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1.
Ethanol-induced cerebellar hypoplasia is associated with inhibition of insulin-stimulated survival signaling. The present work explores the mechanisms of impaired insulin signaling in a rat model of fetal alcohol syndrome. Real-time quantitative RT-PCR demonstrated reduced expression of the insulin gene in cerebella of ethanol-exposed pups. Although receptor expression was unaffected, insulin and insulin-like growth factor (IGF-I) receptor tyrosine kinase (RTK) activities were reduced by ethanol exposure, and these abnormalities were associated with increased PTP1b activity. In addition, glucose transporter molecule expression and steady-state levels of ATP were reduced in ethanol-exposed cerebellar tissue. Cultured cerebellar granule neurons from ethanol-exposed pups had reduced expression of genes encoding insulin, IGF-II, and the IGF-I and IGF-II receptors, and impaired insulin- and IGF-I-stimulated glucose uptake and ATP production. The results demonstrate that ethanol inhibits insulin-mediated actions in the developing brain by reducing local insulin production and insulin RTK activation, leading to inhibition of glucose transport and ATP production.Received 30 December 2004; received after revision 1 March 2005; accepted 10 March 2005 相似文献
2.
Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons 总被引:3,自引:0,他引:3
S.M. de la Monte T.R. Neely J. Cannon J.R. Wands 《Cellular and molecular life sciences : CMLS》2001,58(12-13):1950-1960
Ethanol impairs insulin-stimulated survival and mitochondrial function in immature proliferating neuronal cells due to marked inhibition of downstream signaling through P13 kinase. The present study demonstrates that, in contrast to immature neuronal cells, the major adverse effect of chronic ethanol exposure (50 mM) in post-mitotic rat cerebellar granule neurons is to inhibit insulin-stimulated mitochondrial function (MTT activity, MitoTracker Red fluorescence, and cytochrome oxidase immunoreactivity). Ethanol-impaired mitochondrial function was associated with increased expression of the p53 and CD95 pro-apoptosis genes, reduced Calcein AM retention (a measure of membrane integrity), increased SYTOX Green and propidium iodide uptake (indices of membrane permeability), and increased oxidant production (dihydrorosamine fluorescence and H2O2 generation). The findings of reduced membrane integrity and mitochondrial function in short-term (24 h) ethanol-exposed neurons indicate that these adverse effects of ethanol can develop rapidly and do not require chronic neurotoxic injury. A role for caspase activation as a mediator of impaired mitochondrial function was demonstrated by the partial rescue observed in cells that were pre-treated with broad-spectrum caspase inhibitors. Finally, we obtained evidence that the inhibitory effects of ethanol on mitochondrial function and membrane integrity were greater in insulin-stimulated compared with nerve growth factor-stimulated cultures. These observations suggest that activation of insulin-independent signaling pathways, or the use of insulin sensitizer agents that enhance insulin signaling may help preserve viability and function in neurons injured by gestational exposure to ethanol. 相似文献
3.
Soscia SJ Tong M Xu XJ Cohen AC Chu J Wands JR de la Monte SM 《Cellular and molecular life sciences : CMLS》2006,63(17):2039-2056
In fetal alcohol syndrome (FAS), cerebellar hypoplasia is associated with impaired insulin-stimulated survival signaling.
This study characterizes ethanol dose-effects on cerebellar development, expression of genes required for insulin and insulin-like
growth factor (IGF) signaling, and the upstream mechanisms and downstream consequences of impaired signaling in relation to
acetylcholine (ACh) homeostasis. Pregnant Long Evans rats were fed isocaloric liquid diets containing 0%, 2%, 4.5%, 6.5%,
or 9.25% ethanol from gestation day 6. Ethanol caused dose-dependent increases in severity of cerebellar hypoplasia, neuronal
loss, proliferation of astrocytes and microglia, and DNA damage. Ethanol also reduced insulin, IGF-I, and IGF-II receptor
binding, insulin and IGF-I receptor tyrosine kinase activities, ATP, membrane cholesterol, and choline acetyltransferase (ChAT)
expression. In vitro studies linked membrane cholesterol depletion to impaired insulin receptor binding and insulin-stimulated ChAT. In conclusion,
cerebellar hypoplasia in FAS is mediated by insulin/IGF resistance with attendant impairments in energy production and ACh
homeostasis.
Received 4 May 2006; received after revision 13 June 2006; accepted 20 June 2006 相似文献
4.
Joshi S Guleria RS Pan J Bayless KJ Davis GE Dipette D Singh US 《Cellular and molecular life sciences : CMLS》2006,63(23):2859-2870
Developmental exposure to ethanol impairs fetal brain development and causes fetal alcohol syndrome. Although the cerebellum
is one of the most alcohol-sensitive brain areas, signaling mechanisms underlying the deleterious effects of ethanol on developing
cerebellar granule neurons (CGNs) are largely unknown. Here we describe the effects of in vivo ethanol exposure on neurite formation in CGNs and on the activation of Rho GTPases (RhoA and Rac1), regulators of neurite
formation. Exposure of 7-day-old rat pups to ethanol for 3 h moderately increased blood alcohol concentration (BAC) (∼40 mM)
and inhibited neurite formation and Rac1 activation in CGNs. Longer exposure to ethanol for 5 h resulted in higher BAC (∼80 mM),
induced apoptosis, inhibited Rac1, and activated RhoA. Studies demonstrated a regulatory role of Rho GTPases in differentiation
of cerebellar neurons, and indicated that ethanol-associated impairment of Rho GTPase signaling might contribute to brain
defects observed in fetal alcohol syndrome.
Received 16 July 2006; received after revision 12 September 2006; accepted 13 October 2006 相似文献
5.
Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons 总被引:11,自引:0,他引:11
de la Monte SM Neely TR Cannon J Wands JR 《Cellular and molecular life sciences : CMLS》2000,57(10):1471-1481
Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent
major dementia-associated abnormalities in Alzheimer’s disease (AD). This study examined the role of oxidative stress as a
factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated
with H2O2 (9–90 μM) or desferrioxamine (2–25 μM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function,
and pro-apoptosis and sprouting gene expression. H2O2 treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The
H2O2-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of
the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin,
and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal
loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has
a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated
with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection),
and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast,
hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and
reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD,
both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.
Received 24 May 2000; received after revision 7 July 2000; accepted 27 July 2000 相似文献
6.
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8.
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified as a key regulator of insulin-dependent
glycogen synthesis. GSK-3 was subsequently shown to function in a wide range of cellular processes including differentiation,
growth, motility and apoptosis. Aberrant regulation of GSK-3 has been implicated in a range of human pathologies including
Alzheimer’s disease, non-insulin-dependent diabetes mellitus (NIDDM) and cancer. As a consequence, the regulation of GSK-3
and the therapeutic potential of GSK-3 inhibitors have become key areas of investigation. This review will focus on the mechanisms
of GSK-3 regulation, with emphasis on modulation by upstream signals, control of substrate specificity and GSK-3 localisation.
The details of these mechanisms will be discussed in the context of specific signalling pathways.
Received 30 January 2007; received after revision 5 March 2007; accepted 16 April 2007 相似文献
9.
Justo R Alcolea MP Colom B Riera AN Gianotti M García-Palmer FJ 《Cellular and molecular life sciences : CMLS》2002,59(12):2199-2209
To establish the role of mitochondrial subpopulations in the mitochondrial maturation process, we studied morphological and
functional changes in the mitochondria of different mammalian conceptus tissues during the organogenic and the placentation
processes. Mitochondrial subpopulations of three different conceptus tissues, embryo and visceral yolk sac placenta on gestational
days 11, 12 and 13 and placenta on days 12 and 13, were examined morphologically by transmission electron microscopy. Cytochrome
oxidase activity and protein levels were also measured in each mitochondrial subpopulation. The results indicate two different
mitochondrial subpopulation profiles: a homogeneous one, which corresponds to immature mitochondria, and a heterogeneous one,
which represents the mature mitochondria. The three tissues studied show different morphologic and metabolic patterns of mitochondrial
maturation during the placentation process, rendering them suitable as experimental models to establish the p
ossible relationship between mitochondrial maturation and the mitochondrial subpopulations.
Received 5 August 2002; received after revision 23 September 2002; accepted 8 October 2002
RID="*"
ID="*"Corresponding author. 相似文献
10.
Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression 总被引:1,自引:0,他引:1
Galland S Georges B Le Borgne F Conductier G Dias JV Demarquoy J 《Cellular and molecular life sciences : CMLS》2002,59(3):540-545
The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial
matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible
for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in
hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were
shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular
by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria.
Our study showed that thyroid hormones also increased carnitine bioavailability.
Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002 相似文献
11.
Catassi A Cesario A Arzani D Menichini P Alama A Bruzzo C Imperatori A Rotolo N Granone P Russo P 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2377-2386
The effects of different marine derived agents were studied in A549 cell growth. These drugs induced cell cycle arrest at the G2-M phase associated with the up-regulation of GADD45alpha-gamma and down-regulation of c-Myc. In treated cells, GADD45alpha-gamma and c-Myc were up- and down-regulated, respectively. A cascade of events leading to apoptotic mitochondrial 'intrinsic' pathway was observed in treated cells: (1) dephosphorylation of BAD serine136; (2) BAD dissociation from 14-3-3 followed by its association with BCL-XL; (3) cytochrome c release; (4) caspase-3 activation, and (5) cleavage of vimentin. Caspase(s) inhibitor prevented the formation of cleavage products and, in turn, apoptosis was inhibited through a p53-independent mechanism. Moreover, these compounds did not activate NF-kappaB. Our findings may offer new insights into the mechanisms of action of these agents in A549 cells. The better understanding of their effects might be important to fully exploit the potential of these new drugs. 相似文献
12.
Differential insult-dependent recruitment of the intrinsic mitochondrial pathway during neuronal programmed cell death 总被引:1,自引:1,他引:0
Diwakarla S Nagley P Hughes ML Chen B Beart PM 《Cellular and molecular life sciences : CMLS》2009,66(1):156-172
Programmed cell death contributes to neurological diseases and may involve mitochondrial dysfunction with redistribution of
apoptogenic proteins. We examined neuronal death to elucidate whether the intrinsic mitochondrial pathway and the crosstalk
between caspase-dependent/-independent injury was differentially recruited by stressors implicated in neurodegeneration. After
exposure of cultured cerebellar granule cells to various insults, the progression of injury was correlated with mitochondrial
involvement, including the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Injury
occurred across a continuum from Bax- and caspase-dependent (trophic- factor withdrawal) to Bax-independent, calpain-dependent
(excitotoxicity) injury. Trophic-factor withdrawal produced classical recruitment of the intrinsic pathway with activation
of caspase-3 and redistribution of cytochrome c, whereas excitotoxicity induced early redistribution of AIF and HtrA2/Omi,
elevation of intracellular calcium and mitochondrial depolarization. Patterns of engagement of neuronal programmed cell death
and the redistribution of mitochondrial IMS proteins were canonical, reflecting differential insult-dependencies.
Received 14 August 2008; received after revision 02 October 2008; accepted 23 October 2008 相似文献
13.
Survival of docetaxel-resistant prostate cancer cells in vitro depends on phenotype alterations and continuity of drug exposure 总被引:4,自引:0,他引:4
Makarovskiy AN Siryaporn E Hixson DC Akerley W 《Cellular and molecular life sciences : CMLS》2002,59(7):1198-1211
We evaluated in vitro the effect of paclitaxel and docetaxel on PC-3 and DU-145 prostate cancer cell lines to understand
better the downstream events in drug-induced tumor cell death. Taxane treatments of DU-145 cells induced rapid cell death
by apoptosis, but in PC-3 cells, treatments achieved growth arrest, followed by extensive karyokinesis resulting in multinucleation,
giant-cell formation and delayed cell death. To determine if the giant multinucleated cells were able to produce proliferating
and drug-resistant survivors, we first delineated the kinetics of drug activity and cytotoxic dose range. Analysis of both
lines by colorimetric and cell viability assays demonstrated improved cytotoxicity of taxanes applied continuously. Selected
doses and schedules of docetaxel were used to induce giant multinucleated cells that gave rise to docetaxel-resistant survivors,
which remained sensitive to paclitaxel and other chemotherapeutics. Growth and morphology of the recovered clones was similar
to parental cells. The resistant phenotype of these clones determined by immunofluorescence and immunoblot was associated
with transient expression of the β-tubulin IV isoform and was independent of P-glycoprotein, bcl-2 and bcl-xL. Resistant clones
will be useful to model progression of resistance to taxanes and to identify unknown and clinically important molecular mechanisms
of cell death and resistance.
Received 15 March 2002; received after revision 25 April 2002; accepted 27 May 2002 相似文献
14.
R. J. S. Viana A. F. Nunes R. E. Castro R. M. Ramalho J. Meyerson S. Fossati J. Ghiso A. Rostagno C. M. P. Rodrigues 《Cellular and molecular life sciences : CMLS》2009,66(6):1094-1104
The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis
Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood.
Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells
by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither
matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree
of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule
tauroursodeoxycholic acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the
secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of
Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
Received 20 November 2008; received after revision 12 December 2008; accepted 12 January 2009 相似文献
15.
Melatonin and cell death: differential actions on apoptosis in normal and cancer cells 总被引:2,自引:0,他引:2
Sainz RM Mayo JC Rodriguez C Tan DX Lopez-Burillo S Reiter RJ 《Cellular and molecular life sciences : CMLS》2003,60(7):1407-1426
Melatonin is a natural compound synthesized by a variety of organs. It has been shown to
function as a cell-protective agent. Since 1994, when the first paper was published documenting
the role of melatonin in apoptosis, the number of reports in this area has increased rapidly. Much
of the research conducted falls into three major categories: first, the role of melatonin in
inhibiting apoptosis in immune cells; second, the role of melatonin in preventing neuronal
apoptosis and finally, the role of melatonin in increasing apoptotic cell death in cancer
cells. The mechanisms whereby melatonin influences apoptosis have not clarified, although a number
of mechanistic options have been suggested. Apoptotic cell death is a physiological phenomenon
related to homeostasis and proper functioning of tissues and organs; however, a failure in the
apoptotic program is related to a number of diseases. The participation of melatonin in apoptosis
in numerous cell types and its potential importance in a variety of diseases such as
immunodeficiency, neurodegeneration and cancer is summarized in this review.Received 14 November 2002; received after revision 16 January 2003; accepted 10 February 2003 相似文献
16.
The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously
shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3β have been
implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase
(PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3β (Ser9)
phosphorylation. Pretreatment with 20 μM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased
migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells
grown in control medium. Treatment of cells with a GSK-3β inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited
migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response
to polyamine depletion inhibits migration through GSK-3β and Rac1.
Received 25 August 2006; received after revision 3 October 2006; accepted 16 October 2006 相似文献
17.
Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
18.
Cape A Chen X Wang CE O'Neill A Lin YF He J Xu XS Yi H Li H Li S Li XJ 《Cellular and molecular life sciences : CMLS》2012,69(8):1305-1317
Hap1 was originally identified as a neuronal protein that interacts with huntingtin, the Huntington’s disease (HD) protein. Later studies revealed that Hap1 participates in intracellular trafficking in neuronal cells and that this trafficking function can be adversely affected by mutant huntingtin. Hap1 is also present in pancreatic β-cells and other endocrine cells; however, the role of Hap1 in these endocrine cells remains unknown. Using the Cre-loxP system, we generated conditional Hap1 knockout mice to selectively deplete the expression of Hap1 in mouse pancreatic β-cells. Mutant mice with Hap1 deficiency in pancreatic β-cells had impaired glucose tolerance and decreased insulin release in response to intraperitoneally injected glucose. Using cultured pancreatic β-cell lines and isolated mouse pancreatic islets, we confirmed that decreasing Hap1 could reduce glucose-mediated insulin release. Electron microscopy suggested that there was a reduced number of insulin-containing vesicles docked at the plasma membrane of pancreatic islets in Hap1 mutant mice following intraperitoneal glucose injection. Glucose treatment decreased the phosphorylation of Hap1A in cultured β-cells and in mouse pancreatic tissues. Moreover, this glucose treatment increased Hap1’s association with kinesin light chain and dynactin p150, both of which are involved in microtubule-dependent trafficking. These studies suggest that Hap1 is important for insulin release from β-cells via dephosphorylation that can regulate its intracellular trafficking function. 相似文献
19.
A. F. De Nicola O. Fridman V. G. Foglia 《Cellular and molecular life sciences : CMLS》1977,33(7):974-975
Summary Incorporation of 32P into adrenal mitochondrial phospholipids (PL) increased in ACTH-treated rats, but it decreased in diabetics, inspite of the fact that these animals showed adrenal overactivity. Since diabetics did not show increased 11 -hydroxylation, as opposed to ACTH-treated rats, it is suggested that the stimulation of this enzyme activity by exogenous ACTH is related to an increased turnover of PL at the mitochondrial membrane. This process is impaired in diabetics and prevents the stimulation of 11 -hydroxylation. 相似文献
20.
Matias I Léonhardt M Lesage J De Petrocellis L Dupouy JP Vieau D Di Marzo V 《Cellular and molecular life sciences : CMLS》2003,60(2):382-389
Dietary long-chain polyunsaturated fatty acids are known to influence brain levels of the endocannabinoid anandamide in newborn
pigs and mice. Furthermore, endocannabinoids were shown to control pup suckling and body weight in mice, and food intake in
adult rodents. Here we determined the effect of maternal under-nutrition during gestation, lactation, or both, on body weight,
and on the levels of endocannabinoids and expression of cannabinoid CB1 receptors and fatty acid amide hydrolase in the hypothalamus of rat pups at weaning (21 days old) or adult rats (4 months
old). Maternal under-nutrition resulted in a striking decrease in body weight of weaning rats, paralleled by a decrease in
the hypothalamic levels of the endocannabinoid anandamide, but not of 2-arachidonoylglycerol. No significant change in the
hypothalamic expression of either cannabinoid CB1 receptors or fatty acid amide hydrolase mRNA was detected in any of the three groups of weaned pups. The decrease in pup
body weight and hypothalamic anandamide levels was not observable in 4-month-old rats from any of the three groups. These
data suggest that maternal under-nutrition causes a decrease in hypothalamic anandamide levels and loss of body weight, and
confirm a crucial role for endocannabinoid signalling in neonatal development.
Received 4 November 2002; received after revision 29 November 2002; accepted 16 December 2002
RID="*"
ID="*"Corresponding author. 相似文献