Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Z-ligustilide (Z-LIG) is the primary lipophilic compound of the Chinese medicine Danggui (Radix Angelica sinensis). Previous studies demonstrated that Z-LIG had significant neuroprotective potential in both transient and permanent cerebral ischemia, possibly through antioxidant and anti-apoptotic mechanisms. The present study examined the mechanisms of Z-LIG on hydrogen peroxide (H(2)O(2))-induced injury in PC12 cells. Following exposure of the cells to H(2)O(2 )(500 microM), a significant reduction in cell survival and total antioxidant capacity (TAC), as well as increased intracellular reactive oxygen species (ROS), were observed. In addition, H(2)O(2 )treatment significantly upregulated Bax expression, cleaved-caspase 3, and cytosolic cytochrome-c, and decreased Bcl-2 protein levels. Pretreatment of the cells with Z-LIG (0.1, 1.0, 2.5, or 5.0 microg/ml) significantly attenuated H(2)O(2)-induced cell death, attenuated increased intracellular ROS levels, and decreased Bax expression, cleaved-caspase 3, and cytochrome-c. Further, Z-LIG improved cellular TAC and concentration-dependently upregulated Bcl-2 expression. These results demonstrate that Z-LIG has a pronounced protective effect against H(2)O(2)-induced cytotoxicity, at least partly through improving cellular antioxidant defense and inhibiting the mitochondrial apoptotic pathway. These findings suggest that Z-LIG may be useful in the treatment of neurodegenerative disorders in which oxidative stress and apoptosis are mainly implicated.
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PMID:Protection against hydrogen peroxide-induced injury by Z-ligustilide in PC12 cells. 1771 47

Lithium is a major drug used for the treatment of bipolar mood disorder and has recently been shown to have neuroprotective properties. In this study we investigated the neuroprotective effects of lithium in gerbils subjected to global cerebral ischemia, an animal model of stroke. The ischemia-induced exploratory behavior changes, measured by open field testing, were largely suppressed by lithium treatment for 7 days prior to ischemic onset. Similarly, memory impairments, measured by T-maze testing, were prevented by lithium pretreatment. This is believed to be the first report of lithium-induced protection against hyperactivity in a novel open field and memory impairment in a gerbil model of global ischemia. These behavioral benefits were associated with an increase in viable cells as measured by hematoxylin and eosin staining and a decrease in apoptotic TUNEL-positive cells in the CA1 hippocampal area of ischemic gerbils. Moreover, the lithium-induced neuroprotection was accompanied by down-regulation of pro-apoptotic p53 in the CA1 but up-regulation of anti-apoptotic Bcl-2 and heat shock protein 70 (HSP70) in the ischemic brain. These results underscore the ability of lithium to improve functional behavioral outcome in gerbil and rodent cerebral ischemic models and further indicate the potential therapeutic use of lithium in certain human stroke conditions.
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PMID:Lithium reduces ischemia-induced hippocampal CA1 damage and behavioral deficits in gerbils. 1802 86

Intravenous administration of bone marrow stromal cells (MSCs) in animal models with focal cerebral ischemia has been found to be effective in attenuating neuronal damage. We examined whether intravenously transplanted MSCs alters expression of apoptosis-related proteins. Fisher-344 rats were subjected to 90-min middle cerebral artery occlusion (MCAO). The experimental groups were: (I) vehicle group, with intravenous injection of phosphate-buffered saline (PBS) 3h after MCAO; and (II) transplant group, with intravenous injection of MSCs (3x10(6)cells) 3h after MCAO. Neurological function of rats was evaluated using modified neurological severity score (mNSS) and Rotor-rod Motor Test (RMT). Rats were sacrificed on 1st, 3rd and 7th days of MCAO, and coronal brain sections were stained immunohistochemically to identify the apoptosis-related proteins, namely survivin and Bcl-2. We also examined Terminal Deoxynucleotidyl Transferase-Mediated dUTP-biotin Nick End Labeling (TUNEL)-positive cells on 3rd day of MCAO. Functional recovery according to mNSS and RMT was significantly better in the transplant group as compared with the vehicle group (P<0.05). Immunohistochemical analysis revealed significant expression of survivin on 3rd day and Bcl-2 on 1st and 3rd days in the transplant group. The vehicle group displayed significantly more TUNEL-positive cells than the transplant group on 3rd day (P<0.05). These results suggest that intravenous transplantation of MSCs prevents down-regulation of survivin and Bcl-2 preventing apoptosis and cell death in the ischemic brain leading to motor and sensory function recovery.
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PMID:Intravenous administration of bone marrow stromal cells increases survivin and Bcl-2 protein expression and improves sensorimotor function following ischemia in rats. 1805 46

Cerebral ischemia/reperfusion (I/R) injury triggers multiple and distinct but overlapping cell signaling pathways, which may lead to cell survival or cell damage. There is overwhelming evidence to suggest that besides necrosis, apoptosis do contributes significantly to the cell death subsequent to I/R injury. Both extrinsic and intrinsic apoptotic pathways play a vital role, and upon initiation, these pathways recruit downstream apoptotic molecules to execute cell death. Caspases and Bcl-2 family members appear to be crucial in regulating multiple apoptotic cell death pathways initiated during I/R. Similarly, inhibitor of apoptosis family of proteins (IAPs), mitogen-activated protein kinases, and newly identified apoptogenic molecules, like second mitochondrial-activated factor/direct IAP-binding protein with low pI (Smac/Diablo), omi/high-temperature requirement serine protease A2 (Omi/HtrA2), X-linked mammalian inhibitor of apoptosis protein-associated factor 1, and apoptosis-inducing factor, have emerged as potent regulators of cellular apoptotic/antiapoptotic machinery. All instances of cell survival/death mechanisms triggered during I/R are multifaceted and interlinked, which ultimately decide the fate of brain cells. Moreover, apoptotic cross-talk between major subcellular organelles suggests that therapeutic strategies should be optimally directed at multiple targets/mechanisms for better therapeutic outcome. Based on the current knowledge, this review briefly focuses I/R injury-induced multiple mechanisms of apoptosis, involving key apoptotic regulators and their emerging roles in orchestrating cell death programme. In addition, we have also highlighted the role of autophagy in modulating cell survival/death during cerebral ischemia. Furthermore, an attempt has been made to provide an encouraging outlook on emerging therapeutic approaches for cerebral ischemia.
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PMID:Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. 1806 3

Here we discuss the probable role of autophagy in cerebral ischemia based on our own recent data and the literature. We examined the protein level of Beclin 1 (Bcl-2 interacting protein) and microtubule-associated protein 1 light chain 3 (LC3) which were previously found to promote autophagy. We found a dramatic elevation in Beclin 1 levels and LC3 in the penumbra of rats challenged by cerebral ischemia. We found also that a subpopulation of Beclin 1-upregulating cells is also expressing the active form of caspase-3, and that all Beclin 1 upregulating cells display dense staining of LC3. Neuronal cells that overexpress Beclin 1 may exhibit damaged DNA but without changes in nuclear morphology, which indicates that not all the Beclin 1-upregulating cells are predestined to die. We conclude that the cell death in the penumbra bears a resemblance not only to necrosis, apoptosis, or a compromise between the two, but exhibits also biochemical and morphological characteristics of autophagic cell death. The question that constantly arises, however, is whether autophagic activity in damaged cells is the cause of death or is actually an attempt to prevent it as a part of an endogenous neuroprotective response.
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PMID:Upregulation of Beclin 1 in the ischemic penumbra. 1807 95

Cerebral ischemia followed by oxygen reperfusion induced apoptosis in hippocampal neurons in the stroke-prone spontaneously hypertensive rat (SHRSP) but not in Wistar Kyoto rats (WKY). We investigated whether 2-phenyl-1,2-benzisoselenazol-3(2H)-one, also called PZ51 (ebselen), useful for treating ischemic damage or antihypertension in the brain, can protect against ischemic neuronal damage in SHRSP. In this study, we compared the effects of ebselen, carvedilol, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) as well as vitamin E, added to cultures of neurons after reoxygenation (20% O(2)) following hypoxia (1% O(2)). SHRSP neurons died rapidly during reoxygenation following hypoxia but were rescued in large measure by 10 muM ebselen (neuronal death; 2.7+/-1.4%). In order of neuroprotective potency, the agents ranked as follows: ebselen>carvedilol>MCI-186>vitamin E. In vivo, strong neuroprotection by ebselen was observed in the hippocampal CA1 region of SHRSP (32.9+/-9.5 apoptotic neuron/1000 neurons, 30 mg/kg/day). Ebselen prevented apoptosis as confirmed by morphological observations in vivo. Its effect was associated with the expression of Bcl-2 and Bax. These findings suggest that ebselen has a marked inhibitory effect on neuronal damage during stroke. Ebselen may be effective in the prevention and/or treatment of neurodegenerative diseases associated with excessive apoptosis in patients with stroke.
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PMID:Protective effects of ebselen, a seleno-organic antioxidant on neurodegeneration induced by hypoxia and reperfusion in stroke-prone spontaneously hypertensive rat. 1838 65

The antioxidant activity of C.oil in cerebral stroke has been reported earlier. We have attempted here to clarify the mechanisms underlying the neuroprotection against experimental cerebral ischemia by Curcuma oil (C.oil), isolated from the rhizomes of Curcuma longa. C.oil (250 mg/kg i.p.) was given 30 min before focal ischemia in rats caused by occlusion of the middle cerebral artery (1h of occlusion, 24h of reflow). Ischemia, leads to elevation in [Ca(2+)] this sets into motion a cascades of ischemic injury which was attenuated by C.oil. C.oil reduced post-ischemic brain neutrophil infiltration in the ischemic area, controlled tissue NOx levels and the neuronal levels of nitric oxide, peroxynitrite and reactive oxygen species when measured after 24h of reflow. Double immunofluorescence staining analysis and Western immunoblot analysis with C.oil treatment showed that the expression of nitric oxide synthase (NOS) isoforms were decreased significantly compared to the untreated ischemia group. Ischemia is associated with increased in TUNEL (TdT-mediated dUTP nick-end labeling) positive cells in brain sections indicating DNA fragmentation. The C.oil treated group showed a significant decrease in numbers of apoptotic cells compared to the untreated ischemia group, as seen in the flowcytometric analysis of the neurons. Results of immunohistochemistry and Western immunoblot indicate that C.oil suppressed the elevated protein level of Bax, and aided mitochondrial translocation and activation of Bcl-2 by altered mitochondrial membrane potential. It also inhibits the cytosolic release of apoptogenic molecules like cytochrome c, inhibits the activation of caspase-3 and the expression of p53 ultimately inhibiting apoptosis. Our observations suggest that high levels of NO generated by NOS isoforms are partially responsible for exacerbating the neuronal damage induced by MCAo by intraluminal filament.
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PMID:Curcuma oil modulates the nitric oxide system response to cerebral ischemia/reperfusion injury. 1848 79

Occlusion of a cerebral artery impairs blood flow leading to neuronal death. Reperfusion of the tissue is associated with inflammation, increased reactive oxygen species, necrosis and apoptosis. Hence, damage to the brain will continue even after the blood flow is restored. Isosteviol has been demonstrated to have protective effects against ischemia-reperfusion (IR) injury in the rat heart and the current study was undertaken to determine whether it is also effective in preventing IR injury in the brain. Rats were divided into six groups: a sham-operation control group and 5 IR groups that were pre-treated with either isosteviol 5 mg.kg (-1), 10 mg.kg (-1), 20 mg.kg (-1), nimodipine 5 mg.kg (-1), or saline. Cerebral ischemia was induced for 2 hours. Twenty-two hours after re-perfusion the rats were assessed for neurobehavioral deficit, infarct volume, histological changes, and malondialdehyde, superoxide dismutase (SOD), Bcl-2 and NF-kappaB levels in brain tissue. Pre-treatment with isosteviol reduced infarct volume, ameliorated cell death and infiltration of neutrocytes, improved neuro-locomotor activity, increased SOD activity, induced Bcl-2, suppressed lipid superoxidation and the expression of NF-kappaB, and therefore retarded necrosis and apoptosis of neurons and inflammation. These positive effects were dose-dependent with an isosteviol dose of 20 mg.kg (-1), thus being as effective as nimodipine.
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PMID:The neuroprotective effects of isosteviol against focal cerebral ischemia injury induced by middle cerebral artery occlusion in rats. 1855 71

It has been reported that ischemic insult increases the formation of autophagosomes and activates autophagy. However, the role of autophagy in ischemic neuronal damage remains elusive. This study was taken to assess the role of autophagy in ischemic brain damage. Focal cerebral ischemia was introduced by permanent middle cerebral artery occlusion (pMCAO). Activation of autophagy was assessed by morphological and biochemical examinations. To determine the contribution of autophagy/lysosome to ischemic neuronal death, rats were pretreated with a single intracerebral ventricle injection of the autophagy inhibitors 3-methyl-adenine (3-MA) and bafliomycin A1 (BFA) or the cathepsin B inhibitor Z-FA-fmk after pMCAO. The effects of 3-MA and Z-FA-fmk on brain damage, expression of proteins involved in regulation of autophagy and apoptosis were assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining and immunoblotting. The results showed that pMACO increased the formation of autophagosomes and autolysosomes, the mRNA and protein levels of LC3-II and the protein levels of cathepsin B. 3-MA, BFA and Z-FA-fmk significantly reduced infarct volume, brain edema and motor deficits. The neuroprotective effects of 3-MA and Z-FA-fmk were associated with an inhibition on ischemia-induced upregulation of LC3-II and cathepsin B and a partial reversion of ischemia-induced downregulation of cytoprotective Bcl-2. These results demonstrate that ischemic insult activates autophagy and an autophagic mechanism may contribute to ischemic neuronal injury. Thus, autophagy may be a potential target for developing a novel therapy for stroke.
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PMID:Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. 1856 42

Autophagy, an intracellular bulk degradation process of cellular constituents, plays a key role in cell homeostasis and can be induced by stresses, such as nutrient depletion, closed head injury or focal cerebral ischemia. This study focuses on the role of autophagy in neonatal hypoxia-ischemia (HI). Enhanced beclin 1 expression, a Bcl-2-interacting protein required for autophagy, has been used as a marker of autophagy. Beclin 1 was significantly increased at short times after HI, both in the hippocampus and in the cerebral cortex. Beclin 1-positive cells were found in the injured but not in the contralateral side and co-localized with MAP2 but not with GFAP or ED1, indicating that the protein is over-expressed in neurons. Beclin 1-positive cells were also TUNEL-positive. 3-Methyladenine and wortmannin, that inhibit autophagy, significantly reduced beclin 1 expression and switched the mechanism of the cell death mode from apoptosis to necrosis. Conversely, rapamycin, that increases autophagy, augmented beclin 1 expression, reduced necrotic cell death, and decreased brain injury. A prophylactic treatment with simvastatin or hypoxic preconditioning also increased beclin 1 expression. Taken together, these data indicate that autophagy is increased in neuronal cells after neonatal hypoxia-ischemia and suggest that over-activation of autophagic pathways represents a potential protective mechanism in the early stage of the brain injury.
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PMID:Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. 1876 Mar 64


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