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

In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9-11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage.
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PMID:Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats. 2945 6

Intestinal ischemia/reperfusion injury is a severe disease associated with a high mortality. The mechanisms that cause ischemia/reperfusion injury are complex and many factors are involved in the injury formation process; however, the only available treatment is surgical intervention. Recent studies demonstrated that the intestinal microbiome plays a key role in intestinal ischemia/reperfusion injury and there are many factors associated with intestinal bacteria during the formation of the intestinal ischemia/reperfusion injury. Among the Toll-like receptors (TLR), TLR2, TLR4, and their adaptor protein, myeloid differentiation primary-response 88 (MyD88), have been reported to be involved in intestinal ischemia/reperfusion injury. Oxidative stress and nitric oxide are also associated with intestinal bacteria during the formation of the intestinal ischemia/reperfusion injury. This review focuses on our current understanding of the impact of the microbiome, including the roles of the TLRs, oxidative stress, and nitric oxide, on intestinal ischemia/reperfusion injury.
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PMID:Microbiome and intestinal ischemia/reperfusion injury. 3008 40

The voltage-gated cardiac sodium channel, Nav1.5, is the key component that controls cardiac excitative electrical impulse and propagation. However, the dynamic alterations of Nav1.5 during cardiac ischemia and reperfusion (I/R) are seldom reported. We found that the protein levels of rat cardiac Nav1.5 were significantly decreased in response to cardiac I/R injury. By simulating I/R injury in cells through activating AMPK by glucose deprivation, AMPK activator treatment, or hypoxia and reoxygenation (H/R), we found that Nav1.5 was down-regulated by AMPK-mediated autophagic degradation. Furthermore, AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. This study highlights an instrumental role of AMPK in mediating the autophagic degradation of Nav1.5 during cardiac I/R injury.-Liu, X., Chen, Z., Han, Z., Liu, Y., Wu, X., Peng, Y., Di, W., Lan, R., Sun, B., Xu, B., Xu, W. AMPK-mediated degradation of Nav1.5 through autophagy.
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PMID:AMPK-mediated degradation of Nav1.5 through autophagy. 3075 45

G protein-coupled receptors (GPCRs) represent the largest family of therapeutic targets for FDA approved drugs. Therefore, understanding the molecular regulation of their signaling pathways is of paramount importance. Similarly, the mitogen activated protein kinase (MAPK) p38 is a critical mediator of proinflammatory disease. Yet despite decades of intense investigation, therapeutically viable inhibitors have struggled to make it into the clinic. New studies describing the regulation and activation of a GPCR dependent atypical p38 signaling pathway represents a novel therapeutic avenue to the treatment of many proinflammatory disorders. These recent studies have defined how thrombin and ADP can induce Src dependent activation of the E3 ubiquitin ligase NEDD4-2. Src dependent phosphorylation of a 2,3-linker peptide releases NEDD4-2 auto-inhibition and triggers the induction of proinflammatory atypical p38 signaling from the endosome. Activation of the atypical p38 pathway requires the direct interaction between an adaptor protein TAB1 and p38, that bypasses the requirement for the classical MKK3/6 dependent activation of p38. Therefore, providing a mechanism to specifically block proinflammatory GPCR atypical p38 activation while leaving basic p38 activity intact. Critically, new studies demonstrated that disruption of the TAB1-p38 interface is a druggable target, that would enable the selective inhibition of proinflammatory p38 signaling and ischemic injury. Atypical p38 signaling is linked to multiple clinically relevant pathologies including inflammation, cardiotoxicity, myocardial ischemia and ischemia reperfusion injury. Therefore, GPCR induced endosomal p38 signaling represents a novel understudied branch of proinflammatory p38 signaling and an ideal potential therapeutic target that warrants further investigation.
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PMID:Ubiquitination as a Key Regulator of Endosomal Signaling by GPCRs. 3098 58

Stroke significantly affects white matter in the brain by impairing axon function, which results in clinical deficits. Axonal mitochondria are highly dynamic and are transported via microtubules in the anterograde or retrograde direction, depending upon axonal energy demands. Recently, we reported that mitochondrial division inhibitor 1 (Mdivi-1) promotes axon function recovery by preventing mitochondrial fission only when applied during ischemia. Application of Mdivi-1 after injury failed to protect axon function. Interestingly, L-NIO, which is a NOS3 inhibitor, confers post-ischemic protection to axon function by attenuating mitochondrial fission and preserving mitochondrial motility via conserving levels of the microtubular adaptor protein Miro-2. We propose that preventing mitochondrial fission protects axon function during injury, but that restoration of mitochondrial motility is more important to promote axon function recovery after injury. Thus, Miro-2 may be a therapeutic molecular target for recovery following a stroke.
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PMID:Preserving Mitochondrial Structure and Motility Promotes Recovery of White Matter After Ischemia. 3115 63

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in CD38-/- mice and CD38-/- neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression.
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PMID:CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions. 3236 89

Background: Oxidative stress has emerged as an essential factor in the pathogenesis of intestinal ischemia/reperfusion (I/R) injury. The adaptor protein p66Shc is a key regulator of reactive oxygen species (ROS) generation and a mediator of I/R damage in the intestine, but the upstream mechanisms that directly regulate p66Shc expression during intestinal I/R remain largely unknown. Recent studies have suggested that noncoding RNAs, such as circular RNAs (circRNAs), are important players in physiological and pathological processes based on their versatile regulatory roles in gene expression. The aim of this study was to elucidate the contribution of p66Shc to oxidative damage in intestinal I/R and to investigate the regulation of p66Shc by circRNA sponges. Methods: Intestinal I/R was induced in mice via superior mesenteric artery (SMA) occlusion. A miR-339-5p agomir or circ-protein kinase C beta (PRKCB) siRNA was injected intravenously before I/R challenge. In addition, Caco-2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro to simulate an in vivo I/R model. Results: In vitro, p66Shc deficiency significantly reduced H/R-induced ROS overproduction by attenuating mitochondrial superoxide anion (O2 -) levels, suppressing NADPH oxidase activity and enhancing antioxidant enzyme expression. Moreover, miR-339-5p was identified to directly regulate p66Shc expression in the intestine. Furthermore, we found that a circRNA transcribed from the PRKCB gene, named circ-PRKCB, acted as an endogenous miR-339-5p sponge to regulate p66Shc expression. circ-PRKCB silencing or miR-339-5p overexpression significantly downregulated p66Shc expression and attenuated oxidative stress levels and I/R injury in vivo and in vitro. Notably, the increased circ-PRKCB levels and decreased miR-339-5p levels associated with murine intestinal I/R were consistent with those in patients with intestinal infarction. Conclusions: Our findings reveal a crucial role for the circ-PRKCB/miR-339-5p/p66Shc signaling pathway in regulating oxidative stress in the I/R intestine. This pathway may be a potential therapeutic target for intestinal I/R injury.
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PMID:circ-PRKCB acts as a ceRNA to regulate p66Shc-mediated oxidative stress in intestinal ischemia/reperfusion. 3292 74


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