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)

The effect of ST1942, a 2-aminotetraline derivative with anti-inflammatory properties, was evaluated in ischemia/reperfusion injury in CD1 and C57BL/6 mice. ST1942 or saline were injected intraperitoneally 30 min and 6, 24, 36 h after ischemia. Forty-eight hours after ischemia, ST1942 (25 mg/kg) reduced the infarct volume by 50% in CD1 and 61% in C57BL/6 mice. All subsequent data were obtained from the latter strain. The ischemic lesion was significantly reduced by 30% when the first injection was administered 6 h after ischemia, revealing a broad effective window. Degenerating neurons in striatum, cortex and hippocampus of ischemic mice were markedly decreased by ST1942. Also examined was the effect of ST1942 on general and focal neurological deficits for 4 days after ischemia. Mice receiving the drug twice daily showed constantly reduced deficits. We then investigated the cortical mRNA expression of some inflammatory and apoptotic genes by real-time PCR. Forty-eight hours after ischemia ST1942 treatment significantly counteracted ischemia-induced activation of IL-1beta, TNFalpha, and Bax, and enhanced the expression of the antiapoptotic gene, Bcl-2, showing in vivo anti-inflammatory and antiapoptotic actions. The microglial activation/macrophage recruitment in the ischemic lesion was strongly prevented in mice receiving ST1942. In neuron-microglia cocultures, ST1942 significantly counteracted LPS-induced cytotoxicity. Binding data and experiments on microglial cell cultures indicate that the anti-inflammatory effect of ST1942 may be due to its action on 5-HT2B receptors, thus highlighting the possibility that this 5-HT receptor subtype may represent a novel target for neuroprotective drugs in ischemic injury.
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PMID:2-Aminotetraline derivative protects from ischemia/reperfusion brain injury with a broad therapeutic window. 1711 39

A multifunctional protein metallothionein (MT) is induced by various chemicals and cytokines. We have found novel functions of MT as follows: 1) Cytokine expression such as IL-1alpha, IL-6, and TNFalpha responding to lipopolysaccharide is reduced in MT-deficient macrophages compared with in wild-type cells. 2) Nitric oxide production responding to TNFalpha and LPS is reduced in MT-deficient macrophages compared with in wild-type cells. 3) M-CSF expression responding to zinc is reduced in MT-deficient fibroblasts compared with in wild-type cells, and increased in MT-overexpressed fibroblasts compared with in control cells. 4) LIF, a STAT3 activating cytokine, protects the heart from ischemia/reperfusion injury. Transgenic mice overexpressing STAT3 have tolerance to ischemia/reperfusion-induced damage, whereas MT-null mutation cancels the myocardial protection. In this review, we discuss the relation of MT and stress responses from the point of view of cytokine-induced expression of MT and modulation of cytokine expression by MT.
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PMID:[Cytokine-induced metallothionein expression and modulation of cytokine expression by metallothionein]. 1740 98

Recent clinical studies of patients with sepsis have shown that the delivery of adequate oxygen alone does not necessarily result in improved organ function or survival. This study was undertaken to determine if optical spectroscopy could detect higher intracellular oxygenations in isolated, perfused guinea pig hearts that have been treated with endotoxin (lipopolysaccharide [LPS]) than in controls. Four hours after intraperitoneal injection with LPS, adult guinea pigs were anesthetized, and hearts were excised and perfused in the Langendorff manner. Six control and eight LPS-exposed guinea pigs were studied. Myoglobin oxygen saturation was determined from analysis of optical reflectance spectra acquired from the left ventricular free wall. Myoglobin saturation was significantly higher at baseline with LPS than in controls (96.0% +/- 0.8% vs. 89.4% +/- 1.7%, P < 0.001). At the end of 30 s of ischemia, myoglobin saturation decreased to 15% +/- 1% in controls, but to only 60% +/- 7% in the LPS group. Myocardial performance was determined by measured left ventricular developed pressure, which was significantly depressed in the LPS-exposed hearts relative to controls (30 +/- 4 mmHg vs. 67 +/- 9 mmHg, P < 0.001). Myocardial oxygen consumption, calculated from measurements of arterial and venous PO2 and coronary flow, was lower in LPS hearts relative to controls (0.199 +/- 0.021 mL oxygen x min(-1) x g(-1) vs. 0.157 +/- 0.006 mL oxygen x min(-1) x g(-1)). In this model of sepsis in the perfused guinea pig heart, intracellular oxygenation was higher and oxygen consumption was lower than in controls. Cellular dysfunction seen in sepsis may be caused by compromised oxygen use rather than insufficient oxygen delivery. Optical spectroscopy has the potential to noninvasively monitor patients and their responses to therapy.
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PMID:Optical spectroscopy demonstrates elevated intracellular oxygenation in an endotoxic model of sepsis in the perfused heart. 1750 11

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.
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PMID:Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway. 1752 28

Ghrelin is a novel brain-gut peptide and the endogenous ligand of growth hormone secretagogue receptor 1a (GHSR-1a). Evidences have been shown that ghrelin inhibited cell apoptosis in cardiocytes, endotheliocytes, osteoblasts, and so on. Recently, it was reported that ghrelin inhibited neuronal apoptosis of hypothalamus and hippocampus. However, little is known about the effects of ghrelin on cortical neurons during focal ischemia/reperfusion injury. In the present study, we showed that ghrelin (i.v.) prevented cortical neurons from injury induced by ischemia/reperfusion in vivo and by LPS, glutamate, NMDA and H(2)O(2) in vitro. We found that the expression of ghrelin's receptor (GHSR-1a) in rat cerebral cortex were obviously decreased by ischemia/reperfusion injury and increased by ghrelin (i.v.). Ghrelin up-regulated the expression of Bcl-2/Bax and HSP70, and inhibited caspase8, 9, 3 through GHSR-1a, which was contributed to the neuroprotective mechanism of ghrelin. Ghrelin might be an important regulator in therapeutic strategy of cortex injury.
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PMID:Ghrelin protects cortical neuron against focal ischemia/reperfusion in rats. 1756 May 44

Ischemic stroke induces drastic alterations of the functions of the neurogliovascular unit with dramatic consequences on the well-being of the patients in terms of cognitive and motor handicap. Nowadays, only very few therapeutics are available as a treatment of ischemic stroke. Ischemia is a multifactorial pathology involving different cerebral cellular components such as neurons, astrocytes and vessels working as a functional unit. Recent experimental strategy investigation involving different agents with antioxidant properties (dt-BC, stobadine) or pleiotropic effects (lipopolysaccharide, LPS) has been developed to evaluate whether the vascular wall could be considered as a potential target in neuroprotection concept.
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PMID:Neurogliovascular unit after cerebral ischemia: is the vascular wall a pharmacological target. 1762 44

Multiorgan failure is a major cause of late morbidity and mortality after trauma. Reactive oxygen species generated during shock/resuscitation contribute to tissue injury by priming the immune system for an exaggerated response to subsequent inflammatory stimuli such as LPS. Stilbazulenyl nitrone (STAZN) is a novel second-generation azulenyl nitrone that has been shown to have potent antioxidant properties in a rat model of brain ischemia. We hypothesized that STAZN may confer protection against lung injury after shock/resuscitation and LPS by reducing oxidative stress and lowering the production of NF-kappaB-dependent pro-inflammatory cytokines. Sprague-Dawley rats were submitted to a two-hit model of lung injury involving hemorrhagic shock/resuscitation and subsequent intratracheal LPS injection, with and without intraperitoneal injections of STAZN. STAZN reduced overall lung injury in response to LPS alone and also after shock/resuscitation plus LPS. STAZN also reduced plasma levels of 8-isoprostane, a proxy measure of oxidative stress, indicating its antioxidant activity in vivo. The effect of STAZN was, at least in part, related to its effect on nuclear translocation of NF-kappaB and generation of the pro-inflammatory cytokine TNF-alpha. Azulenyl nitrones such as STAZN represent a promising novel class of antioxidants for treating organ injury.
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PMID:Stilbazulenyl nitrone decreases oxidative stress and reduces lung injury after hemorrhagic shock/resuscitation and LPS. 1771 98

Gut mucosal injury observed during ischemia-reperfusion is believed to trigger a systemic inflammatory response leading to multiple organ failure. It should be interesting to demonstrate this relationship between gut and multiple organ failure in a sepsis model. Intestinal preconditioning (PC) can be used as a tool to assess the effect of intestinal ischemia in inflammatory response after LPS challenge. The aim of this study was to investigate the protective effect of PC against LPS-induced systemic inflammatory and intestinal heme oxygenase-1 (HO-1) expression. ES was performed with LPS (10 mg/kg iv) with or without PC, which was done before LPS. Rats were first subjected to sham surgery or PC with four cycles of 1 min ischemia and 4 min of reperfusion 24 h before LPS challenge or saline administration. PC significantly reduced fluid requirements, lung edema, intestinal lactate production, and intestinal injury. Inflammatory mRNA expressions for intestine and lung ICAM and TNF were significantly reduced after PC, and these effects were significantly abolished by zinc-protoporphyrin (a specific HO-1 activity inhibitor) and mimicked by bilirubin administration. Intestinal PC selectively increased HO-1 mRNA expression in intestine, but we have observed no expression in lungs. These findings demonstrate that intestinal injury is a important event for inflammatory response and multiple organ injury after LPS challenge. Intestinal HO-1 expression attenuates LPS-induced multiple organ failure by modulating intestine injury and its consequences on inflammatory response. Identification of the exact mechanisms responsible for intestine HO-1 induction may lead to the development of new pharmacological interventions.
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PMID:Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model. 1782 16

Ischemic gut contributes to the development of sepsis and organ failure in critically ill patients. Toll-like receptors (TLRs) have been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We hypothesize that LPS, a ligand for TLR4, decreases mesenteric I/R injury-induced gut damage through tumor necrosis factor alpha (TNF-alpha) signaling. First, wild-type (WT) mice were fed with oral antibiotics for 4 weeks to deplete the intestinal commensal microflora. At week 3, drinking water was supplemented with LPS (10 microg/microL) to trigger TLRs. The intestinal mucosa was harvested for TLR4 protein, caspase 3 activity, and terminal deoxynucleotide transferase labeling assay. Second, WT and Tnfrsf1a mice received 30-min ischemia and 30-min reperfusion (30I-30R) or 30I-180R of the intestine; intestinal permeability and lipid peroxidation of the intestine were examined. Third, WT and Tnfrsf1a mice were fed with oral antibiotics with or without LPS and received 30I-180R of the intestine. The intestinal mucosa was harvested for lipid peroxidation; glutathione (GSH) level; nuclear factor kappaB (NF-kappaB) and AP-1 DNA-binding activity; Bcl-w, TNF-alpha, and CXCR2 mRNA expression; and HSP70 protein assay. Commensal depletion increased caspase 3 activity as well as villi apoptosis and decreased TLR4 expression of the intestinal mucosa. LPS increased TLR4 expression and decreased villi apoptosis. Commensal depletion augmented 30I-180R-induced intestine permeability as well as lipid peroxidation and decreased GSH level in WT mice but not in Tnfrsf1a mice. LPS decreased 30I-180R-induced intestinal permeability as well as lipid peroxidation and increased GSH level of the intestinal mucosa in WT mice but not in Tnfrsf1a mice. Commensal depletion with 30I-180R increased NF-kappaB and AP-1 DNA-binding activity, HSP70 protein expression, and decreased Bcl-w and TNF-alpha mRNA expression of the intestinal mucosa in WT mice but not in Tnfrsf1a mice. Collectively, commensal microflora induces TLR4 expression and decreases apoptosis of the intestinal mucosa. Commensal depletion enhances I/R-induced gut damage. LPS prevents I/R-induced intestinal permeability, lipid peroxidation, and decrease in GSH level. Given that the preventive effect of LPS on I/R-induced gut damage and NF-kappaB activity of the intestine is abolished in Tnfrsf1a mice, we conclude that TLR ligand decreases mesenteric I/R injury-induced gut damage through TNF-alpha signaling.
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PMID:TLR ligand decreases mesenteric ischemia and reperfusion injury-induced gut damage through TNF-alpha signaling. 1831 7

Multiple studies of left ventricular dysfunction suggest that females may be more resistant to ischemia or endotoxemia. However, sex differences in right ventricular (RV) responses to pressure overload and/or endotoxemia have not been elucidated. We hypothesized that females would maintain better RV function during acute pressure overload (APO), endotoxemia, or a simultaneous insult from both processes. Age-matched male and proestrus female Sprague-Dawley rats were given an intraperitoneal injection of either phosphate buffered saline or LPS. Six hours after injection, hearts were removed by median sternotomy and isolated via Langendorff. End-diastolic pressures were sequentially elevated past physiologic levels by increasing the volume of a latex balloon that was inserted into the RV. Male RV function was depressed to a greater degree after APO injury compared with that in females (developed pressure: male, 44.97 mmHg vs. female, 58.23 mmHg). Interestingly though, at a physiologic end-diastolic pressure of 5 mmHg, endotoxic males and females maintained equivalent RV function. However, with concurrent endotoxic insult and APO, RV function was better maintained in males as compared with that in females (developed pressure: male, 59% of control versus female, 41% of control). Furthermore, tissue levels of IL-1 and IL-6, but not IL-10, were increased after endotoxin exposure but did not differ based on sex. Through this study, we have shown that sex differences exist in RV dysfunction, and that different cardiac insults diversely affect myocardial function. Understanding these differences may allow for the implementation of novel therapeutic treatment options that are designed to attenuate RV cardiovascular collapse.
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PMID:Proestrus female rats are more resistant to right ventricular pressure overload. 1832 33


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