Model Of Reperfusion Injury Research Articles

Effect and Mechanism of Portal Blood Stasis Removal on Intestinal Endotoxemia and Hepatic Ischemia Reperfusion Injury

ObjectiveWe used a rabbit model of hepatic ischemia reperfusion in situ to observe the change of portal venous endotoxin level before reperfusion, and the effect of portal blood stasis removal on intestinal endotoxemia and hepatic ischemia reperfusion injury. The purpose was to find an ideal method for portal blood stasis removal and provide the experimental proof for clinical application of hepatectomy. Methods and MaterialsTo investigate the effect of portal blood stasis removal on intestinal endotoxemia and hepatic ischemia reperfusion injury, a rabbit hepatic ischemia reperfusion injury model was established and treated with removal of portal blood stasis before the portal blood circulation was resumed. Serum endotoxin content, alanine aminotransferase (ALT), hyaluronic acid (HA), and content of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD) and activation of nuclear factor-κB (NF-κB) in liver tissue were examined respectively. ResultsIn portal blood stasis the level of serum endotoxin significantly decreased with each 2.5 mL blood removal (P < .01), subsequently reaching a minima at the 7.5 mL blood removal (P > .05). Removing portal blood stasis ameliorated endotoxemia and hepatic ischemia reperfusion injury as shown by ALT, HA, MDA, SOD, TNF-α, IL-6, and activation of NF-κB compared to no removal. The first 5 mL portal blood stasis contains high volume of endotoxin which may be responsible for hepatic reperfusion injury. ConclusionRemoval of portal blood stasis before the resume of splanchnic circulation may ameliorate intestinal endotoxemia and hepatic ischemia reperfusion injury.

Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery.

Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases.

The cardioprotective effect of salidroside against myocardial ischemia reperfusion injury in rats by inhibiting apoptosis and inflammation

The main purpose of this study was to investigate effect of salidroside (Sal) on myocardial ischemia reperfusion injury in rats and the underlying mechanism. Myocardial ischemia reperfusion injury (MI/RI) model was treated with 30min of left anterior descending (LAD) occlusion followed by 24h of reperfusion. The male Sprague-Dawley rats were randomly divided into 7 groups: (1) Sham; (2) Sham+diltiazem (Dit, 10mg/kg); (3) Sham+Sal (40mg/kg); (4) I/R; (5) I/R+diltiazem (Dit, 10mg/kg); (6) I/R+Sal (20mg/kg); (7) I/R+Sal (40mg/kg). Sal could ameliorate myocardial ischemia reperfusion injury as evidenced by Histopathological examination and triphenyl tetrazolium chloride (TTC) staining. Moreover, terminal deoxynucleotidyl transferase dUTP nickend labeling (TUNEL) assay demonstrated that Sal suppressed myocardial apoptosis, which may be related to up-regulation of Bcl-2/Bax ratio and inhibition of caspase-3, caspase-9 activation. Pretreatment with Sal affected serum biochemical parameters and cardiac dysfunction compared with I/R group. Sal also attenuated the pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 in serum by inhibiting TLR4/NF-κB signaling pathway. Sal exerts strong favorable cardioprotective function on myocardial I/R injury which may relate to the down-regulation of the TLR4/NF-κB signaling pathway and the inhibition of cell apoptosis.

Transplantation of induced pluripotent stem cell-derived renal stem cells improved acute kidney injury.

BackgroundAcute kidney injury (AKI) is a severe disease with high morbidity and mortality. Methods that promote repair of the injured kidney have been extensively investigated. Cell-based therapy with mesenchymal stem cells or renal progenitor cells (RPCs) resident in the kidney has appeared to be an effective strategy for the treatment of AKI. Embryonic stem cells or induced pluripotent stem cells (iPSCs) are also utilized for AKI recovery. However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.MethodsIn this study, we induced iPSCs differentiation into RPCs using a nephrogenic cocktail of factors combined with the renal epithelial cell growth medium. We then established the rat ischemia–reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel. Next, we examined the renal function-related markers and renal histology to assess the therapeutic effect of the injected cells. Moreover, we investigated the mechanism by which iPSC-derived RPCs affect AKI caused by IR.ResultsWe showed that the differentiation efficiency of iPSCs to RPCs increased when cultured with renal epithelial cell growth medium after stimulation with a nephrogenic cocktail of factors. The transplantation of iPSC-derived RPCs decreased the levels of biomarkers indicative of renal injury and attenuated the necrosis and apoptosis of renal tissues, but resulted in the up-regulation of renal tubules formation, cell proliferation, and the expression of pro-renal factors.ConclusionOur results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-015-0040-z) contains supplementary material, which is available to authorized users.

Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury

Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood–brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression.

The effects of pentobarbital, ketamine-pentobarbital and ketamine-xylazine anesthesia in a rat myocardial ischemic reperfusion injury model.

To achieve reliable experimental data, the side-effects of anesthetics should be eliminated. Since anesthetics exert a variety of effects on hemodynamic data and incidence of arrhythmias, the selection of anesthetic agents in a myocardial ischemic reperfusion injury model is very important. The present study was performed to compare hemodynamic variables, the incidence of ventricular arrhythmias, and infarct size during 30 min of ischemia and 120 min of reperfusion in rats using pentobarbital, ketamine-pentobarbital or ketamine-xylazine anaesthesia. A total of 30 rats were randomly divided into three groups. In group P, pentobarbital (60 mg/kg, intraperitoneally [IP]) was used solely; in group K-P, ketamine and pentobarbital (50 and 30 mg/kg, respectively, IP) were used in combination; and in group K-X, ketamine and xylazine (75 and 5 mg/kg, respectively, IP) were also used in combination. Hemodynamic data and occurrence of ventricular arrhythmias were recorded throughout the experiments. The ischemic area was measured by triphenyltetrazolium chloride staining. The combination of ketamine-xylazine caused bradycardia and hypotension. The greatest reduction in mean arterial blood pressure during ischemia was in the P group. The most stability in hemodynamic parameters during ischemia and reperfusion was in the K-P group. The infarct size was significantly less in the K-X group. Whereas none of the rats anesthetized with ketamine-xylazine fibrillated during ischemia, ventricular fibrillation occurred in 57% of the animals anesthetized with pentobarbital or ketamine-pentobarbital. Because it offers the most stable hemodynamic parameters, it is concluded that the ketamine-pentobarbital anesthesia combination is the best anesthesia in a rat ischemia reperfusion injury model.

Effects of electroacupuncture on angiogenesis after ischemia and reperfusion

Objective To explore the effect of eletroacupuncture (EA) on angiogenesis after cerebral ischemia and reperfusion through observing the number of peripheral blood endothelial progenitor cells (EPCs) and the expression of vascular endothelial growth factor (VEGF) in the hippocampus. Methods Among 50 male Sprague-Dawley (SD) rats, 10 were randomly selected as a control group (CG). Qi deficiency and blood stasis were induced in the other 40 rats by intragastric administration of dahuang daily for 7 days. A model of focal cerebral ischemia and reperfusion injury was then created by thread-occlusion of the middle cerebral artery, except in 10 rats selected for the sham operation group (SOG) who received the same operation without tightening the thread. The successfully modeled rats were divided into a model group (MG, n=10) and an electroacupuncture group (EAG, n=10). The rats in EAG started acupuncture treatment the next day after modeling, while no treatment was given to those in the other groups. On day 1, 3 and 7 after the modeling, the neurological functioning of the 4 groups was assessed using Basso-Beattie-Bresnahan locomotion scoring and the number of EPCs in the peripheral circulation was detected by flow cytometry. On the 8th day, all the rats were decapitated and the VEGF expression was detected immunohistochemically. Results The average BBB locomotion score of the EAG rose significantly from (4.50±1.05) on day 1, to (13.67±1.21) on day 3, and then further to (20.00±0.89) by day 7, significantly higher than that of MG at the same time points, but still significantly lower than that of the control group. The average number of EPCs in the peripheral circulation in the MG also increased from (26.83±6.05) on day 1 to (33.67±5.39) on day 3, and decreased to (32.83±5.04) on day 7 after modeling, significantly lower than that of the CG [(45.50±9.40), (42.17±4.62) and (41.33±5.50)], the SOG [(58.00±8.05), (59.67±4.84) and (53.83±5.38)] and the EAG [(66.17±4.36), (127.50±73.75) and (55.00±35.15)] at each time point. After occlusion, the average expression of VEGF-positive cells in the hippocampus of the EAG [(27.80±2.39)%] was significantly higher than that of the MG, and both were significantly higher than that of the CG. Conclusions Eletroacupuncture can up-regulate VEGF expression and EPCs in the peripheral blood in rats after cerebral ischemia-reperfusion, which can promote angiogenesis and neural functional recovery. Key words: Eletroacupuncture; Brain; Ischemia; Endothelial growth factors; Endothelial progenitor cells

Cardiac MRI detection of infarct size reduction with hypothermia in porcine ischemia reperfusion injury model

Background Hypothermia has been shown to provide cardiac protection after a STEMI insult in prior animal and post-hoc human studies. However, the influence of pre-reperfusion temperature on myocardial infarct size is not fully characterized. We employed cardiac MRI to determine the impact of moderate hypothermia (32C) upon infarct size in a porcine ischemia-reperfusion injury (IR) model using an endovascular cooling catheter. Methods

Argon: a novel therapeutic option to treat neuronal ischemia and reperfusion injuries?

Neuronal injury and neuroprotection: Ischemia and reperfusion injuries in neuronal cells such as acute ischemic stroke - represent the third leading cause of death in the world. Current therapeutic concepts mainly aim to re-establish cerebral blood flow within a time window of less than 3 hours with the goal of limiting secondary brain injury. Secondary brain injury of the “penumbra” develops exponentially, causing severe mental and physical disabilities. The resulting morbidity and mortality in patients of all ages leads to an enormous economic burden. Neurons are well-known to possess a limited potential to recover and regenerate their basic function once damaged. Therefore the protection and especially the therapy of neuronal injuries in cells and organ systems has emerged as a major focus of research in recent years. The aim is to maximize neuronal function not only by restoring sufficient blood flow to the areas at risk, but also by protecting neuronal cells with various novel interventions. Many of these interventions, such as intravascular cooling, focus on the reduction of neuronal metabolism in an effort to induce protection.

Ischemic Postconditioning and Subanesthetic S(+)-Ketamine Infusion: Effects on Renal Function and Histology in Rats.

Background. Ischemic postconditioning (IP) in renal Ischemia reperfusion injury (IRI) models improves renal function after IRI. Ketamine affords significant benefits against IRI-induced acute kidney injury (AKI). The present study investigated the effects of IP and IP associated with subanesthetic S(+)-ketamine in ischemia-reperfusion-induced AKI. Methods. Forty-one Wistar rats were randomized into four groups: CG (10), control; KG (10), S(+)-ketamine infusion; IPG (10), IP; and KIPG (11), S(+)-ketamine infusion + IP. All rats underwent right nephrectomy. IRI and IP were induced only in IPG and KIPG by left kidney arterial occlusion for 30 min followed by reperfusion for 24 h. Complete reperfusion was preceded by three cycles of 2 min of reocclusion followed by 2 min of reperfusion. Renal function was assessed by measuring serum neutrophil gelatinase-associated lipocalin (NGAL), creatinine, and blood urea nitrogen (BUN). Tubular damage was evaluated by renal histology. Results. Creatinine and BUN were significantly increased. Severe tubular injury was only observed in the groups with IRI (IPG and KIPG), whereas no injury was observed in CG or KG. No significant differences were detected between IPG and KIPG. Conclusions. No synergic effect of the use of subanesthetic S(+)-ketamine and IP on AKI was observed in this rat model.

Lipocalin-2 promotes m1 macrophages polarization in a mouse cardiac ischaemia-reperfusion injury model.

Ischaemia-reperfusion (IR) injury is a major issue in cardiac transplantation. Inflammatory processes play a major role in myocardial IR injury. Lipocalin-2 (Lcn2), which is also known as neutrophil gelatinase-associated lipocalin, has multiple functions that include the regulation of cell death/survival, cell migration/invasion, cell differentiation and iron delivery. In our study, the hearts of C57BL/6 mice were flushed with and stored in cold Bretschneider solution for 8h and then transplanted into a syngeneic recipient. We found that Lcn2 neutralization decreased the recruitment of neutrophils and macrophages. Troponin T (TnT) production, 24h after myocardial IR injury, was reduced through anti-Lcn2 antibody administration. The cardiac output at 60mmHg of afterload pressure was significantly increased in hearts administrated with anti-Lcn2 antibody administration (anti-Lcn-2: 58.9±5.62ml/min; control: 25.8±4.1ml/min; P<0.05). Anti-Lcn2 antibody treatment suppressed M1 marker (IL-12, IL-23 and iNOS) expression but increased M2 marker (IL-10, Arg1 and Mrc1) expression. Furthermore, in our vitro and vivo experiments, we found that anti-Lcn2 antibody treatment failed to induce M1-related gene expression in response to LPS and that Lcn2 neutralization enhanced the expression of M2-related genes following IL-4 treatment. In conclusion, Lcn2 promotes M1 polarization, and Lcn2 neutralization attenuates cardiac IR injury.

Cardioprotection of recombinant human MG53 protein in a porcine model of ischemia and reperfusion injury

Ischemic heart disease is a leading cause of death in human population and protection of myocardial infarction (MI) associated with ischemia–reperfusion (I/R) remains a challenge. MG53 is an essential component of the cell membrane repair machinery that protects injury to the myocardium. We investigated the therapeutic value of using the recombinant human MG53 (rhMG53) protein for treatment of MI. Using Langendorff perfusion of isolated mouse heart, we found that I/R caused injury to cardiomyocytes and release of endogenous MG53 into the extracellular solution. rhMG53 protein was applied to the perfusion solution concentrated at injury sites on cardiomyocytes to facilitate cardioprotection. With rodent models of I/R-induced MI, we established the in vivo dosing range for rhMG53 in cardioprotection. Using a porcine model of angioplasty-induced MI, the cardioprotective effect of rhMG53 was evaluated. Intravenous administration of rhMG53, either prior to or post-ischemia, reduced infarct size and troponin I release in the porcine model when examined at 24h post-reperfusion. Echocardiogram and histological analyses revealed that the protective effects of rhMG53 observed following acute MI led to long-term improvement in cardiac structure and function in the porcine model when examined at 4weeks post-operation. Our study supports the concept that rhMG53 could have potential therapeutic value for treatment of MI in human patients with ischemic heart diseases.

A murine model of lung ischemia and reperfusion injury: tricks of the trade

BackgroundPulmonary ischemia–reperfusion injury (IRI) causes postoperative morbidity in patients undergoing lung transplantation, isolated lung perfusion, and cardiopulmonary bypass and may lead to potentially lethal pathologies such as respiratory shock. In-depth study of this pathology requires a reliable animal model. Mice are a popular species to develop experimental models because of their logistic advantages and the availability of knock outs. However, their small size warrants microsurgical techniques and a skilled surgeon. Materials and methodsWe developed a murine model of pulmonary anoxic IRI through hilar clamping using adult female Swiss mice. After left thoracotomy, we expose the pulmonary hilum keeping the ribs and the muscles of back and forepaw intact. A microvascular clamp is placed over the entire hilum, occluding bronchus, pulmonary artery, and vein. ResultsOur model proved to be simple, reliable, and reproducible, showing minimal preoperative and postoperative mortality. Histopathologic analysis indicated all characteristic features of pulmonary IRI, such as an early recruitment of lymphocytes followed by neutrophil influx. ConclusionsThis article presents a murine surgery model for pulmonary IRI based on a muscle-sparing thoracotomy. The minimal approach limits manipulation of lung tissue, minimizing mortality and non–IRI-induced injury.

Homocysteine-induced attenuation of vascular endothelium-dependent hyperalgesia in the rat

We have recently demonstrated a role of the vascular endothelium in peripheral pain mechanism by disrupting endothelial cell function using intravascular administration of octoxynol-9, a non-selective membrane active agent. As an independent test of the role of endothelial cells in pain mechanisms, we evaluated the effect of homocysteine, an agent that damages endothelial cell function. Mechanical stimulus-induced enhancement of endothelin-1 hyperalgesia in the gastrocnemius muscle of the rat was first prevented then enhanced by intravenous administration of homocysteine, but was only inhibited by its precursor, methionine. Both homocysteine and methionine significantly attenuated mechanical hyperalgesia in two models of ergonomic muscle pain, induced by exposure to vibration, and by eccentric exercise, and cutaneous mechanical hyperalgesia in an ischemia–reperfusion injury model of Complex Regional Pain Syndrome type I, all previously shown responsive to octoxynol-9. This study provides independent support for a role of the endothelial cell in pain syndromes thought to have a vascular basis, and suggests that substances that are endothelial cell toxins can enhance vascular pain.

Effective inhibition of cardiomyocyte apoptosis through the combination of trimetazidine and N-acetylcysteine in a rat model of myocardial ischemia and reperfusion injury

Objective: Apoptosis is the early and predominant form of cell death in infarcted myocardia. The aim of the study was to investigate the effects of trimetazidine (TMZ) and N-acetylcysteine (NAC), used alone or in combination, on oxidative stress, infarct size, and ischemia-reperfusion (IR)-induced cardiomyocyte apoptosis in a rat model of myocardial IR. Methods and results: Myocardial IR was established by ligating an area under the left main coronary artery for 30 min followed by 3 h of reperfusion. Saline (1 ml/kg), NAC (50, 150 mg/kg), or TMZ (3, 5 mg/kg) was intravenously injected during the middle of the ischemic period. At the end of the reperfusion, blood samples were collected from the animals to measure serum M30 and M65 levels, which are markers of cell death, the S100b level, which is a marker of inflammation, and the malondialdehyde (MDA) level, which is a marker of oxidative stress. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by caspase-3 immunostaining and a TUNEL assay. TMZ and NAC, either alone or in combination, significantly reduced serum MDA levels, infarct area and apoptotic activity compared to those observed in saline group. Interestingly, the infarct area was more smaller in TMZ (3 and 5 mg/kg) injected groups (9.72 ± 1.3% and 9.96 ± 2.3%) than those observed in NAC (50 and 150 mg/kg) (16.1 ± 2.5% and 19.1 ± 2.14%) or TMZ (5 mg/kg)- NAC (150 mg/kg) combination groups (16.9 ± 1.6%). However, the apoptotic activity was reduced more significantly in the combination of TMZ (5 mg/kg)-NAC (50 mg/kg) compared to TMZ-only group. Neither TMZ or NAC treatments nor the combination of the drugs significantly affected serum M30, M65 and S100B levels. Conclusion: Intravenous NAC and TMZ administration decreased oxidative stress, infarct area and apoptotic activity in a rat model of IR. Although the combination treatment was more effective in reducing the apoptotic activity than either treatment groups alone, TMZ treatment was more successful in reducing the infarct area than NAC or combination treatments. Present results suggest that, in addition to mechanical attempts to secure myocardial reperfusion, the use of TMZ and NAC may help to reduce IR injury.

Nuclear factor erythroid 2-related factor 2 regulates toll-like receptor 4 innate responses in mouse liver ischemia-reperfusion injury through Akt-forkhead box protein O1 signaling network.

Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant host defense, maintains the cellular redox homeostasis. This study was designed to investigate the role and molecular mechanisms by which Nrf2 regulates toll-like receptor (TLR)4-driven inflammation response in a mouse model of hepatic warm ischemia (90 min) and reperfusion (6 hr) injury (IRI). Activation of Nrf2 after preconditioning of wild-type mouse recipients with cobalt protoporphyrin ameliorated liver IRI, evidenced by improved hepatocellular function (serum alanine aminotransferase levels), and preserved tissue architecture (histology Suzuki's score). In marked contrast, ablation of Nrf2 signaling exacerbated IR-induced liver inflammation and damage in Nrf2 knockout hosts irrespective of adjunctive cobalt protoporphyrin treatment. The Nrf2 activation reduced macrophage and neutrophil trafficking, proinflammatory cytokine programs, and hepatocellular necrosis or apoptosis while increasing antiapoptotic functions in IR-stressed livers. At the molecular level, Nrf2 activation augmented heme oxygenase-1 expression and Stat3 phosphorylation and promoted PI3K-Akt while suppressing forkhead box O (Foxo)1 signaling. In contrast, Nrf2 deficiency diminished PI3K-Akt and enhanced Foxo1 expression in the ischemic livers. In parallel in vitro studies, Nrf2 knockdown in lipopolysaccharide-stimulated bone marrow-stimulated bone marrow-derived macrophages (BMMs) decreased heme oxygenase-1 and PI3K-Akt yet increased Foxo1 transcription, leading to enhanced expression of TLR4 proinflammatory mediators. Moreover, pretreatment of bone marrow-derived macrophages with PI3K inhibitor (LY294002) activated Foxo1 signaling, which in turn enhanced TLR4-driven innate responses in vitro. Activation of Nrf2 promoted PI3K-Akt, and inhibited Foxo1 activity in IR-triggered local inflammation response. By identifying a novel integrated Nrf2-Akt-Foxo1 signaling network in PI3K-dependent regulation of TLR4-driven innate immune activation, this study provides the rationale for refined therapeutic approaches to manage liver inflammation and IRI in transplant recipients.

Protective effects of Acanthopanax polysaccharides on cerebral ischemia–reperfusion injury and its mechanisms

A kind of Acanthopanax polysaccharides extracted from the root of Acanthioanax senticosus was named CASPs. The protective effect of CASPs on the cerebral ischemia–reperfusion injury was observed and the underlying mechanism was explored. Wistar male rats were randomly divided into six groups, namely, sham-operated group, model group, nimodipine group (15mg/kg/day) and CASPs groups (50, 100 and 200mg/kg/day). The suture method was used to embolize the middle cerebral artery to establish a rat cerebral ischemia–reperfusion injury model. On day 15 before the surgery, the intragastric administration of agents started once daily. The results confirmed that the CASPs could improve the symptoms of rats with the cerebral ischemia–reperfusion injury, and reduce the brain infarct volume and brain water content. In addition, CASPs could elevate SOD and GSH-Px activities and IL-10 levels, and reduce MDA, IL-1β and TNF-α levels in the brain tissue of rats with the cerebral ischemia–reperfusion injury. The results indicate that CASPs can play a certain protective role in the cerebral ischemia–reperfusion injury, and the protective effect may be related to the improvement of CASPs on the antioxidant capacity of brain tissue and the inhibition of overproduction of inflammatory cytokines.

Picroside II decreases the development of fibrosis induced by ischemia/reperfusion injury in rats

In kidney transplantation, renal ischemia and reperfusion injury was one of the leading factors to the development of renal fibrosis, which was the main cause of graft loss. The fibrogenic changes were associated with the long term inflammation elicited by ischemia and reperfusion injury. In the present study, we investigated the role of the Picroside II, the main active constituents of the extract of picrorrhiza scrophulariiflora roots, in attenuating renal fibrosis in a renal ischemia and reperfusion injury model. We induced ischemia and reperfusion injury in kidneys treated with or without Picroside II. We observed that inflammation and tissue fibrosis were increased in ischemia and reperfusion injury group compared to Picroside II group, however, these changes were significantly decreased by the treatment with Picroside II. We concluded that Picroside II can protect the ischemic kidney against renal fibrosis and its mechanism may be through the inhibition of the long term inflammation.

Study on attenuate and synergistic mechanism between Aconiti Lateralis Praeparata Radix and Glycyrrhizae Radix for toxicity reduction based on metabonomic of MI-RI mouse cardiomyocytes

Sini decoction (SND), a classical traditional Chinese medicine emergency formula recorded in Shanghan Lun (Treatise on Febrile Diseases), which is composed of Aconiti Lateralis Preparata Radix, Glycyrrhizae Preparata Radix and Zingiberis Rhizoma. Modern clinical and pharmacological researches have shown that SND can protect the myocardium effectively during myocardial ischemia reperfusion injury (MI-RI). A myocardial ischemia reperfusion injury model of H9c2 cardiomyocytes in vitro has been established. Four groups, control group, MI-RI Model group, SND group and SND without Glycyrrhizae Radix group, were arranged. The livability, the level of LDH and CK activity in H9c2 cardiomyocytes in different groups were tested. By combining with principal components analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares projection of latent structures-discriminant analysis (OPLS-DA), 17 biomarkers in extracellular fluid were identified and 15 of them were related to the pathway of biological processes. The results showed that the attenuate and synergistic mechanism between Aconiti Lateralis Praeparata Radix and Glycyrrhizae Radix for toxicity reduction was related with the glycolysis, lipid metabolism, citrate cycle and nitrogen metabolism of amino acids metabolism. The study proved the effect on H9c2 cardiomyocyte treated by MI-RI injury both SND group and SND without Glycyrrhizae Radix group, and compared with the SND without Glycyrrhizae Radix, the protective effect of myocardial ischemia reperfusion injury model of H9c2 cardiomyocyte from SND was stronger.

Self-navigated low-rank MRI for MPIO-labeled immune cell imaging of the heart.

Super-paramagnetic iron oxide (SPIO) particles can magnetically label immune cells in circulation; the accumulation of labeled cells can then be detected by magnetic resonance imaging (MRI). This has enormous potential for imaging inflammatory responses in the heart, but it has been difficult to do in vivo using conventional free-breathing, ungated cardiac imaging. Subspace imaging with temporal navigation and sparse sampling of (k, t)-space has previously been used to accelerate several cardiac imaging applications, conventionally alternating between acquiring navigator data and sparse data every other TR. Here we describe a more efficient self-navigated pulse sequence to acquire both navigator and sparse (k, t)-space data in the space of a single TR, doubling imaging speed to approach 100 frames per second (fps). We show the feasibility of using the resulting method to assess myocardial inflammation in a pre-clinical rodent ischemic reperfusion injury (IRI) model using micron-sized paramagnetic iron oxide (MPIO) particles to label immune cells in situ.