Pioglitazone Attenuates Ischemia/Reperfusion–Induced Liver
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Pioglitazone
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Pioglitazone
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Society of Critical Care Medicine; 28th Educational and Scientific Symposium; San Francisco, California, USA; January 23-27, 1999: Poster Presentations: Poster Hall
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Introduction Testicular torsion might affect adolescent boys and adults and is considered one of the causes of reduced fertility. Purpose This study was carried out to describe late structural and ultrastructural changes in the rat testis following torsion/detorsion and to shed light on the possible protective effect of L-carnitine. Materials and methods Under general anesthesia, torsion was conducted by rotating the left testis 720º in a clockwise direction for 5 h followed by detorsion. The rats were divided into 3 equal groups: group I: Sham-operated control. Group II; torsion and detorsion were conducted as described. Group III; L-carnitine was injected intraperitoneally at a dose of 100 mg/kg, 1 h before detorsion. Seven days after detorsion, paraffin sections were obtained from the left testes of all groups and stained with hematoxylene and eosin and eendothelial nitric oxide synthase immunoreactivity. Fine specimens were processed to be examined with transmission electron microscope. Results Marked degenerative changes were seen in the seminiferous tubule manifested as irregularity of the basement membrane and cellular disarray. In addition, there were numerous apoptotic cells. An associated increase in eNOS immunoreactivity was detected. Ultrastructurally, spermatogonia appeared irregular and swollen with condensed nuclei. Spermatocytes showed relatively condensed nuclei and vacuoles that were variable in size and electron density. Sertoli cells appeared irregular with swollen mitochondria. In contrast, L-carnitine-treated animals exhibited less degenerative features and an unremarkable change in eendothelial nitric oxide synthase immunoreactivity. Conclusion L-carnitine might be of benefit in treatment of testicular dysfunction resulting from torsion.
Seminiferous tubule
Spermatic Cord Torsion
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Ischemic Preconditioning
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Inflammatory response
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Arginase has recently emerged a critical regulator of NO synthesis that may contribute to the development of numerous pathologies, including vascular disease, diabetes, hypertension and arthritis. In this study we tested a novel arginase inhibitor, for its ability to improve survival and attenuate loss of kidney function in a model of renal ischemia and reperfusion injury (IRI) and in a model of ischemia induced renal transplant rejection in mice. IR injury was induced in male C57Bl/6 mice by bilateral renal pedical clamping for 30 min. Treatment with arginase inhibitor AX-01128 was tested in two different dosages (10 and 30 mg/kg body weight) versus vehicle (PBS). The medication was administered intravenously 15 min before placing the clamps and at 5 minutes prior to releasing the clamps. Survival and renal function was monitored. In the renal transplant model C57 Bl/6 (H2b) donor kidneys were transplanted into BALB/c (H2d) recipients. Arginase inhibitor AX-01128 was tested in three different dosages (1, 3, and 10 mg/kg body weight) versus control (PBS). The medication was administered intravenously to both donor and recipient 15 min before surgery and the second injection was given to the recipients at 5 minutes after transplantation. Results: AX-01128 (10mg/kg and 30 mg/kg) was effective in reducing mortality and improved renal function in a dose dependent manner after acute kidney injury. Treatment with 10 and 30 mg/kg AX-01128 resulted in 20% and 30% long-term survival, respectively, whereas all mice of the control group died within 5 days after surgery. In the transplant experiments AX-01128 was able to reduce acute tubular necrosis but had little effect on inflammation. Conclusion: AX-01128 is a novel and promising therapeutic agent for acute ischemia reperfusion injury in the kidney.
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Hepatic ischemia/reperfusion (I/R) injury leads to oxidative stress and acute inflammatory responses that cause liver damage and have a considerable impact on the postoperative outcome. Much research has been performed to develop possible protective techniques. We aimed to investigate the efficacy of SPA0355, a synthetic thiourea analog, in an animal model of hepatic I/R injury. Male C57BL/6 mice underwent normothermic partial liver ischemia for 90 min followed by varying periods of reperfusion. The animals were divided into three groups: sham operated, I/R, and SPA0355 pretreated. Pretreatment with SPA0355 protected against hepatic I/R injury, as indicated by the decreased levels of serum aminotransferase and reduced parenchymal necrosis and apoptosis. Liver synthetic function was also restored by SPA0355 as reflected by the prolonged prothrombin time. To gain insight into the mechanism involved in this protection, we measured the activity of nuclear factor-κB (NF-κB), which revealed that SPA0355 suppressed the nuclear translocation of NF-κB subunits. Concomitantly, the expression of NF-κB target genes such as IL-1β, IL-6, TNF-α, and iNOS was significantly down-regulated. Lastly, the liver antioxidant enzymes superoxide dismutase, catalase, and glutathione were up-regulated by SPA0355 treatment, which correlated with the reduction in serum malondialdehyde. Our results suggest that SPA0355 pretreatment prior to I/R injury could be an effective method to reduce liver damage.
Malondialdehyde
Liver function
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Renal ischemia
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Ischemia-reperfusion injury (IRI) is unavoidable event in renal transplantation, causing the delayed graft function and increased immunogenicity. We investigated whether paricalcitol is renoprotective in a mouse model of IRI, and whether potential mechanism is related with modulation of renal inflammation and prostaglandin E2 (PGE2) synthesis. Paricalcitol (0.3 μ/Kg) was administered to male C57BL/6 mice 24 hours before IRI, and mice were killed at 72 hours after IRI. Treatment with paricalcitol decreased blood urea nitrogen levels, serum creatinine levels, tubular necrosis score. Paricalcitol decreased the number of TUNEL-positive cells and reduced the expression of apoptotic markers. The production of RANTES and tumor necrosis factor-α were reduced by paricalcitol and the infiltration of CD40-positive antigen-presenting cells were decreased in the paricalcitol-treated kidneys. Paricalcitol inhibited the production of Th1 cytokines interleukin (IL)-2 and interferon-γ, which was accompanied with decreased infiltration of T-cells and macrophages. The immunomodulatory effects of paricalcitol also affected the decreased production of Th2 cytokines IL-4 and IL-10. Paricalcitol induced the increased cyclooxygenase (COX)-2 expression and decreased the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) production, which lead to increased endogenous PGE2 synthesis. Of the PGE2 receptors, the expression of EP1 and EP4 were increased in the paricalcitol-treated kidneys and the activation of EP4 receptors increased the expression of survival kinase Akt. In conclusion, our study demonstrated that paricalcitol has a protective effect on renal IRI and that this effect is associated with inhibition of renal inflammatory infiltration, increased PGE2 synthesis and EP4 receptor activation.
Paricalcitol
Proinflammatory cytokine
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117 Background; Although adenosine is known to exert protective role in ischemia and reperfusion injury of the liver via A2 receptor activation, it also stimulates A1 receptor that encounters benefical effect of adenosine. We tested our hypothesis that adenosine A1 receptor inhibition by adenosine A1 receptor antagonist, KW3902 attenuates ischemia-reperfusion injury of the liver. Material and method: Adult female beagle dogs underwent 2-hr hepatic vascular exclusion with venovenous bypass. Nontreated animals were used as the control (Group CT,n=12). KW3902 was given to the animals by continuous intraportal infusion for 60 min before ischemia at a dose of 1f gE/kg/min (Group KW, n=6). Animal survival, hemodynamics, hepatic tissue blood flow (HTBF), liver enzyme release, adenine nucleotides and purine catabolites concentration in liver tissue, cAMP concentration in liver tissue, and histopathologiy were examined. Statistics: Values are expressed as mean SEM. Animal survival was determined using the Fisher's exact test. Inter-group analysis was performed using Mann-Whitney U-test. A p-value less than 0.05 was considered statistically significant. Result: Two-week animal survival was 25% in Group CT and 83.3% in Group KW. Postreperfusion HTBF was markedly improved in Group KW. Treatment significantly attenuated liver enzyme relaese and changes in adenine nucleotides. In Group KW, cAMP concentration was maintained higher during ischemia and after reperfusion than control group. Histopathologic examination revealed better preservation of hepatic.archItecture in Group KW. (Figure)FigureConclusion: Administration of adenosine A1 receptor antagonist before ischemia attenuates ischemia-reperfusion injury of the liver. Adenosine A1 receptor antagonists may be useful for the prevention of ischemia-reperfusion injury after transplant surgery and during surgical procedures associated.
Ischemic Preconditioning
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