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Methane is the simplest hydrocarbon, consisting of one carbon atom and four hydrogen atoms. It is abundant in marsh gas, livestock rumination, and combustible ice. Little is known about the use of methane in human disease treatment. Current research indicates that methane is useful for treating several diseases including ischemia and reperfusion injury, and inflammatory diseases. The mechanisms underlying the protective effects of methane appear primarily to involve anti-oxidation, anti-inflammation, and anti-apoptosis. In this review, we describe the beneficial effects of methane on different diseases, summarize possible mechanisms by which methane may act in these conditions, and discuss the purpose of methane production in hypoxic conditions. Then we propose several promising directions for the future research.
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OBJECTIVE@#To study the protective mechanism of Chinese medicine Suxiao Jiuxin Pills (, SXJ) on myocardial ischemia and reperfusion (I/R) injury.@*METHODS@#Mouse myocardial I/R injury model was created by 30-min coronary artery occlusion followed by 24-h reperfusion, the mice were then divided into the sham group (n=7), the I/R group (n=13), the tirofiban group (TIR, positive drug treatment, n=9), and the SXJ group (n=11). Infarct size (IS), risk region (RR), and left ventricle (LV) were analyzed with double staining methods. In addition, H9C2 rat cardiomyocytes were cultured with NaSO to simulate I/R in vitro. The phosphorylation of extracellular regulated protein kinases1/2 (ERK1/2), protein kinase B (AKT), glycogen synthase kinase-3β (GSK3β), and protein expression of GATA4 in nucleus were detected with Western blot assay.@*RESULTS@#The ratio of IS/RR in SXJ and TIR groups were lower than that in I/R group (SXJ, 22.4% ±6.6%; TIR, 20.8%±3.3%; vs. I/R, 35.4%±3.7%, P<0.05, respectively). In vitro experiments showed that SXJ increased the NaSO-enhanced phosphorylation of AKT/GSK3β and nuclear expression of GATA4.@*CONCLUSION@#SXJ prevents myocardial I/R injury in mice by activating AKT/GSK3β and GATA4 signaling pathways.
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Objective To investigate whether silencing repulsive guidance molecule A (KGMa) shows protective effects on blood brain barrier (BBB) and tight junction protein after the injury of cerebral ischemia and reperfusion (I/H) in rats. Methods Middle cerebral artery occlusion (MCAO)reperfusion was employed to establish the models in the male adult rats. Fourty male Sprague-Dawley rats were divided into blank control group (sh-con) and RGMa interference group (sh-RGMa). The effects of adenovirus on RGMa were observed at day 1 and day 3 after injection. The remaining 120 SD rats were randomly divided into sham group, I/R group, I/'R+sh-con group and I/R+sh-RGMa group. After reperfusion for 72 hours, the neurological recovery was evaluated in rats by neurological deficit score, the infarcted volume was measured by 2,3,5-triphenyl tetrazolium chloride (TTC) staining and the permeability of BBB was performed through evans blue by tail vein injection. The expression of RGMa was detected by Western blotting and immunohistochemistry assay. The expression of claudin-5, matrix metalloprotein 9 (MMP-9)and zonula occludin l(ZO-l)were detected by Western blotting. Results Silencing RGMa could improve the permeability of BBB, the infarcted volume, down-regulate the expression of MMP-9, and up-regulate the expression of claudin-5 and Z0-1. Conclusion Silencing RGMa shows protective effects on BBB after I/R injury in rats.
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OBJECTIVE： To study the protective effects of Polygonum orientale extract on myocardial ischemia-reperfusion injury （MIRI） model rats， and to provide reference for it’s deeply development of medicinal source. METHODS： Totally 24 rats were randomly divided into sham operation group （normal saline）， model group （normal saline）， Compound danshen tablet group （positive group， 0.17 g/kg） and P. orientale extract group （86 g/kg， calculated by crude drug）， with 6 rats in each group. All groups were given drugs 2 mL/100 g intragastrically once a day. After 4 d of consecutive administration， MIRI model was induced by the left anterior descending branch of arteria coronaria in all groups except for sham operation group. 24 h after reperfusion， they were given related medicine again. After medication， the changes of electrocardiogram ST segment were monitored in each group. The plasma levels of LDH， CK-MB， CK， cTn-I， SOD and NO were detected in each group. The myocardial infarction rate in each group was calculated and the pathomorphological changes in the myocardium were observed. RESULTS： Compared with sham operation group， ST segment of myocardial electrocardiogram was increased in model group （P＜0.01）. The plasma levels of LDH， CK， CK-MB and cTn-I were increased significantly （P＜0.01）， while the plasma levels of SOD and NO were decreased significantly （P＜0.01）. The rate of myocardial infarction was increased significantly （P＜0.01）， and pathomorphological changes were observed in myocardial tissue such as infiltration of inflammatory cells and loose cytoplasm of cardiac myocytes. Compared with model group， ST segment of myocardial electrocardiogram was decreased significantly in Compound danshen tablet group and P. orientale extract group （P＜0.05）； the plasma levels of LDH， CK， CK-MB and cTn-I were decreased significantly （P＜0.05）， while the plasma levels of SOD and NO were increased significantly （P＜0.05）； the rate of myocardial infarction was decreased significantly （P＜0.05）， and inflammatory cell infiltration and tissue edema in myocardium were relieved to varying degrees. CONCLUSIONS： The protective effect of P. orientale extract protect on MIRI may be exerted by anti-oxidative damage.
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Objective: To investigate the protective effects of the combination of Xuesaitong (XST) and aspirin on cerebral ischemia and reperfusion injury (CIRI) in rats, and further explore the underlying mechanisms. Methods: A total of 150 male Sprague-Dawley (SD) rats were randomly divided into five groups with 30 rats in each group: sham group, middle cerebral artery occlusion/reperfusion (MCAO/R) model group, XST group, aspirin group, and XST + aspirin group. Rats were pretreated with XST, aspirin, or XST + aspirin for 7 d. One hour after the last administration, a model of CIRI was induced by MCAO/R. Neurological deficits were assessed using Longa's five-point scale. Cerebral edema was detected by the measurement of brain water content. The volume of cerebral infarction was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as levels of malonaldehyde (MDA) were detected by commercial kits. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of interleukin-1 (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), and kynurenine in serum, cerebral cortex, and hippocampus of MCAO/R rats. The protein expression of nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase-1 (HO-1), I-kappa B alpha (IκBα), and nuclear factor kappa B (NF-κB)/p65 in the cortex were analyzed by western blotting. Results: Treatment of XST, aspirin, and XST + aspirin significantly alleviated the neurological deficits, cerebral edema, and cerebral infarct volume induced by MCAO/R. Treatment of XST, aspirin, and XST + aspirin also reduced MDA, IL-1β IL-6,TNF-α MCP-1, and kynurenine levels, and increased SOD, CAT, GSH-Px, IL-4, and IL-10 levels in serum, cerebral cortex, and hippocampus of MCAO/R rats. Furthermore, treatment of XST, aspirin, and XST + aspirin decreased the expression of nuclear NF-κB/p65 and increased the expression of IκBα nuclear Nrf2, and HO-1. Importantly, the combination of XST and aspirin enhanced the protective effects of XST or aspirin treatment alone on CIRI in rats. Conclusion: The combination of XST and aspirin significantly inhibited oxidative stress and inflammation in serum, cerebral cortex, and hippocampus of MCAO/R rats. The combination of XST and aspirin exerted more protective effects than XST or aspirin treatment alone. The combination of XST and aspirin might provide the synergistic therapeutic effects on CIRI, and deserve further clinical investigation.
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<p><b>OBJECTIVE</b>To observe the effects of low-intensity pulsed ultrasound (LIPUS) pretreatment on pulmonary expression of high mobility group box-1 (HMGB1) in a rat model of lung ischemia-reperfusion (IR).</p><p><b>METHODS</b>Thirty-two male SpragueDawley rats weighing 250-300 g were randomly divided (=8) into sham-operated group, lung IR group, LIPUS pretreatment group and pretreatment with α7-nicotinic cholinergic receptor (α7nAChR) antagonist group. In the sham-operated group, the left pulmonary hilum was dissociated without occlusion; in the other 3 groups, the left pulmonary hilum was occluded for 45 min followed by reperfusion for 180 min; LIPUS pretreatment for 30 min and intraperitoneal injection of methyllycaconitine (2 mg/kg), an α7nAChR antagonist, were administered before the operation. The wet/dry weight ratio (W/D) and pulmonary permeability index (LPI) of the lung tissue were measured, and the lung histopathology was observed and scored. The contents of interleukin-1 (IL-1) and IL-6 in the lung tissues were measured using ELISA, and the pulmonary expression of HMGB1 protein was detected using immunofluorescence assay and Western blotting.</p><p><b>RESULTS</b>Compared with those in the sham-operated group, the W/D of the lung tissue, LPI, pathological scores, IL-1 and IL-6 contents in the lung tissue, and pulmonary HMGB1 expression all significantly increased in the other 3 groups ( < 0.05). LIPUS preconditioning significantly lowered the W/D values, LPI, pathological score, IL-1 and IL-6 contents and HMGB1 expression in the lung tissues following lung IR, and these effects were significantly inhibited by administration of methyllycaconitine.</p><p><b>CONCLUSIONS</b>LIPUS preconditioning can reduce lung IR injury possibly by activating α7nAChR-dependent cholinergic anti-inflammatory pathway to reduce lung tissue HMGB1 expression.</p>
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<p><b>OBJECTIVE</b>To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury.</p><p><b>METHODS</b>Myocardial I/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before I/R (SAL group). The SAL group was compared with SHAM (no I/R and no salvianolate), I/R (no salvianolate), and ischemia preconditioning (IPC) groups. Furthermore, an ERK1/2 inhibitor PD98059 (1 mg/kg), and a phosphatidylinositol-3-kinase (PI3-K) inhibitor, LY294002 (7.5 mg/kg), were administered intraperitoneal injection (i.p) for 30 min prior to salvianolate, followed by I/R surgery in LY and PD groups. By using a double staining method, the ratio of the infarct size (IS) to left ventricle (LV) and of risk region (RR) to LV were compared among the groups. Correlations between IS and RR were analyzed. Western-blot was used to detect the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation changes.</p><p><b>RESULTS</b>There were no significant differences between RR to LV ratio among the SHAM, I/R, IPC and SAL groups (P>0.05). The SAL and IPC groups had IS of 26.1%±1.4% and 22.3%±2.9% of RR, respectively, both of which were significantly smaller than the I/R group (38.5%±2.9% of RR, P<0.05, P<0.01, respectively). Moreover, the phosphorylation of ERK1/2 was increased in SAL group (P<0.05), while AKT had no significant change. LY294002 further reduced IS, whereas the protective role of salvianolate could be attenuated by PD98059, which increased the IS. Additionally, the IS was not linearly related to the RR (r=0.23, 0.45, 0.62, 0.17, and 0.52 in the SHAM, I/R, SAL, LY and PD groups, respectively).</p><p><b>CONCLUSION</b>Salvianolate could reduce myocardial I/R injury in mice in vivo, which involves an ERK1/2 pathway, but not a PI3-K signaling pathway.</p>
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Animals , Male , Blotting, Western , Cardiotonic Agents , Pharmacology , Therapeutic Uses , Flavonoids , Pharmacology , Heart Ventricles , Pathology , MAP Kinase Signaling System , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase 1 , Metabolism , Mitogen-Activated Protein Kinase 3 , Metabolism , Myocardial Reperfusion Injury , Drug Therapy , Pathology , Organ Size , Phosphorylation , Plant Extracts , Chemistry , Pharmacology , Therapeutic Uses , Protein Kinase Inhibitors , Pharmacology , Staining and LabelingABSTRACT
Objective Ischemia reperfusion injury (IRI) is a major limiting factor of graft survival in organ transplantation.We've established a novel procedure called ischemia-free liver transplantation (IFLT) in big animal study.In this report,we aimed to investigate the feasibility and early outcomes of IFLT.Methods We have performed 3 cases of IFLT during July 23,2017 to August 9,2017.We analyzed the surgical methods,normothermic perfusion parameters,blood gas analysis,liver function tests and complications early after liver transplantation.Pathologic studies and immunohistochemical staining of donor liver biopsies were conducted before procurement,at the end of machine perfusion,as well as after re-vascularization for evaluating IRI.Results The surgical procedures of all 3 patients were successful,without stoppage of blood supply for the liver grafts throughout organ procurement,ex vivo preservation and implantation.During normothermic perfusion,the pH value was stable within the normal range and the lactate levels dropped quickly to lower than detected (＜0.3 mmol/L) within 1.5-3 h.The livers continued to produce bile with the volume of 2-6 mL/h.Hematoxylin and eosin (HE) staining evaluation and TdT-mediated dUTP nick end labeling (TUNEL) assay of biopsies taken from liver tissues before procurement,at the end of machine perfusion and after re-vascularization,showed few necrostic and apoptotic hepatocytes in the liver biopsies.The immunohistochemical staining of IL-1β and vWF suggested no inflammatory cytokine release and sinusoidal endothelial cell activation.The three patients recovered smoothly without rejection,vascular and biliary complications.Conclusion IFLT is a feasible and effective procedure,which is able to overcome the major limitations of conventional procedure.The novel IFLT will become one of the mainstream transplant procedures in the future.
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Kidney ischemia and reperfusion injury (IRI) is associated with a high mortality rate, which is attributed to tubular oxidative and nitrative stresses; however, an effective approach to limit IRI remains elusive. Spermidine, a naturally occurring polyamine, protects yeast cells against aging through the inhibition of oxidative stress and necrosis. In the present study, spermidine supplementation markedly attenuated histological damage and kidney dysfunction during IRI. In addition, exogenous spermidine potently inhibited poly(ADP-ribose) polymerase 1 (PARP1) activation and DNA nitrative/oxidative stress following IRI. Conversely, inhibition of ornithine decarboxylase (ODC) via siRNA transfection in vivo significantly enhanced DNA nitration, PARP1 activation, and functional damage during IRI. Finally, in ODC knockdown kidneys, PARP1 inhibition attenuated histological and functional damage induced by IRI, but not DNA nitrative stress. In conclusion, these data suggest that spermidine protects kidneys against IRI through blocking DNA nitration and PARP1 activation and this finding provides a novel target for prevention of acute kidney injury including IRI.
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Acute Kidney Injury , Aging , DNA , Ischemia , Kidney , Mortality , Necrosis , Ornithine Decarboxylase , Oxidative Stress , Poly(ADP-ribose) Polymerases , Reperfusion Injury , Reperfusion , RNA, Small Interfering , Spermidine , Transfection , YeastsABSTRACT
Objective To investigate the alternation of mitochondrial oxidative phosphorylation post-ischemia/reperfusion myocardial injury in mice. Methods The C57BL/6 mice were randomly divided into five groups. The mouse hearts in the time control group (TC) were perfused for 45 min in identical Krebs-Henseleit buffer without any treatment. In the ischemia/reperfusion groups, the mouse hearts were treated with different reperfusion time including 5, 10, 15 or 30 min, following by the same ischemia period of 25 min. The mitochondria were extracted from the left ventricular post-reperfusion. The respiratory function including R3, R4, RCR, and the maximal rate of state 3 respiration (2 mmol/L ADP) were measured. Results The R3, RCR and P/O of mitochondria, using glutamate + malate as substrates, were decreased significantly at 10 min, 15 min and 30 min post-ischemia/reperfusion (P < 0.05, respectively), but not in the 5-min-reperfusion group compared with the time control group. And the respiratory function, using succinate, and TMPD-ascorbate as substrates, decreased significantly in different ischemia/reperfusion groups compared with the time control (P < 0.05, respectively). Conclusions The mitochondrial respiratory function changes differently in different complex at the early stage of reperfusion after ischemia. So different ischemia/reperfusion time should be chosen to detect the alternations of different mitochondrial complex after heart injury.
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This study was designed to evaluate the protective effect of Korean red ginseng (KRG) against ischemia/reperfusion (I/R) injury in isolated guinea pig heart. KRG has been shown to possess various ginsenosides, which are the major components of Panax ginseng. These components are known naturally occurring compounds with beneficial effects and free radical scavenging activity. The heart was induced to ischemia for 60 min, followed by 120 min reperfusion. The hearts were randomly allocated into five groups (n=8 for each group): normal control (N/C), KRG control, I/R control, 250 mg/kg KRG group and 500 mg/kg KRG group. KRG significantly increased hemodynamics parameters such as aortic flow, coronary flow and cardiac output. Moreover, KRG significantly increased left ventricular systolic pressure (LVSP), the maximal rate of contraction (+dP/dtmax) and maximal rate of relaxation (-dP/dtmax). Also, treatment of KRG ameliorated electrocardiographic index such as the QRS, QT and RR intervals. Moreover, KRG significantly suppressed the lactate dehydrogenase, creatine kinase-MB fraction and cardiac troponin I and ameliorated the oxidative stress markers such as malondialdehyde and glutathione. KRG was standardized through ultra performance liquid chromatograph analysis for its major ginsenosides. Taken together, KRG has been shown to prevent cardiac injury by normalizing the biochemical and oxidative stress.
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Animals , Blood Pressure , Cardiac Output , Contracts , Creatine , Electrocardiography , Ginsenosides , Glutathione , Guinea , Guinea Pigs , Heart , Hemodynamics , Ischemia , L-Lactate Dehydrogenase , Malondialdehyde , Myocardial Ischemia , Oxidative Stress , Panax , Relaxation , Reperfusion , Troponin IABSTRACT
Objective: To investigate the protective effect of sinomenine on the cold ischemia/reperfusion injury during orthotopic liver transplantation (OLT) in rats. Methods: OLT were performed in normal rats using Kamada's two-cuff technique. The rats were randomly divided into sham operation, control and two sinomenine groups. Animals in sinomenine groups were treated with low (40 mg/kg) or high dose (80 mg/kg) of sinomenine. The serum and tissue samples of rats in each group were collected 2, 6, 12, and 24 h after reperfusion,and the one-week survival rate was observed. The apoptosis index (AI) of liver cells after OLT was detected by TUNEL. The expression of TNF-α and IL-Iβ mRNA in the liver were detected by RTPCR. Results: Compared with the control group, the level of ALT was significantly decreased in the two sinomenine treatment groups at different time points after transplantation, and their one-week survival rates were also significantly increased (75%, 75% vs 12.5%, P<0.01). Compared with the control group, the AI of liver cells was markedly decreased in sinomenine treatment groups (P<0.01). Sinomenine treatment also significantly decreased the expression of TNF-α and IL-1β mRNA (P< 0.01) and greatly ameliorated the focal necrosis of hepatocytes and sinusoidal endothelial cells (SECs). Conclusion: Sinomenine can inhibit hepatocyte apoptosis by inhibiting the synthesis of TNF-α and IL-1β. sinomenine can prevent hepatic cells and SECs from cold ischemia/reperfusion injury during orthotopic liver transplantation in rats.
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Mitochondrial aldehyde dehydrogenase(ALDH2),one of the isoforms of aldehyde dehydrogenase,has multiple enzymatic functions including the activity of dehydrogenase and esterase.The metabolisms of ethanol,amino acids,biogenic amine,vitamin or steroid in the body produce various substances of aldehyde.With the help of co-factor NAD(P)+,ALDH2 can convert aldehydes into corresponding carboxylic acid,which plays a key role in reducing toxic effects of aldehydes on the body.It does not need co-factor when ALDH2 works as esterase.It can convert carboxylic ester or other acids into corresponding carboxylic acids or alcohols.Recently,it has been shown that the decrease of ALDH2 activity exacerbates multiple factors(such as ethanol,ischemia)-induced myocardial injury and accelerates the development of nitroglycerin tolerance.Therefore,the development of specific agonists of ALDH2 may provide a novel approach to the therapy and prevention of heart diseases.
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PURPOSE: Bacterial translocation is a major problem after ischemic bowel injuries such as mesenteric vessel obstruction or bowel strangulation. In this study, we investigated the differential character of bacterial translocation from the large and small bowel using Escherichia coli labeled with technetium 99m (99mTc-E.coli). METHOD: Male Sprague-Dawley rats weighing 200~300 g underwent laparotomy. The superior mesenteric artery and marginal arteries of the proximal jejunum and distal colon were occluded for 30 minutes and then re-perfused for 4 hours. A suspension containing 99mTc-E.coli was injected into the lumen of the proximal colon (group 1) and distal ileum (group 2). In the sham operation group (groups 3, 4), 99mTc-E.coli was also injected in the same manner without induction of ischemia and reperfusion injury. Two hours after E. coli injection, blood, mesenteric lymph nodes (MLN), liver, spleen, and lung were collected for quantitative analysis of radioactivity. Large and small bowel specimens were also harvested for microscopic examination. Student's t-test was used for statistical analysis. P< or =0.05 was considered statistically significant. RESULT: Compared with group 1, group 2 showed a significant increase in 99mTc-E.coli translocation from the lumen to all organs investigated, except with regard to MLN. The sham operation group (groups 3, 4) showed scanty bacterial translocation. The mucosal epithelial cell layers of both groups (groups 1, 2) were comparatively intact. CONCLUSION: The 99mTc-E.coli method was found to be suitable for studies of bacterial translocation from the small and large bowels. Bacterial translocation is much more likely to occur across the small bowel wall than across the large bowel wall.
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Humans , Male , Arteries , Bacterial Translocation , Colon , Epithelial Cells , Escherichia coli , Glycosaminoglycans , Ileum , Ischemia , Jejunum , Laparotomy , Liver , Lung , Lymph Nodes , Mesenteric Artery, Superior , Radioactivity , Rats, Sprague-Dawley , Reperfusion , Reperfusion Injury , Salicylamides , Spleen , TechnetiumABSTRACT
Cerebral ischemia and reperfusion can cause delayed neuronal death in rodents,such as Mongolian gerbils and stroke-prone spontaneously hypertensive rats(SHRSP),which are used as an experimental stroke model.The protective effects of antioxidant nutrients such as vitamin E,green tea extract,ginkgo biloba extract,resveratrol,niacin and isoflavones in cerebral ischemia and reperfusion brain injury were reviewed.
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@# ObjectiveTo observe effects of Naofucong grain on learning and memory in cerebral ischemic mice, and identify the mechanisms on N-methyl-D-aspartate (NMDA) receptor.MethodsExperimental dementia mice were induced by ischemia reperfusion injury, and treated with Naofucong grain or Dangguishaoyao powder (positive control medicine). Learning and memory were tested in the Morris water maze. Activities of NMDA receptor in brain cortex and hippocampus were detected ResultsIncubation periods of mice treated with Naofucong grain were significantly shorter than that of ischemic model mice (P<0.01) Activities of NMDA receptor in brain cortex and hippocampus showed no difference between Naofucong grain treated mice and normal mice (P>0.05)Activities of NMDA receptor in brain cortex and hippocampus in Naofucong grain treated mice were significantly lower than that in ischemic model mice(P<0.01) ConclusionThe improvement of Naofucong grain in the memory and learning in cerebral ischemic mice may be related to the inhibition of the activity of NMDA receptor.