pyrimidinones and Reperfusion-Injury

The objective of this research was to survey the therapeutic action of simvastatin (Sim) on intestinal ischemia/reperfusion injury (II/RI) by modulating Omi/HtrA2 signaling pathways.. Sprague Dawley rats were pretreated with 40 mg/kg Sim and then subjected to 1 hour of ischemia and 3 hours of reperfusion. The blood and intestinal tissues were collected, pathologic injury was observed, the contents of serum tumor necrosis factor-α and interleukin-6 (IL-6) were estimated, and superoxide dismutase, methane dicarboxylic aldehyde, and cysteinyl aspartate specific proteinase-3 (caspase-3) levels, as well as the expressions of Omi/HtrA2 and caspase-3, were measured in the intestinal tissues.. Sim preconditioning mitigated the damnification of intestinal tissues by decreasing oxidative stress, inflammatory damage, and apoptosis and downregulating the expression of Omi/HtrA2 compared to the ischemia/reperfusion group, while Sim+Ucf-101 significantly augmented this effect.. These results suggest that Sim may alleviate intestinal ischemia/reperfusion injury by modulating Omi/HtrA2 signaling pathways.

Topics: Animals; Anticholesteremic Agents; Apoptosis; Biomarkers; Caspase 3; High-Temperature Requirement A Serine Peptidase 2; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mitochondrial Proteins; Pyrimidinones; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Simvastatin; Superoxide Dismutase; Thiones

This study was aimed to investigate the treatment mechanisms of 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) in cerebral ischemia-reperfusion (CIR) model rats. Total of 54 healthy male Wistar rats were randomly assigned into three groups, namely sham group, vehicle group, and UCF-101 group. The CIR-injured model was established by right middle cerebral artery occlusion and reperfusion. Neurological function was assessed by an investigator according to the Longa neurologic deficit scores. Meanwhile, the cerebral tissue morphology and apoptotic neurons were evaluated by H&E and TUNEL staining, respectively. Additionally, the expressions of caspase 3, p-p38, and p-ERK were detected by immunohistochemistry or/and Western blotting assays. As results, neurologic deficit and pathological damage were obviously enhanced and TUNEL positive neurons were significantly increased in CIR-injured rats, as compared with those in sham group. Furthermore, the expressions of caspase 3, p-p38, and p-ERK were also significantly increased in vehicle group than those in sham group (P < 0.05). However, UCF-101 treatment could markedly weaken the neurologic deficit with lower scores and improve pathological condition. After UCF-101 treatment, TUNEL positive neurons as well as the expression of caspase 3 were significantly decreased than those in vehicle group (P < 0.05). Besides, p-p38 was decreased while p-ERK was increased in UCF-101 group than those in vehicle group (P < 0.05). Therefore, we concluded that the protective effects of UCF-101 might be associated with apoptosis process and MAPK signaling pathway in the CIR-injured model.

Topics: Animals; Apoptosis; Brain Ischemia; Disease Models, Animal; Infarction, Middle Cerebral Artery; Male; MAP Kinase Signaling System; Pyrimidinones; Rats, Wistar; Reperfusion Injury; Thiones

Compound PDMpT.HCI reduces intensity of lipoperoxidation, activates antioxidant system and increases animal life expectancy under hypoxic circumstance.

Topics: Animals; Animals, Outbred Strains; Antioxidants; Gravitation; Hypoxia-Ischemia, Brain; Lipid Peroxidation; Longevity; Male; Mice; Picolines; Pyrimidines; Pyrimidinones; Rats; Reperfusion Injury; Superoxide Dismutase; Toluene

Macrophages play a critical role in the pathophysiology of liver ischemia and reperfusion (IR) injury (IRI). However, macrophages that overexpress antioxidant heme oxygenase-1 (HO-1) may exert profound anti-inflammatory functions. This study explores the cytoprotective effects and mechanisms of ex vivo modified HO-1-expressing bone marrow-derived macrophages (BMDMs) in well-defined mouse model of liver warm ischemia followed by reperfusion. Adoptive transfer of Ad-HO-1-transduced macrophages prevented IR-induced hepatocellular damage, as evidenced by depressed serum glutamic-oxaloacetic transaminase (sGOT) levels and preserved liver histology (Suzuki scores), compared to Ad-beta-gal controls. This beneficial effect was reversed following concomitant treatment with HO-1 siRNA. Ad-HO-1-transfected macrophages significantly decreased local neutrophil accumulation, TNF-alpha/IL-1beta, IFN-gamma/E-selectin, and IP-10/MCP-1 expression, caspase-3 activity, and the frequency of apoptotic cells, as compared with controls. Unlike in controls, Ad-HO-1-transfected macrophages markedly increased hepatic expression of antiapoptotic Bcl-2/Bcl-xl and depressed caspase-3 activity. These results establish the precedent for a novel investigative tool and provide the rationale for a clinically attractive new strategy in which native macrophages can be transfected ex vivo with cytoprotective HO-1 and then infused, if needed, to prospective recipients exposed to hepatic IR-mediated local inflammation, such as during liver transplantation, resection, or trauma.

Topics: Animals; Blotting, Western; Caspase 3; Cell Line; Cells, Cultured; Chemokine CCL2; E-Selectin; Heme Oxygenase-1; Interferon-gamma; Interleukin-1beta; Liver; Macrophages; Male; Mice; Mice, Inbred C57BL; Pyrimidinones; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Thiazoles; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the therapeutic efficacy and neuroprotective mechanisms of UCF-101, a novel Omi/HtrA2 inhibitor, following ischemia/reperfusion brain injury. Male Wistar rats were subjected to 2 hr of middle cerebral artery occlusion followed by reperfusion. Animals were divided into 3 groups: sham, vehicle-treated ischemia/reperfusion, and UCF-101 treatment. In the UCF-101 treatment group, rats were intraperitoneally administered UCF-101 (1.5 micromol/kg) 10 min prior to reperfusion. The rats were evaluated for neurological deficits, and brain infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride. TUNEL staining was utilized to evaluate the amount of apoptosis. In addition, expressions of protein caspase-8, caspase-3, FasL, and FLIP were examined by Western blot analysis. Results demonstrated that UCF-101 treatment significantly decreased cerebral infarct size by about 16.27% (P < 0.05) and also improved neurological behavior. TUNEL staining revealed that UCF-101 treatment significantly reduced TUNEL-positive cells in the cerebral cortex. Furthermore, the upregulation in the expression of FasL and the cleavage products of active caspase-8 and caspase-3 induced by ischemia was attenuated in mice treated with UCF-101, whereas upregulation of FLIP levels was increased. The present results demonstrated that UCF-101 protects against cerebral ischemia/reperfusion injury in mice. UCF-101 provided neuroprotection in vivo, and this was correlated with regulation of Fas-mediated apoptotic proteins. Taken together, the use of UCF-101 is a potent, neuroprotective factor for the treatment of focal cerebral ischemia.

Topics: Animals; Apoptosis; Blotting, Western; Brain Ischemia; Caspase 3; Caspase 8; Cerebral Infarction; Enzyme Inhibitors; High-Temperature Requirement A Serine Peptidase 2; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Male; Mitochondrial Proteins; Nerve Tissue Proteins; Neuroprotective Agents; Pyrimidinones; Rats; Rats, Wistar; Reperfusion Injury; RNA-Binding Proteins; Serine Endopeptidases; Serine-Arginine Splicing Factors; Thiones

Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 microg/kg; sildenafil-analog (n=5) 500 microg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes . cm . sec(-5) at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.

Topics: Acute Disease; Animals; Blood Pressure; Cardiopulmonary Bypass; Hypertension, Pulmonary; Milrinone; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidinones; Reperfusion Injury; Sildenafil Citrate; Sulfones; Sus scrofa; Vascular Resistance

Vascular inflammation and enhanced production of angiotensin II (ANG II) are involved in the pathogenesis of hypertension and diabetes, disease states that predispose the afflicted individuals to ischemic disorders. In light of these observations, we postulated that ANG II may play a role in promoting leukocyte rolling (LR) and adhesion (LA) in postcapillary venules after exposure of the small intestine to ischemia-reperfusion (I/R). Using an intravital microscopic approach in C57BL/6J mice, we showed that ANG II type I (AT(1)) or type II (AT(2)) receptor antagonism (with valsartan or PD-123319, respectively), inhibition of angiotensin-converting enzyme (ACE) with captopril, or calcitonin gene-related peptide (CGRP) receptor blockade (CGRP8-37) prevented postischemic LR but did not influence I/R-induced LA. However, both postischemic LR and LA were largely abolished by concomitant AT(1) and AT(2) receptor blockade or chymase inhibition (with Y-40079). Additionally, exogenously administered ANG II increased LR and LA, effects that were attenuated by pretreatment with a CGRP receptor antagonist or an NADPH oxidase inhibitor (apocynin). Our work suggests that ANG II, formed by the enzymatic activity of ACE and chymase, plays an important role in inducing postischemic LR and LA, effects that involve the engagement of both AT(1) and AT(2) receptors and may be mediated by CGRP and NADPH oxidase.

Topics: Acetophenones; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcitonin Gene-Related Peptide; Captopril; Cell Adhesion; Chymases; Disease Models, Animal; Endothelial Cells; Imidazoles; Intestines; Ischemia; Leukocyte Rolling; Leukocytes; Male; Mice; Mice, Inbred C57BL; Microscopy, Video; NADPH Oxidases; Pyridines; Pyrimidinones; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Calcitonin Gene-Related Peptide; Reperfusion Injury; Tetrazoles; Valine; Valsartan; Venules