Rat Model Of Ischemia-reperfusion Injury Research Articles

Protective effects of rosiglitazone on hepatic ischemia reperfusion injury in rats

To explore the protective effect of rosiglitazone (RGZ) on hepatic ischemia reperfusion injury (HIRI) and the underlying mechanisms. Methods: A rat model of ischemia-reperfusion injury was established by clamping the left and middle lobe of liver with noninvasive vascular clamp. A total of 30 Sprague-Dawley rats were randomly divided into a sham group, an HIRI group, and a RGZ group (10 rats in each group). Two hours after reperfusion, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, lactate dehydrogenase (LDH) level, malondialdehyde (MDA) content and catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were examined. HE staining was used to observe liver pathological morphology. The liver peroxisome proliferators-activated receptor γ (PPAR-γ), p-PPAR-γ, nuclear factor related factor 2 (Nrf-2), antioxidant response element (ARE), heme oxygenase 1 (HO-1) and quinone oxidoreductase-1 (NQO-1) were detected by Western blot. Results: Compared with the HIRI group, the levels of ALT, AST, LDH and MDA in the RGZ group were significantly decreased (all P<0.05), while the levels of Nrf-2, ARE, HO-1 and NQO-1 in the RGZ group were significantly increased. The hepatic swelling, necrosis and pathological damage were decreased (all P<0.05). In addition, there was no difference in the level of PPAR-γ between the 2 groups (P>0.05). Conclusion: PPAR-γ agonist RGZ can attenuate HIRI, which may be related to activating Nrf2/ARE signaling pathway and enhancement of antioxidant ability.

Human Urine-Derived Stem Cells could Protect Renal Function by Releasing miR-129-5p which Targets High-Mobility Group box-1 (HMGB1) in Rat Ischemia Reperfusion Injury Model

Human Urine-Derived Stem Cells could Protect Renal Function by Releasing miR-129-5p which Targets High-Mobility Group box-1 (HMGB1) in Rat Ischemia Reperfusion Injury Model

Comparison between iloprost and alprostadil for protection against ischemia/reperfusion injury in a rat model

Background/aim: Alprostadil and iloprost are successful agents used for both pulmonary hypertension and extremity ischemia treatment. Different systemic effects of these agents may change the preferences of clinical usage. Superiority of preventing ischemia/ reperfusion (IR) injury is a criterion for clinical preference of these agents. The present study was designed to compare the protective effects of alprostadil and iloprost in a rat model of IR injury. Materials and methods: Twenty-three male Sprague Dawley rats were used (aged 8-12 weeks, mean weight 230 ± 30 g). They were randomized into 4 groups: Group 1 (iloprost + IR), Group 2 (alprostadil + IR), Group 3 (saline + IR), and Group 4 (control). Under general anesthesia, in all groups except Group 4, the abdominal region was explored and the abdominal aorta was temporarily clamped for 60 min. After the clamp was removed, 120 min of reperfusion was applied. In Group 4, the rats were placed under general anesthesia and abdominal exploration was performed without the IR procedure. For all rats, body temperature was kept at 36 °C with a heater pad through the whole procedure. The rats were euthanized under general anesthesia to remove the kidneys and lungs for study. Histopathological and biochemical analyses were conducted with kidney and lung tissues. Histopathological scoring was done by analyzing cellular damage at tissue level. Malondialdehyde (MDA), superoxide dismutase, and glutathione levels were studied for biochemical analysis. Results: Histopathologic analysis showed that, as compared with alprostadil, iloprost provided a significantly higher level of renal protection against IR injury (P < 0.01). Renal tissue levels of MDA were significantly lower in the alprostadil group as compared to Group 3 (P < 0.05). Conclusion: Alprostadil and iloprost seem to provide protection against IR injury, with iloprost being more protective in renal tissue. Alprostadil is more effective than iloprost in protecting lung tissue against IR injury.

Renoprotective Effects of Artesunate against Renal Ischemia-Reperfusion Injury in Rat Model

Renal ischemia-reperfusion (Renal I/R) leads to acute kidney injury (AKI),a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models,both in vitro and in vivo,have been used to study the pathogenic mechanisms of ischemic AKI and to test reno-protective strategies. Aim: To study potential protective effects of artesunate on renal I/R injury. Renal I/R injury was unilaterally induced in adult (3 to 5 months) male Sprague-Dawely rats,whose weights ranged from 180 to 390 g. Thereafter,the animals were pre-treated with artesunate intra-peritoneally,and at the end of reperfusion sacrificed humanely. Plasma,serum and tissue samples were obtained for analysis. Plasma concentrations of NGAL (neutrophil gelatinase associated lipocalin),an iron-trafficking protein involved in multiple processes such as apoptosis,innate immunity and renal development,and tissue concentrations of IL-18 (Interleukin-18) were measured via ELISA analysis. Serum urea and creatinine were also measured in the samples. Artesunate improved renal ischemia reperfusion,including renal function and brought about reductions in inflammatory mediators and kidney tissue injury. Plasma concentrations of NGAL and tissue concentrations of IL-18 were significantly (p &lt; 0.05) lower in the artesunatepretreated group than in the vehicle and control groups. Furthermore,serum concentrations of urea and creatinine were significantly (p &lt; 0.05) decreased in the pretreated group as compared to the control group. Artesunate can significantly improve renal function following I/R through down-regulation of inflammatory parameters and NGAL expression. Furthermore,it could serve as a potential therapy in ischemia reperfusion-induced acute kidney injury.

Protective effects of Epigallocatechin gallate on liver ischemia reperfusion injury in rats

Objective To investigate the protective roles of Epigallocatechin gallate (EGCG) on li-ver ischemia reperfusion injury (IRI) in rats. Methods 30 healthy male SD rats were selected and equally and randomly divided into 3 groups. Sham group, IRI group and IRI-EGCG group were established to construct 70% liver IRI rat model. Drinking water with 0.4 mg/ml EGCG was administered for 2 weeks before the experiment in IRI-EGCG group. HE staining was performed to evaluate the injury. Transaminases in serum were investigated to assess liver injury. p-p85 and p-AKT was detected by Western-blot assay. qPCR was carried out to study the mRNA expression of TNF-α, IL-6 and IL-1β in liver tissue. The secretion of TNF-α, IL-6 and IL-1β in serum was examined with ELISA assay. Results EGCG pretreatment reduced AST and ALT in serum [AST: (550.0±66.5) IU/L vs. (220.0±63.5) IU/L; ALT: (376.0±25.7) IU/L vs. (158.0±33.1) IU/L, all P<0.05] and mitigated liver tissue damage. p-p85 and p-AKT increased due to liver IRI, and IRI-EGCG group showed higher expression of p85 and AKT. The proinflammatory cytokines of TNF-α, IL-6 and IL-1β exhibited a relatively lower mRNA expression in IRI-EGCG group comparing with IRI group. IRI-EGCG group also revealed a decreased secretion of TNF-α, IL-6 and IL-1β in serum [TNF-α: (398.0±33.4) ng/L vs. (211.0±23.6) ng/L; IL-6: (341.0±27.3) ng/L vs. (187.0±19.6) ng/L; IL-1β: (486.0±43.7) ng/L vs. (352.0±31.5) ng/L; all P<0.05]. Conclusion EGCG pretreatment can enhance IRI-induced activation of PI3K/AKT signaling and reduce the release of proinflammatory cytokines to exert liver protective effects. Key words: Liver; Ischemia reperfusion injury (IRI); Epigallocatechin gallate (EGCG); Signal transduction, PI3K/AKT; Inflammatory cytokine

Protective effects of N(2)‑L‑alanyl‑L‑glutamine mediated by the JAK2/STAT3 signaling pathway on myocardial ischemia reperfusion.

To explore the protective effect of N(2)-L-alanyl-L-glutamine (NLAG) on myocardial ischemia-reperfusion injury (IRI), and observe the influence of NLAG on the Janus activated kinase signal transducer 2 and activator of transcription 3 (JAK2/STAT3) signaling pathway-associated molecules. Wistar rats were randomly divided into three groups: Sham, IRI and NLAG. In the IRI rat model, the cardiac hemodynamics, the maximum rate of left ventricular pressure (+dP/dtmax) and the left ventricular end-diastolic pressure (LVDP) were recorded. Hematoxylin-eosin and Masson staining were used to detect myocardial histological changes. The levels of plasma interleukin (IL)-1β and −6, tumor necrosis factor (TNF)-α, lactase dehydrogenase (LDH), troponin (cTn)I, creatine kinase (CK), heart type fatty acid binding protein (hFABP), malondialdehyde (MDA) and succinate dehydrogenase (SDH) were determined with ELISA. The protein expression levels of B-cell lymphoma (Bcl)-2, Bcl2-associated X protein (Bax), Caspase-3, JAK2, phosphorylated (p)-JAK2, STAT3 and p-STAT3 were detected by western blot analysis. The IRI model demonstrated notable myocardial injury; myocardial cells were arranged disorderly with some nuclei disappearing, and cardiac muscular fibers were degenerated. Following 60 min of reperfusion, LVDP, HR and +dP/dtmax were 31.3±4.53 mmHg, 239.17±8.45 beats/min and 615.17 mmHg/sec, respectively. Compared with the Sham group, the levels of LDH, cTnI, CK, hFABP release, inflammatory factors (IL-1β, IL-6 and TNF-α) and oxygen free radical (MDA and SDH) levels were increased in the IRI group. In the NLAG group, myocardial injury was improved, the concentrations of LDH, cTnI, CK, hFABP, IL-1β, IL-6, TNF-α, MDA were decreased, and SDH release was increased compared with the IRI group. In addition, NLAG significantly increased Bcl-2, JAK2, p-JAK2, STAT3 and p-STAT3 protein expression, and decreased Bax protein expression compared with the IRI group. In conclusion, myocardial ischemia-reperfusion can lead to myocardial cell apoptosis and myocardial injury and NLAG attenuates the IRI-induced mitochondrial oxidative stress injury and apoptosis by activating the JAK2/STAT3 signaling pathway, thus exerting protective effects against IRI.

Ziziphora clinopodioides Flavonoids Protect Myocardial Cell Damage from Myocardial Ischemia-Reperfusion Injury.

To investigate effects of Ziziphora clinopodioides Lam. flavonoids on ischemia-reperfusion injury of myocardial cells. After application of 6.25, 25, and 100 μg/mL Ziziphora clinopodioides Lam. flavonoids to H9C2 myocardial cells for 24H, they were treated for 4 hours with hydrogen peroxide to induce oxidative damage, whereas controls were cells without treatment and cells only incubated with hydrogen peroxide. Cell viability, lactate dehydrogenase release and mitochondrial membrane potential, intracellular Na+/K+-ATPase activity and ATP content, and reactive oxygen species formation were monitored. An ischemia-reperfusion injury rat model was established by left anterior descending coronary artery ligature in 48 Sprague-Dawley rats, which were divided into positive control with isosorbide mononitrate (10 mg/kg) injection (n=8), model (ischemia-reperfusion, n=8), sham-operated (n=8), and Ziziphora clinopodioides Lam. flavonoids low (75 mg/kg, n=8), medium (150 mg/kg, n=8), and high concentration (300 mg/kg, n=8) groups. Superoxide dismutase activity and malondialdehyde content in homogenized hearts were measured and ischemic and infarction areas were triphenyl tetrazolium chloride and H&E stained for pathological and morphological examinations. Ziziphora clinopodioides Lam. flavonoids preconditioning improved cell viability (P<0.01), intracellular Na/K ATPase activity (P<0.001), and intracellular ATP content (P<0.001) and maintained mitochondrial membrane potential (P<0.05) in hydrogen peroxide treated H9C2 cells as well as rescued superoxide dismutase activity (P<0.01), decreased the malondialdehyde content (P<0.001), and reduced myocardial damage in the ischemia-reperfusion rat model (P<0.001) compared to the controls. Ziziphora clinopodioides Lam. flavonoids may be an effective drug for protecting myocardial tissue from ischemia-reperfusion injury by reducing reactive oxygen species related damage.

Extracellular Vesicles Derived from Hypoxic Human Mesenchymal Stem Cells Attenuate GSK3β Expression via miRNA-26a in an Ischemia-Reperfusion Injury Model.

PurposeBioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotective effects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effects of EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs).Materials and MethodsEV solutions (0.4 µg/µL) derived from normoxia-preconditioned MSCs (EVNM) and hypoxia-preconditioned MSCs (EVHM) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26 staining in hearts from EV-treated rats.ResultsEVHM significantly reduced infarct size (24±2% vs. 8±1%, p<0.001), and diminished arrhythmias by recovering electrical conduction, INa current, and Cx43 expression. EVHM also reversed reductions in Wnt1 and β-catenin levels and increases in GSK3β induced after IR injury. miRNA-26a was significantly increased in EVHM, compared with EVNM, in real-time PCR. Finally, in in vitro experiments, hypoxia-induced increases in GSK3β expression were significantly reduced by the overexpression of miRNA-26a.ConclusionEVHM reduced IR injury by suppressing GSK3β expression via miRNA-26a and increased Cx43 expression. These findings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway.

Unilateral nephrectomy diminishes ischemic acute kidney injury through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses.

While unilateral nephrectomy (UNx) is suggested to protect against ischemia-reperfusion injury (IRI) in the remaining kidney, the mechanisms underlying this protection remain to be elucidated. In this study, functional MRI was employed in a renal IRI rat model to reveal global and regional changes in renal filtration, perfusion, oxygenation and sodium handling, and microarray and pathway analyses were conducted to identify protective molecular mechanisms. Wistar rats were randomized to either UNx or sham UNx immediately prior to 37 minutes of unilateral renal artery clamping or sham operation under sevoflurane anesthesia. MRI was performed 24 hours after reperfusion. Blood and renal tissue were harvested. RNA was isolated for microarray analysis and QPCR validation of gene expression results. The perfusion (T1 value) was significantly enhanced in the medulla of the post-ischemic kidney following UNx. UNx decreased the expression of fibrogenic genes, i.a. Col1a1, Fn1 and Tgfb1 in the post-ischemic kidney. This was associated with a marked decrease in markers of activated myofibroblasts (Acta2/α-Sma and Cdh11) and macrophages (Ccr2). This was most likely facilitated by down-regulation of Pdgfra, thus inhibiting pericyte-myofibroblast differentiation, chemokine production (Ccl2/Mcp1) and macrophage infiltration. UNx reduced ischemic histopathologic injury. UNx may exert renoprotective effects against IRI through increased perfusion in the renal medulla and alleviation of the acute pro-inflammatory and pro-fibrotic responses possibly through decreased myofibroblast activation. The identified pathways involved may serve as potential therapeutic targets and should be taken into account in experimental models of IRI.

MAPK pathway mediates the anti-oxidative effect of chicoric acid against cerebral ischemia-reperfusion injury in vivo.

The aim of the present study was to investigate the protective effect of chicoric acid on oxidative stress and inflammation in rats with cerebral ischemia-reperfusion injury. A cerebral ischemia-reperfusion injury rat model was created via transient middle cerebral artery occlusion (MCAO) and rats were treated with various doses of chicoric acid (0, 1, 10 and 100 mg/kg). Neurological deficits and infarct volume were used to estimate the protective effects of chicoric acid treatment. Levels of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, nitric oxide (NO) and prostaglandin E2 (PGE2) were assessed. Western blot analysis was also used to measure the expression of cyclooxygenase (COX)-2, p38-mitogen activated protein kinase (MAPK), c-Jun, phosphorylated protein kinase B (p-AKT) and AKT. Chicoric acid exposure was observed to reduce neurological deficits and infarct volume in rats with cerebral ischemia-reperfusion injury. In addition, ROS production and inflammation were significantly suppressed following treatment with chicoric acid. Chicoric acid was demonstrated to significantly inhibit the upregulation of NO and PGE2 levels in rats following MCAO. Furthermore, chicoric acid significantly suppressed the MCAO-induced promotion of COX-2, p38-MAPK and c-Jun protein expression and enhanced the inhibition of p-AKT/AKT. These results suggest that chicoric acid has a protective effect, preventing oxidative stress and inflammation in rats with cerebral ischemia-reperfusion injury via the p38-MAPK, c-Jun and AKT signaling pathways.

Protective Effects of Resveratrol in a Rat Model of Ischemia-Reperfusion Injury of Sciatic Nerve

Objective: The aim of this study was to determine the effects of resveratrol on ischemia- reperfusion (I/R) injury in the rats sciatic nerve. Methods: We used 18 Wistar rats anesthetized with ketamine (50 mg/kg-im). In the sham group, we only performed the surgery and not administer any medication. In the ischemia group, we generated I/R injury in 5 minute intervals with medical treatment of saline only. In the resveratrol group, we brought about the same I/R injury but gave resveratrol before the surgery by per oral. After sacrifice, we studied blood and nerve tissue samples. We evaluated the damage with malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), both in tissue and blood. Results: Evaluation of serum levels of antioxidant markers and tissue samples demonstrated statistically significant effects of resveratrol in ischemia-reperfusion injury. Conclusion: This study revealed the antioxidant effect of resveratrol as an inhibitor of lipid peroxidation.

Pharmacological modulation of C-X-C motif chemokine receptor 4 influences development of acute respiratory distress syndrome after lung ischaemia-reperfusion injury.

Activation of C-X-C motif chemokine receptor 4 (CXCR4) has been reported to result in lung protective effects in various experimental models. The effects of pharmacological CXCR4 modulation on the development of acute respiratory distress syndrome (ARDS) after lung injury, however, are unknown. Thus, we studied whether blockade and activation of CXCR4 influences development of ARDS in a unilateral lung ischaemia-reperfusion injury rat model. Anaesthetized, mechanically ventilated animals underwent right lung ischaemia (series 1, 30minutes; series 2, 60minutes) followed by reperfusion for 300minutes. In series 1, animals were treated with vehicle or 0.7μmol/kg of AMD3100 (CXCR4 antagonist) and in series 2 with vehicle, 0.7 or 3.5μmol/kg ubiquitin (non-cognate CXCR4 agonist) within 5minutes of reperfusion. AMD3100 significantly reduced PaO2 /FiO2 ratios, converted mild ARDS with vehicle treatment into moderate ARDS (PaO2 /FiO2 ratio<200) and increased histological lung injury. Ubiquitin dose-dependently increased PaO2 /FiO2 ratios, converted moderate-to-severe into mild-to-moderate ARDS and reduced protein content of bronchoalveolar lavage fluid (BALF). Measurements of cytokine levels (TNFα, IL-6, IL-10) in lung homogenates and BALF showed that AMD3100 reduced IL-10 levels in homogenates from post-ischaemic lungs, whereas ubiquitin dose-dependently increased IL-10 levels in BALF from post-ischaemic lungs. Our findings establish a cause-effect relationship for the effects of pharmacological CXCR4 modulation on the development of ARDS after lung ischaemia-reperfusion injury. These data further suggest CXCR4 as a new drug target to reduce the incidence and attenuate the severity of ARDS after lung injury.

RETRACTED: Activation of the PI3K-Akt pathway promotes neuroprotection of the δ-opioid receptor agonist against cerebral ischemia-reperfusion injury in rat models

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The authors contacted the journal to request a retraction: "Recently, we found that some experimental animal samples from another research were mistakenly used in this paper, resulting in the results and conclusions unreliable". Concern was also raised about the reliability of the brain section images in Figure 1, which seem to appear in other publications, as detailed here: https://pubpeer.com/publications/8AF402957928F3F27A1F46B6D556AD; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. In addition, suspected image duplications were detected in Figures 2A, 3B and 4B. The journal requested the corresponding author comment on these concerns and provide the raw data. The author did not fulfil this request and the Editor-in-Chief decided to retract the article.

Change in iron metabolism in rats after renal ischemia/reperfusion injury.

Previous studies have indicated that hepcidin, which can regulate iron efflux by binding to ferroportin-1 (FPN1) and inducing its internalization and degradation, acts as the critical factor in the regulation of iron metabolism. However, it is unknown whether hepcidin is involved in acute renal ischemia/reperfusion injury (IRI). In this study, an IRI rat model was established via right renal excision and blood interruption for 45 min in the left kidney, and iron metabolism indexes were examined to investigate the change in iron metabolism and to analyze the role of hepcidin during IRI. From 1 to 24 h after renal reperfusion, serum creatinine and blood urea nitrogen were found to be time-dependently increased with different degrees of kidney injury. Regular variations in iron metabolism indexes in the blood and kidneys were observed in renal IRI. Renal iron content, serum iron and serum ferritin increased early after reperfusion and then declined. Hepcidin expression in the liver significantly increased early after reperfusion, and its serum concentration increased beginning at 8 h after reperfusion. The splenic iron content decreased significantly in the early stage after reperfusion and then increased time-dependently with increasing reperfusion time, and the hepatic iron content showed a decrease in the early stage after reperfusion. The early decrease of the splenic iron content and hepatic iron content might indicate their contribution to the increase in serum iron in renal IRI. In addition, the duodenal iron content showed time-dependently decreased since 12 h after reperfusion in the IRI groups compared to the control group. Along with the spleen, the duodenum might contribute to the decrease in serum iron in the later stage after reperfusion. The changes in iron metabolism indexes observed in our study demonstrate an iron metabolism disorder in renal IRI, and hepcidin might be involved in maintaining iron homeostasis in renal IRI. These findings might suggest a self-protection mechanism regulating iron homeostasis in IRI and provide a new perspective on iron metabolism in attenuating renal IRI.

The Protective Effect of Curcumin on a Spinal Cord Ischemia-Reperfusion Injury Model

The purpose of this study is to investigate the neurological, biochemical, and histopathologic effects of both the acute and maintenance treatment of curcumin on an experimental spinal cord ischemia-reperfusion injury model in rats. The animals were randomly divided into 4 groups: (1) Sham, (2) ischemia-reperfusion (IR), (3) curcumin, and (4) solvent. Spinal cord ischemia was induced by clamping the aorta with minivascular clamps at a position just below the left renal artery and just proximal to the aortic bifurcation for 45min. After 72hr of reperfusion, neurological function was evaluated with a modified Tarlov score. In spinal cords, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and nitric oxide (NO) levels were detected biochemically. Immunohistochemical staining was performed by antibodies against interleukin-6 (IL-6) and myeloperoxidase. Histopathologic changes were examined with hematoxylin and eosin staining. Although MDA tissue levels were elevated significantly in the IR group compared with the sham group, SOD and GPx levels decreased. After the administration of curcumin, MDA levels in the spinal cord decreased, and SOD and GPx levels increased. Those changes were statistically significant. There was no significance at NO levels. Among all groups, there was no difference in IL-6 and myeloperoxidase immunostaining. Histopathological analysis showed that histopathological changes in the IR group were improved by curcumin treatment. In the curcumin group, neurological outcome scores were significantly better statistically when compared with the IR group. We believe that curcumin possesses antioxidant, antiproliferative, and anticarcinogenic properties and may be an effective drug for the prevention of spinal cord IR injury in light of the neurologic, biochemical, and histopathological data of this study and published scientific literature.

Effect of electroacupuncture at Neiguan (PC 6) and Baihui (GV 20) on CHOP and caspase-12 gene expressions in rats after ischemia-reperfusion injury

To investigate the effects of electroacupuncture (EA) at Neiguan (PC 6) and Baihui (GV 20) by observing the changes of CCAAT/enhancer-binding protein(C/EBP) homologous protein (CHOP) and caspase-12 gene expressions in rats after cerebral ischemia-reperfusion injury (IRI), and explore whether the apoptosis pathway of endoplasmic reticulum stress (ERS) is involved in the protective mechanisms of EA. Sixty rats were randomly assigned to five groups (12 in each group): a normal control group (group A), a sham-operation group (group B), an operation group (group C), an Edaravone group (group D) and an EA group (group E). The cerebral IRI rat model was induced by middle cerebral artery occlusion (MCAO) using intraluminal monofilament. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was adopted in the measurement of cerebral infarction volume. Real-time polymerase chain reaction (RT-PCR) was used to determine the mRNA expressions of CHOP and caspase-12. Compared with group A and group B, the volume of cerebral infarction and mRNA expressions of CHOP and caspase-12 in group C, group D and group E were increased, with statistical significances (P 0.05). EA at Neiguan (PC 6) and Baihui (GV 20) can effectively suppress the volume of cerebral infarction. Furthermore, the underlying mechanism of EA at Neiguan (PC 6) and Baihui (GV 20) is possibly related to the down-regulation of CHOP and caspase-12 mRNA expressions, so as to decrease cell apoptosis.

A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model

BackgroundThere is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models.Methods and ResultsEighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing ≥ 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon.ConclusionsNP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic modality for IR injury in acute myocardial infarction.

Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung

Ischemia/reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage and inflammation contribute to its development. Imatinib has been reported to regulate vascular permeability by maintaining endothelial junctions and showing antiinflammatory effects through inhibition of the Abl kinases. We hypothesized that imatinib could have a protective effect against IRI. Male Lewis rats were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes followed by reperfusion for 120 minutes. Imatinib mesylate (50 mg/kg) and a solvent were administered intraperitoneally 20 minutes before ischemia in the imatinib group and the vehicle group, respectively (n= 7 in each group). After reperfusion, lung function, lung wet to dry weight (W/D) ratio, and histologic findings were obtained. The expression of vascular endothelial cadherin (VEC), the phosphorylation level of CrkL (pCrkL) (an exclusive target of Abl kinases), and the cytokine level were evaluated using lung tissue lysate. The imatinib concentrations of plasma and lungs after reperfusion were measured in this hilar clamp model (n= 7). In the imatinib group, lung function was improved with a lower W/D ratio. Perivascular edema and neutrophil infiltration were ameliorated. The imatinib group demonstrated maintained expression of VEC, inhibition of pCrkL, and a significantly higher level of interleukin (IL)-10. The imatinib concentration in both lungs showed a strong correlation with plasma concentration. In a rat IRI model, imatinib attenuated lung injury by an antipermeability and antiinflammatory effect. The delivery and function of imatinib in the lung was also confirmed in this model.

Synchronous Kikuchi-Fujimoto disease and gastric adenocarcinoma mimicking malignant lymphoma on 18F-FDG PET/CT

The Notch signaling pathway consists of several receptors and their ligands Delta and Jagged and is important for embryogenesis, cellular differentiation and proliferation. Activation of Notch receptors causes their cleavage yielding cytoplastic domains that translocate into the nucleus to induce target proteins such as the basic-loop-helix proteins Hes and Hey. Here we sought to clarify the significance of the Notch signaling pathway in acute kidney injury using a rat ischemia-reperfusion injury model and cultured NRK-52E cells. Analysis of the whole kidney after injury showed increased expression of Delta-1 and Hes-1 mRNA and protein along with processed Notch-2. Confocal microscopy, using specific antibodies, showed that Delta-1, cleaved Notch-2 and Hes-1 colocalized in the same segments of the injured renal proximal tubules. Recombinant Delta-1 significantly stimulated NRK-52E cell proliferation. Our study suggests that the Delta-1/Notch-2/Hes-1 signaling pathway may regulate the regeneration and proliferation of renal tubules during acute kidney injury.

σ1-Receptor Agonism Protects against Renal Ischemia-Reperfusion Injury.

Mechanisms of renal ischemia-reperfusion injury remain unresolved, and effective therapies are lacking. We previously showed that dehydroepiandrosterone protects against renal ischemia-reperfusion injury in male rats. Here, we investigated the potential role of σ1-receptor activation in mediating this protection. In rats, pretreatment with either dehydroepiandrosterone or fluvoxamine, a high-affinity σ1-receptor agonist, improved survival, renal function and structure, and the inflammatory response after sublethal renal ischemia-reperfusion injury. In human proximal tubular epithelial cells, stimulation by fluvoxamine or oxidative stress caused the σ1-receptor to translocate from the endoplasmic reticulum to the cytosol and nucleus. Fluvoxamine stimulation in these cells also activated nitric oxide production that was blocked by σ1-receptor knockdown or Akt inhibition. Similarly, in the postischemic rat kidney, σ1-receptor activation by fluvoxamine triggered the Akt-nitric oxide synthase signaling pathway, resulting in time- and isoform-specific endothelial and neuronal nitric oxide synthase activation and nitric oxide production. Concurrently, intravital two-photon imaging revealed prompt peritubular vasodilation after fluvoxamine treatment, which was blocked by the σ1-receptor antagonist or various nitric oxide synthase blockers. In conclusion, in this rat model of ischemia-reperfusion injury, σ1-receptor agonists improved postischemic survival and renal function via activation of Akt-mediated nitric oxide signaling in the kidney. Thus, σ1-receptor activation might provide a therapeutic option for renoprotective therapy.