rats after 8 hours of cold preservation in University of Wisconsin solution. Donor rats were exposed to CO at a concentration of 250 parts per million for 24 hours via a gas-exposure chamber. Severity of myocardial injury was determined by total serum creatine phosphokinase and troponin I levels at three hours after reperfusion. In addition, Affymetrix gene array analysis of mRNA transcripts was performed on the heart graft tissue prior to implantation. Recipients of grafts from CO-exposed donors had lower levels of serum troponin I and creatine phosphokinase; less upregulation of mRNA for interleukin-6, intercellular adhesion molecule-1, and tumor necrosis factor-α; and fewer infiltrating cells. Although donor pretreatment with CO altered the expression of 49 genes expressly represented on the array, we could not obtain meaningful data to explain the mechanisms by which CO potentiated the protective effects. Pretreatment with CO gas before organ procurement effectively protected cardiac grafts from ischemia reperfusion-induced injury in a rat heterotopic cardiac transplant model. A clinical report review indicated that CO-poisoned organ donors may be comparable to non-poisoned donors.

Synergistic neroprotective activiity of benfotiamine co administered with erythropoietin in chemotherapy induced peripheral neuropathy in rats

Chemotherapeutic drugs like Cisplatin, Taxols used in cancer are associated with the development of peripheral neuropathy (PN). Severe neuropathy can occur in 3% to 7% of treated cases with single agents but the severity can increase to 38% with combined regimens. The treatment options for PN currently include anti-depressants, anti-convulsants and opioid analgesics. These agents are modestly effective for symptomatic relief, but they neither affect the underlying pathology nor do they slow progression of the disease. Therefore, effective treatment for chemotherapy induced neuropathy would be a major advantage for cancer patients. Benfotiamine (BT) a lipid soluble form of thiamine plays important role in various biological pathways reported beneficial effect in diabetic retinopathy. Erythropoietin (EPO) has recently been considered as a tissue protective cytokine.EPO is reported to protect neurons from ischemia reperfusion-induced injury, metabolic stress, HIV-induced damage or even mechanical injury such as nerve compression or trauma . Thereforethe present study was undertaken to evaluate the individual and combination effects of BT and EPO in cisplatin induced peripheral neuropathy in rats . PN was induced by Cisplatin - 2mg/kg,i.p. twice weekly for 8 weeks. The degree of protection was determined by measuring electrophysiological properties of sciatic nerve like nerve conduction velocity, behavioralparameters like motor in-coordination, thermal & cold hyperalgesia, grip strength, biochemal parameters like measurement of endogenous antioxidants and histopathological studies.PN was evidenced in Cisplatin control rats and ameliorated with administration of BT (100 mg/kg p.o daily)and EPO (500U/kg i.p. thrice weekly) for 8 weeks by augmenting all the above parameters.T4 exhibited neuroprotective activity, which would be attributed to its activity as neurotrophic effect.

Rac1 contributes to cerebral ischemia reperfusion-induced injury in mice by regulation of Notch2

Background: Cerebral ischemia–reperfusion (IR) injury is a complex pathological process that can cause irreversible brain damage, neuronal injury or death from brain ischemia. Rac1 GTPase is involved in cellular protection from IR injury. However, the mechanism of protection and the molecules affected by Rac1 remain to be defined. Methods and results: C57BL/6 mice were subjected to middle cerebral artery occlusion for 1h, followed by 24-h reperfusion. In this in vivo model of cerebral IR injury, mice treated with the Rac GTPase inhibitor NSC23766 or Rac1 small interfering RNA (siRNA) had better short-term (72h) neurologic scores, less infarction volume, higher production of antioxidant enzymes, lower lipid peroxide, and reduced apoptosis compared with a vehicle-treated group or a control-siRNA group. However, long-term (14day) neurologic scores were worse for the two treatments compared to controls. Microarray and quantitative polymerase chain reaction (PCR) revealed that Notch2 was downregulated under NSC23766 treatment. Notch2 protein levels decreased with NSC23766 and Rac1 siRNA in vitro and in vivo. Cell survival increased with the Notch signaling inhibitor DAPT or Notch2 siRNA and NICD2 attenuated the NSC23766 effect. In addition, immunoblotting showed that DAPT and Notch2 siRNA changed the levels of apoptosis-regulating proteins. NFkB mediated Rac1, which regulated Notch2 in an oxygen glucose deprivation model. Both inhibitors of Notch2 and Rac1 enhanced neural stem cell differentiation. Conclusions: This study demonstrated the importance of Rac1 regulation of Notch2 in mediating cerebral IR-induced production of injurious reactive oxygen species and cell death in vitro and in vivo in the short term. Targeted inhibition of Rac1 or Notch2 is new avenue for in vivo therapy aimed at protecting organs at risk from IR injury.