Gene/Protein Disease Symptom Drug Enzyme Compound
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 58,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor phosphatase and tensin homologue (PTEN) is a protein and lipid phosphatase. PTEN mutations have been associated with a large number of human cancers. To understand the physiological role of PTEN in the brain and its relationship to Akt in ischemic injury, we first investigated the localization of PTEN immunoreactivity in the brains of normal adult rats using immunohistochemistry. We then detected the modulation of PTEN and p-Akt following transient global ischemia by Western blot and immunohistochemistry analyses. Our observation of normal brains showed that PTEN was heterogeneously distributed in the cytoplasm, nuclei, and processes in different regions. It was shown immunohistochemically that PTEN was distributed differentially in rat brain, with the highest levels in the anterior olfactory nucleus, cerebral cortex, amygdaloid nucleus, hippocampus, Purkinje's cells, and several nuclei in the basal ganglia, thalamus, midbrain, and pons. After global cerebral ischemia, PTEN and p-Akt immunoreactivities were increased in the cerebral cortex. This was accompanied by the nuclear translocation of p-Akt. Double-labeling experiments revealed that PTEN and p-Akt were most likely localized to neurons. These results suggest a role for PTEN in normal adult brain and that the PTEN/Akt pathway may be involved in neuronal survival or plasticity after ischemic injury.
Anat Rec (Hoboken) 2009 Apr
PMID:Differential expression of PTEN in normal adult rat brain and upregulation of PTEN and p-Akt in the ischemic cerebral cortex. 1914 97

The aim of this study was to investigate the therapeutic efficacy and neuroprotective mechanisms of UCF-101, a novel Omi/HtrA2 inhibitor, following ischemia/reperfusion brain injury. Male Wistar rats were subjected to 2 hr of middle cerebral artery occlusion followed by reperfusion. Animals were divided into 3 groups: sham, vehicle-treated ischemia/reperfusion, and UCF-101 treatment. In the UCF-101 treatment group, rats were intraperitoneally administered UCF-101 (1.5 micromol/kg) 10 min prior to reperfusion. The rats were evaluated for neurological deficits, and brain infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride. TUNEL staining was utilized to evaluate the amount of apoptosis. In addition, expressions of protein caspase-8, caspase-3, FasL, and FLIP were examined by Western blot analysis. Results demonstrated that UCF-101 treatment significantly decreased cerebral infarct size by about 16.27% (P < 0.05) and also improved neurological behavior. TUNEL staining revealed that UCF-101 treatment significantly reduced TUNEL-positive cells in the cerebral cortex. Furthermore, the upregulation in the expression of FasL and the cleavage products of active caspase-8 and caspase-3 induced by ischemia was attenuated in mice treated with UCF-101, whereas upregulation of FLIP levels was increased. The present results demonstrated that UCF-101 protects against cerebral ischemia/reperfusion injury in mice. UCF-101 provided neuroprotection in vivo, and this was correlated with regulation of Fas-mediated apoptotic proteins. Taken together, the use of UCF-101 is a potent, neuroprotective factor for the treatment of focal cerebral ischemia.
Anat Rec (Hoboken) 2009 Jun
PMID:UCF-101, a novel Omi/HtrA2 inhibitor, protects against cerebral ischemia/reperfusion injury in rats. 1946 55

This study describes and exemplifies generally applicable design-based stereological methods for obtaining quantitative estimates of the numbers and sizes of capillaries, cardiomyocytes, and cardiomyocyte nuclei in immersion-fixed human left ventricles (N = 6). The design-based stereological methods are valid in all cardiac investigations onto quantifying changes in structure and function as seen under various conditions such as during development, aging, hypertrophy, and following ischemia/reperfusion. The applied principles of unbiased stereology were as follows: 1) uniform random sampling was taken at all levels, also in respect to orientations, for estimates of length and mean sizes. 2) All global structural quantities were estimated as total quantity = density x volume of the left ventricle. As an example, the left ventricle contains 1.5 x 10(9) capillaries with a total length of just below 200 km. 3) Stereological methods were used for estimating the volume density, surface area density, and length density of capillaries and cardiomyocytes. The numerical density of cardiomyocyte nuclei and capillaries was estimated, using the optical and physical disector, respectively. 4) In all local quantities, "size" was estimated either directly, using unbiased estimators to obtain the average individual size and size distribution parameters, or indirectly, using the relationship that: average size = total quantity/total number. In the six hearts constituting this study, we observed the anticipated correlation between left ventricular volume and global estimates such as total number of capillaries. There were no correlation between local quantities and total left ventricular volume (e.g., average star volume of individual cardiomyocytes).
Anat Rec (Hoboken) 2009 Oct
PMID:The application of stereological methods for estimating structural parameters in the human heart. 1971 57

The immunosuppressant FK506 (1 mg/kg, i.p.) reduces the infarct size following 90 min occlusion of the middle cerebral artery (MCAo) in adult rat brain. Here we have investigated the effect of FK506 on cerebral immune cells that are considered to contribute to neurodegeneration. FK506 substantially attenuated the response of resident and peripheral immune cells following transient ischemia. Between 24 hr and 5 days after MCAo, FK506 reduced the T-cell infiltration in the infarct area as well as the presence of activated and/or phagocytic OX-18, OX-42, GSA-IB4, Iba1, and ED1 positive microglia/macrophages. FK506 also lowered the protein levels of TNFalpha and IL-2 in ischemic brain areas. Repetitive application of FK506 over 20 days attenuated the activation of microglia in the substantia nigra (SN), an area of secondary degeneration. Importantly, FK506 conferred also lasting protection of the neurons of SN; these neurons degenerate by withdrawal of neurotrophic factors from the striatum that undergoes necrotic death as part of the ischemic core. To understand the molecular basis of FK506 effects in cerebral immune cells, we determined in primary postnatal day 0/1 (P0/P1) microglia (i) the expression of the FK506 binding proteins FKBP12, FKBP52, and FKPB65 and (ii) that FK506 (1-100 ng/mL) lowered the number of resting or lipopolysaccharide stimulated microglia as well as we induced the lipopolysaccharide release of TNFalpha in a dose-dependent manner. In summary, FK506 confers rescue of brain tissue following cerebral ischemia not only by neuronal protection, but also by suppression of microglial activation and peripheral immune responses.
Anat Rec (Hoboken) 2009 Dec
PMID:FK506 protects against various immune responses and secondary degeneration following cerebral ischemia. 1972 59

Synaptotagmins (Syts) are transmembrane proteins involved in the regulation of membrane trafficking. Here, we summarize literature data that provide growing evidence that several Syts are involved in the pathophysiological mechanisms of temporal lobe epilepsy and Parkinson's disease, as well as few reports related to brain ischemia and Alzheimer's disease (AD). We also report new data from our laboratories, showing changes of the expression of several Syts in Tg2576 mouse model of AD that may be related to neuroinflammation surrounding the beta-amyloid plaques. Furthermore, we demonstrate N-methyl-D-aspartate receptor-mediated upregulation of Syt 4 mRNA in a model of excitotoxic striatal lesion induced by unilateral striatal injection of quinolinic acid, associating the upregulation of Syt 4 with mechanisms of excitotoxicity. We propose that pharmacological manipulation of Syt expression in animal models of neurodegeneration should be further explored, as it may help to clarify the role of individual Syt isoforms in the regulation of membrane trafficking in neurodegeneration.
Anat Rec (Hoboken) 2009 Dec
PMID:Synaptotagmins in neurodegeneration. 1994 39

Cerebral ischemic injury resulting from either focal or global circulatory arrests in the brain is one of the major causes of death and disability in the adult population. The hippocampus, playing important roles in learning and memory, is selectively vulnerable to ischemic insults. Distinct populations of hippocampal neurons are targeted by ischemia and multiple factors, including excitotoxicity, oxidative stress, and inflammation, are responsible for their damage and death. Modifications of synapses occur very early after ischemia, reflecting related changes in synaptic transmission. These modifications structurally relate to spatial patterns formed by synaptic vesicles, geometry of postsynaptic density, and so forth. Ischemia-induced changes of synaptic contacts can be implicated in the mechanisms leading to delayed neuronal death. In this review, we summarize the available data on the structural aspects of ischemic injury of the hippocampus obtained in tissue culture and animal models and discuss pathways of neurodegeneration common for cerebral ischemia and various neurodegenerative disorders.
Anat Rec (Hoboken) 2009 Dec
PMID:Structural features of ischemic damage in the hippocampus. 1994 45

The phenomenon of ischemic tolerance perfectly describes this quote "What does not kill you makes you stronger." Ischemic pre- or postconditioning is actually the strongest known procedure to prevent or reverse neurodegeneration. It works specifically in sensitive vulnerable neuronal populations, which are represented by pyramidal neurons in the hippocampal CA1 region. However, tolerance is effective in other brain cell populations as well. Although, its nomenclature is "ischemic" tolerance, the tolerant phenotype can also be induced by other stimuli that lead to delayed neuronal death (intoxication). Moreover, the recent data have proven that this phenomenon is not limited to application of sublethal stimuli before the lethal stress but reversed arrangement of events, sublethal stress after lethal insult, is rather equally effective. A very important term is called "cross conditioning." Cross conditioning is the capability of one stressor to induce tolerance against another. So, since pre- or post-conditioners can be used plenty of harmful stimuli, hypo- or hyperthermia and some physiological compounds, such as norepinephrine, bradykinin. Delayed neuronal death is the slow development of postischemic neurodegeneration. This allows an opportunity for a great therapeutic window of 2-3 days to reverse the cellular death process. Moreover, it seems that the mechanisms of ischemic tolerance-delayed postconditioning could be used not only after ischemia but also in some other processes leading to apoptosis.
Anat Rec (Hoboken) 2009 Dec
PMID:Ischemic tolerance: the mechanisms of neuroprotective strategy. 1994 53

Oxidative stress-induced necrosis plays an important role in ischemia-reperfusion injury, such as stroke and heart attack. Here, we describe the development of selective inhibitors of necrosis, MS-1 and IM-54, as potential cardioprotective agents and biological tools for investigating the molecular mechanisms of cell death. By means of chemical modifications of kinase inhibitor BM I, its affinity for various kinases was successfully removed and a potent and selective inhibitor of necrosis, IM-54, was obtained. IM-54 inhibits necrosis induced by oxidative stress, but not apoptosis induced by anticancer drugs.
Chem Rec 2010 Oct
PMID:Development of selective inhibitors of necrosis. 2084 66

Cryopreserving ovarian tissue followed by transplantation has been suggested to preserve fertility for young cancer survivors. However, ischemia in the early stage after transplantation causes massive follicle loss. The aim was to investigate the histological and ultrastructural characteristics of the frozen-thawed human fetal ovarian tissue after xenotransplantation and the effects of Salviae miltiorrhizae (SM) on the angiogenesis. The human fetal ovarian tissues were frozen-thawed, xenografted into the immunodeficient nu/nu mice, and then collected 2, 7, and 28 days after transplantation. SM was administered. Compared with that of the frozen-thawed ovarian tissue, the total follicle number of the grafts was greatly reduced. Nearly half of the primordial follicles were damaged at different levels on day 2. Moreover, edema was prevalent in the stroma during the first week after the graft, especially on day 2. The microvessel density of the grafts was increased on day 2, reached a peak on day 7, and then declined on day 28. Both healthy primordial follicle proportion and the total healthy primordial follicles pool in the SM group were significantly higher than those of the control group (P = 0.003 and P = 0.001). We found a statistically significant difference of microvessel density between the two groups on day 2 (P < 0.001). In the frozen-thawed fetal ovarian grafts, angiogenesis has been begun on day 2, and the first week is the critical time for the grafts to regain their function, in which SM can facilitate graft vascularization and improve the preservation of primordial follicles.
Anat Rec (Hoboken) 2010 Dec
PMID:Angiogenesis of the frozen-thawed human fetal ovarian tissue at the early stage after xenotransplantation and the positive effect of Salviae miltiorrhizae. 2108 46

Oxidative stress has been implicated as a cause of hair cell damage after ischemia reperfusion injury, noise trauma, and ototoxic injury. Oxidative stress can induce both apoptosis or necrosis depending on the degree of exposure. To study how reactive oxygen species (ROS) interacts with hair cells, we have developed an in vitro model of oxidative stress using organ of Corti cultures exposed to physiologically relevant concentrations of hydrogen peroxide (H(2) O(2) ). Treatment of organ of Corti cultures with low concentrations of H(2) O(2) results in loss of outer hair cells in the basal turn of the explant. Higher concentrations of peroxide result in more extensive outer hair cell injury as well as loss of inner hair cells. Early outer hair cell death appears to occur though apoptosis as demonstrated by staining of activated caspase. The effect of oxidative stress on mitochondrial function is a key determinant of degree of damage. Oxidative stress results in reduction of the mitochondrial membrane potential and reduction of mitochondrial produced antioxidants. Low doses of oxidative stress induce changes in mitochondrial gene expression and induce mitochondrial DNA deletions. Recurrent oxidative stress or inhibition of mitochondrial function significantly enhanced hair cell death. This tissue culture model of oxidative hair cell injury maintains a pattern of injury similar to what is observed in vivo after oxidative injury and can be used to study the effects of ROS on hair cells over the time period of the culture.
Anat Rec (Hoboken) 2012 Nov
PMID:Low dose oxidative stress induces mitochondrial damage in hair cells. 2304 77


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