Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia-reperfusion (I/R)-induced lung injury undermines lung transplantation (LTx) outcomes by predisposing lung grafts to primary graft dysfunction (PGD). Necrosis is a feature of I/R lung injury. However, regulated necrosis (RN) with specific signaling pathways has not been explored in an LTx setting. In this study, we investigated the role of RN in I/R-induced lung injury. To study I/R-induced cell death, we simulated an LTx procedure using our cell culture model with human lung epithelial (BEAS-2B) cells. After 18 h of cold ischemic time (CIT) followed by reperfusion, caspase-independent cell death, mitochondrial reactive oxygen species production, and mitochondrial membrane permeability were significantly increased. N-acetyl-Leu-Leu-norleucinal (ALLN) (calpain inhibitor) or necrostatin-1 (Nec-1) [receptor interacting serine/threonine kinase 1 (RIPK1) inhibitor] reduced these changes. ALLN altered RIPK1/RIPK3 expression and mixed lineage kinase domain-like (MLKL) phosphorylation, whereas Nec-1 did not change calpain/calpastatin expression. Furthermore, signal transducer and activator of transcription 3 (STAT3) was demonstrated to be downstream of calpain and regulate RIPK3 expression and MLKL phosphorylation during I/R. This calpain-STAT3-RIPK axis induces endoplasmic reticulum stress and mitochondrial calcium dysregulation. LTx patients' samples demonstrate that RIPK1, MLKL, and STAT3 mRNA expression increased from CIT to reperfusion. Moreover, the expressions of the key proteins are higher in PGD samples than in non-PGD samples. Cell death associated with prolonged lung preservation is mediated by the calpain-STAT3-RIPK axis. Inhibition of RIPK and/or calpain pathways could be an effective therapy in LTx.
 ...
PMID:Ischemia-reperfusion induces death receptor-independent necroptosis via calpain-STAT3 activation in a lung transplant setting. 3002 6

The proteins which bind to calmodulin in a Ca2+-dependent and reversible manner are known as calmodulin-binding proteins. These proteins are involved in a multitude of processes in which Ca2+ and calmodulin play crucial roles. Our group elucidated the mechanism and importance of these proteins in normal and diseased conditions. Various calmodulin-binding proteins were discovered and purified from bovine tissue including a heat stable calmodulin-binding protein 70, calmodulin-dependent protein kinase VI and a high molecular weight calmodulin-binding protein (HMWCaMBP). We observed a complex interplay occurs between these and other Ca2+ and calmodulin-binding proteins during cardiac ischemia and reperfusion. Purified cardiac HMWCaMBP is a homolog form of calpastatin and an inhibitor of the Ca2+-activated cysteine proteases, calpains and therefore can have cardioprotective role in ischemic conditions. Calcineurin is a Ca2+ and calmodulin-dependent serine/threonine protein phosphatase showed increased phosphatase activity in ischemic heart through its direct interaction with Hsp70 and expression of calcineurin following ischemia suggests self-repair and favorable survival outcomes. Calcineurin was also found to be present in other tissues including the eye; where its expression and calcineurin phosphatase activity varied. In neurons, calcineurin may play a key role in initiating apoptosis-related pathways especially in epilepsy. In colorectal cancer we demonstrated high calcineurin phosphatase activity and simultaneous overexpression of calcineurin. The impact of calcineurin signaling on neuronal apoptosis in epilepsy and its use as a diagnostic marker for colorectal cancer requires in-depth study.
 ...
PMID:Calmodulin-binding proteins: A journey of 40 years. 3020 93

The protein levels and activities of calpain-1 and calpain-2 are increased in cardiac mitochondria under pathological conditions including ischemia, diabetes, and sepsis, and transgenic overexpression of mitochondrial-targeted calpain-1 induces dilated heart failure, which underscores an important role of increased calpain in mitochondria in mediating myocardial injury. However, it remains to be determined whether selective inhibition of calpain in mitochondria protects the heart under pathological conditions. In this study, we generated transgenic mice overexpressing mitochondrial-targeted calpastatin in cardiomyocytes. Their hearts were isolated and subjected to global ischemia/reperfusion. Hyperglycemia was induced in the transgenic mice by injections of STZ. We showed that transgenic calpastatin was expressed exclusively in mitochondria isolated from their hearts but not from other organs including skeletal muscle and lung tissues. Transgenic overexpression of mitochondrial-targeted calpastatin significantly attenuated mitochondrial oxidative stress and cell death induced by global ischemia/reperfusion in isolated hearts, and ameliorated mitochondrial oxidative stress, cell death, myocardial remodeling and dysfunction in STZ-treated transgenic mice. The protective effects of mitochondrial-targeted calpastatin were correlated with increased ATP5A1 protein expression and ATP synthase activity in isolated hearts subjected to global ischemia/reperfusion and hearts of STZ-treated transgenic mice. In cultured rat myoblast H9c2 cells, overexpression of mitochondrial-targeted calpastatin maintained the protein levels of ATP5A1 and ATP synthase activity, prevented mitochondrial ROS production and decreased cell death following hypoxia/reoxygenation, whereas upregulation of ATP5A1 or scavenging of mitochondrial ROS by mito-TEMPO abrogated mitochondrial ROS production and decreased cell death. These results confirm the role of calpain in myocardial injury, suggesting that selective inhibition of calpain in myocardial mitochondria by mitochondrial-targeted calpastatin is an effective strategy for alleviating myocardial injury and dysfunction in cardiac pathologies.
 ...
PMID:Targeted inhibition of calpain in mitochondria alleviates oxidative stress-induced myocardial injury. 3296 9


<< Previous 1 2 3 4 5 6