Ischemic/reperfusion model

Resident CSCs were first isolated in murine hearts. Characterization of these cells was based on the expression of the stem cell-related surface antigens c-Kit and Sea-1. In the first study, freshly isolated c-Kit /Lin cells were shown to be clono-genic and to differentiate into myocytes, smooth muscle cells, and endothelial lineage cells [35]. Those cells generated functional myocardium when injected into ischemic areas of the heart. The second study characterized CSCs as Sca-l/c-Kit. When treated in culture with 5-azacytidine, those cells differentiated into a myogenic lineage. Subsequently, intravenous injection of the cells in an ischemia/reperfusion model resulted in infarct healing with cardiomyocyte transdifferentiation... 

Studies in various animal models and in human hearts suggest that apoptosis does occur in ischemia/reperfusion injury of the heart, though the relative contribution of apoptosis in comparison with necrosis to cell loss in ischemia/ reperfusion injury is still controversial. Cardiomyocyte apoptosis was first reported by Gottlieb et al. [107], who studied the ischemia/reperfusion in rabbit hearts and found the hallmark of apoptosis in ischemic/reperfused hearts but not in the normal or ischemic-only rabbit hearts. Identification of apoptosis was based on the presence of fragmented DNA in electrophoretic gels, on in situ nick end-labeling assays, and on electron microscopy. They concluded that apoptosis may be a specific feature of reperfusion injury in cardiac myocytes. Subsequent studies have shown that apoptosis probably occurs both in ischemia and reperfusion [108], It appears that apoptosis is more prominent after ischemia followed by reperfusion than after ischemia alone [109, 110],... 

Renal ischemia/reperfusion injury in vivo activates caspase-1 and caspase-3 [62, 70]. In a murine model of ischemia/ reperfusion injury, ZVAD-fmk, a pancaspase inhibitor, was shown to attenuate reperfusion-induced DNA damage (as determined by TUNEL assay) and inflammation [65]. Down-regulation of caspase-3 and caspase-8 by siRNA provided protection from acute kidney injury in a mice model of ischemia-reperfusion injury (71). Recent studies by Edelstein et al. [66, 72] help estabhsh a hnk between the inflammatory aspects of the ischemic/reperfusion injury and caspase activation. In these studies it was observed that caspase 1 deficient mice were protected from ischemia-reperfusion... 

Liposomal ATP protected human endothelial cells from energy failure in a cell culture model of sepsis (21). ATP-L increased the number of ischemic episodes tolerated before electrical silence and brain death in the rat (22,23). In a hypovolemic shock-reperfusion model in rats, the administration of ATP-L increased hepatic blood flow during shock and reperfusion of the liver (24). The addition of the ATP-L during cold storage preservation of rat liver improved its energy state and metabolism (25,26). Co-incubation of ATP-L with sperm cells improved their motility (27). Finally, biodistribution studies demonstrated significant accumulation of ATP-L in ischemia-damaged canine myocardium (28). 

In support of this possibility, resveratrol shows estrogenlike effect by stimulating proliferation and differentiation of osteoblasts. Mizutani et al. ° reported that resveratrol increased alkaline phosphatase activity, an osteoblast-specific marker, and DNA synthesis in mouse osteoblastic MC3T3-C1 cells in a dose-dependent fashion. Instead of accelerating bone loss like tamoxifen, resveratrol not only prevented bone loss but also stimulated osteoblast formation. Thus, resveratrol may serve as a beneficial agent in the prevention of and therapy for osteoporosis in postmenopausal women. It is also suggested that resveratrol has cardioprotective effect in isolated ischemic/reperfused rat heart model by its free-radical-scavenging effect. ... 

Lanthanum was used to demonstrate that astrogaloside IV, a small moleeule extraeted fi om a traditionally used medieinal herb (Astragalus membranaceus), maintains the BBB after ischemic/reperfusion injury in a murine model (Qu, Li et al. 2009). The meehanism for this is supposedly an upregulation of the expression of the TJ proteins oeeludin and ZO-1 and inhibition of the release of inflammatory cytokines from endothelial cells. 

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

Taken together, using a mouse model of hindlimb skeletal muscle injury, all three adenosine receptor subtypes could each individually induce protection from ischemia-reperfusion injury in skeletal muscle. Due to the lack of a highly selective A2B receptor agonist and antagonist, its role in mediating an anti-ischemic effect in skeletal muscle remains to be determined. 

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