Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebrotendinous xanthomatosis (CTX) is a hereditary lipid storage disease characterized by hyper-cholestanolemia, cerebellar ataxia, xanthoma, and cataract. We hypothesized that cholestanol in serum of CTX patients might induce neuronal cell death in the cerebellum and eventually lead to cerebellar ataxia. To gain support for this hypothesis we developed hyper-cholestanolemia rats by feeding cholestanol. Neuronal cells, especially Purkinje cells in the cerebellum were stained by Sudan black B only in the cholestanol-fed rats, indicating the deposit of cholestanol in cerebellum. To examine effects of cholestanol in vitro, cerebellar neuronal cells were cultured with cholestanol. The cholestanol concentration increased and the viability decreased in cells cultured with cholestanol. Apoptosis was evident in cells cultured with cholestanol more frequently than in control cells, determined using the terminal deoxynucleotidyl transferase (TdT) dUTP nick end-labeling (TUNEL) method. As activities of interleukin-1beta-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis of cerebellar neuronal cells. Our observations may explain the mechanism of cerebellar ataxia of CTX patients.
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PMID:Cholestanol induces apoptosis of cerebellar neuronal cells. 1006 46

Cataract was induced by a single intraperitoneal injection of 100 mg/kg N-methyl-N-nitrosourea (MNU) to 0-, 5-, 10-, 15-, or 20-day-old male and female Sprague-Dawley rats. In day 0, 5, 10, and 15 MNU-treated rats, mature cataracts were constantly seen 7, 14, 14, and 30 days after dosing, respectively. In the day 20 MNU-treated rats, only subcapsular cataract was seen 30 days after dosing. Therefore, the rats exposed to MNU at an earlier age caused cataract more rapidly and severely. In the day 0 MNU-treated rats, 7-methyldeoxyguanosine DNA adduct was detected in the lens epithelial nuclei 12 hours after MNU dosing, followed by apoptosis, which was confirmed by morphology, by TUNEL signals, and by DNA ladder and peaked 3 days after MNU dosing. In the apoptosis cascade, upregulation of Bax, downregulation of Bcl-2, and increased CPP32 protease (caspase-3) activity were seen 12 hours after MNU dosing. Therefore, the pathogenesis of MNU-induced cataract was associated with DNA adduct formation in the lens epithelial cell nuclei leading to apoptosis by upregulation of Bax protein, downmodulation of Bcl-2 protein, and activation of caspase-3.
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PMID:Cataractogenesis in neonatal Sprague-Dawley rats by N-methyl-N-nitrosourea. 1093 42

The purposes of this experiment were (1) to determine if apoptosis was accelerated during formation of selenite cataract, and (2) to determine the role of calpains and caspases in lens apoptosis. Evidence for apoptosis in selenite-injected rats included: approximately 7-8% of epithelial cells in germinative zone were positive, disappearance of the nuclear membrane, condensation of the chromatin, and breakdown of PARP. Activation of calpains was indicated by characteristic limited proteolysis of crystallins, breakdown of alpha-spectrin to 150/145 kDa fragments, hydrolysis of vimentin, and autolytic breakdown of m-calpain. Selenite cataract did not have an appreciable effect on the mRNA levels for caspase-3, calpains, and calpastatin. This indicated the increased enzyme activity of m-calpain and caspase-3 in selenite cataract occurred at the enzyme level rather than by upregulation of mRNAs. Increased calpain and caspase activity may be linked to the selenite-induced apoptosis. Such data are important because they indicate that apoptosis may be a fairly early event in selenite cataract.
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PMID:Evidence for apoptosis in the selenite rat model of cataract. 1096 62

It is well established that the proto-oncogene, bcl-2, can prevent apoptosis induced by a variety of factors. Regarding the mechanism by which BCL-2 prevents cell death, one theory suggests that it acts by protecting cells from oxidative stress. In the lens system, oxidative stress-induced apoptosis is implicated in cataractogenesis. To explore the possibility of anti-apoptotic gene therapy development for cataract prevention and also to further test the anti-oxidative stress theory of BCL-2 action, we have introduced the human bcl-2 gene into an immortalized rabbit lens epithelial cell line, N/N1003A. The stable expression clones of both vector- and bcl-2-transfected cells have been established. Treatment of the two cell lines with H(2)O(2) revealed that bcl-2-transfected cells were less capable of detoxifying H(2)O(2) than the control cells. Moreover, bcl-2-transfected cells are more susceptible to H(2)O(2)-induced apoptosis. To explore why bcl-2-transfected cells have reduced resistance to H(2)O(2)-induced apoptosis, we examined the expression patterns of several relevant genes and found that expression of the alphaB-crystallin gene was distinctly down-regulated in bcl-2-transfected cells compared with that in vector-transfected cells. This down-regulation was specific because a substantial inhibition of BCL-2 expression through antisense bcl-2 RNA significantly restored the level of alphaB-crystallin and, moreover, enhanced the ability of the bcl-2-transfected cells against H(2)O(2)-induced apoptosis. Introduction of a mouse alphaB-crystallin gene into bcl-2-transfected cells also counteracted the BCL-2 effects. Down-regulation of alphaB-crystallin gene was largely derived from changed lens epithelial cell-derived growth factor activity. Besides, alphaB-crystallin prevents apoptosis through interaction with procaspase-3 and partially processed procaspase-3 to prevent caspase-3 activation. Together, our results reveal that BCL-2 can regulate gene expression in rabbit lens epithelial cells. Through down-regulation of the alphaB-crystallin gene, BCL-2 attenuates the ability of rabbit lens epithelial cells against H(2)O(2)-induced apoptosis.
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PMID:Human bcl-2 gene attenuates the ability of rabbit lens epithelial cells against H2O2-induced apoptosis through down-regulation of the alpha B-crystallin gene. 1154 95

Apoptosis has been implied in normal lens development in the embryo as well as in lens fibre differentiation. It has also been suggested to play a role in non-congenital cataract and in the formation of posterior subcapsular opacification, but data on the presence of apoptosis in human lens epithelium from cataractous lenses are scarce and conflicting. The present study aimed to investigate apoptosis in lens epithelium from patients undergoing cataract surgery. The amount of apoptosis detected was correlated to age, gender, type of cataract, medications and disease. Moreover, the ability of human lens epithelial cells in culture to respond to the apoptosis-inducing agent staurosporin by activation of caspase-3 was investigated. Human lens capsulotomy specimens were collected immediately after surgery, frozen and later analysed with respect to caspase-3 activity, using the fluorogenic substrate Ac-DEVD-AMC. Generally, the activity of caspase-3 detected in this manner was very low and in 23% of the specimens it was non-detectable. However, there were differences in caspase activity between lens epithelial cells from different types of cataract, where samples from lenses with posterior subcapsular cataract exhibited significantly lower caspase-3 activity than lenses with a clear subcapsular zone. Age, gender or medications did not show any correlation with caspase activity but human capsulotomy specimens from diabetic patients exhibited significantly lower caspase-3 activity. Staurosporin caused a concentration-dependent increase in caspase activity in cultured human lens epithelial cells and the amount of apoptotic nuclei was also increased as viewed by staining with Hoechst 33342, showing chromatin condensation and nuclear fragmentation. Similar results were obtained when fresh human lens capsulotomy specimens were exposed to 1000 nM staurosporin for 24 hr. To conclude, the present data indicate that human lens epithelial cells have the ability to respond to apoptosis-inducing agents with caspase-3 dependent apoptosis, and that even though the general level of apoptosis in human lens epithelium in vivo is low, there are differences in caspase-3 activity levels in lenses with or without posterior subcapsular cataract. The latter finding supports previous studies indicating that this type of cataract may result from defective differentiation, in which apoptosis may play an important role.
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PMID:Decreased caspase-3 activity in human lens epithelium from posterior subcapsular cataracts. 1256 5

Exposure to ultraviolet radiation (UVR) and reactive oxygen species (ROS) can damage the human lens and contribute to cataract formation. Recent evidence suggests that apoptosis in lens epithelial cells (LEC) is an initiating event in noncongenital cataract formation in humans and animals. The present study examines the cellular and molecular mechanisms by which environmental (ultraviolet B [UVB]) and chemical (hydrogen peroxide [H(2)O(2)], t-butyl hydroperoxide [TBHP]) stress induces cell death in an SV-40 immortalized human lens epithelial (HLE) cell line. Treatment of HLE cells with UVB, H(2)O(2), and TBHP significantly decreased cell density with LD50 values of 350 J/m(2), 500 muM, and 200 muM, respectively. Cellular morphology, DNA fragmentation, and annexin/propidium iodide staining consistent with apoptosis was observed only in UVB-treated cells, whereas lactate dehydrogenase (LDH) release was significantly higher in H(2)0(2)- and TBHP-treated cells. In addition, activation of apoptotic stress-signaling proteins, including c-Jun NH2-terminal kinase (JNK), caspase-3, and DNA fragmentation factor 45 (DFF45) was observed only in UVB-treated cells. Inhibition of JNK activity increased UVB-induced cell death, suggesting that this pathway may serve a prosurvival role in HLE cells. These findings suggest UVB predominantly induces apoptosis in HLE cells, whereas H(2)O(2) and TBHP induce necrosis.
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PMID:Apoptotic and necrotic mechanisms of stress-induced human lens epithelial cell death. 1552 44

Heat shock protein 27 (Hsp27) is a stress-inducible protein in cells that functions as a molecular chaperone and also as an anti-apoptotic protein. Methylglyoxal (MGO) is a reactive dicarbonyl compound produced from cellular glycolytic intermediates that reacts non-enzymatically with proteins to form products such as argpyrimidine. We found considerable amount of Hsp27 in phosphorylated form (pHsp27) in human cataractous lenses. pHsp27 was the major argpyrimidine-modified protein in brunescent cataractous lenses. Modification by MGO enhanced the chaperone function of both pHsp27 and native Hsp27, but the effect on Hsp27 was at least three-times greater than on pHsp27. Phosphorylation of Hsp27 abolished its chaperone function. Transfer of Hsp27 using a cationic lipid inhibited staurosporine (SP)-induced apoptotic cell death by 53% in a human lens epithelial cell line (HLE B-3). MGO-modified Hsp27 had an even greater effect (62% inhibition). SP-induced reactive oxygen species in HLE-B3 cells was significantly lower in cells transferred with MGO-modified Hsp27 when compared to native Hsp27. In vitro incubation experiments showed that MGO-modified Hsp27 reduced the activity of caspase-9, and MGO-modified pHsp27 reduced activities of both caspase-9 and caspase-3. Based on these results, we propose that Hsp27 becomes a better anti-apoptotic protein after modification by MGO, which may be due to multiple mechanisms that include enhancement of chaperone function, reduction in oxidative stress, and inhibition of activity of caspases. Our results suggest that MGO modification and phosphorylation of Hsp27 may have important consequences for lens transparency and cataract development.
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PMID:Effect of methylglyoxal modification and phosphorylation on the chaperone and anti-apoptotic properties of heat shock protein 27. 1661 38

The apoptosis of lens epithelial cells has been proposed as the common basis of cataract formation, with oxidative stress as the major cause. This study was performed to investigate the protective effect of the herbal constituent parthenolide against oxidative stress-induced apoptosis of human lens epithelial (HLE) cells and the possible molecular mechanisms involved. HLE cells (SRA01-04) were incubated with 50 microM H(2)O(2) in the absence or presence of different doses of parthenolide (10, 20 and 50 microM). To study apoptosis, the cells were assessed by morphologic examination and Annexin V-propidium iodide double staining flow cytometry; to investigate the underlying molecular mechanisms, the expression of caspase-3 and caspase-9 were assayed by Western blot and quantitative RT-PCR, and the activities of caspase-3 and caspase-9 were measured by a Chemicon caspase colorimetric activity assay kit. Stimulated with H(2)O(2) for 18 h, a high fraction of HLE cells underwent apoptosis, while in the presence of parthenolide of different concentrations, dose-dependent blocking of HLE cell apoptosis was observed. The expression of caspase-3 and caspase-9 induced by H(2)O(2) in HLE cells was significantly reduced by parthenolide both at the protein and mRNA levels, and the activation of caspase-3 and caspase-9 was also suppressed by parthenolide in a dose-dependent manner. In conclusion, parthenolide prevents HLE cells from oxidative stress-induced apoptosis through inhibition of the activation of caspase-3 and caspase-9, suggesting a potential protective effect against cataract formation.
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PMID:Parthenolide protects human lens epithelial cells from oxidative stress-induced apoptosis via inhibition of activation of caspase-3 and caspase-9. 1733 84

Oxidative stress plays a significant role in the progression of cataract. We aimed to investigate the protective effect of magnolol, a compound extracted from the Chinese herb Magnolia officinalis, against oxidative stress in human lens epithelial (HLE) cells as well as the possible molecular mechanism involved. In this study, magnolol was observed to protect against H2O2-induced cytotoxicity in HLE B-3 cells. Magnolol inhibited the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (Delta psi m) and release of cytochrome c from mitochondria caused by H2O2 into cytosol in HLE B-3 cells. Magnolol also inhibited H2O2-induced expressions of caspase-9 and caspase-3 and reduction of Bcl-2/Bax ratio. Moreover, magnolol attenuated the deactivation of ERK/MAPK (extracellular signal-regulated kinase/mitogen activated protein kinase) and the enhanced activation of p38, JNK (c-Jun N-terminal kinase) induced by H2O2. Magnolol could be useful in protecting against oxidative stress in HLE cells, suggesting a potential protective effect against cataractogenesis effect against cataractogenesis.
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PMID:Protective effect of magnolol against hydrogen peroxide-induced oxidative stress in human lens epithelial cells. 1965 15

Epidemiologic studies have revealed a higher incidence of cataracts in estrogen-deprived postmenopausal women, although the pathogenic mechanism has not yet been elucidated. Apoptosis of lens epithelial cells has been associated with cataractogenesis. The aim of the study reported here was to investigate the effect of estrogen replacement therapy (ERT) on lens epithelial cell apoptosis in an experimental rat model. Forty female Wistar rats were randomized into four groups: ERT (17beta-estradiol, 10 microg/kg/day) for 3 months without ovariectomy (group 1) and with ovariectomy (group 2); only ovariectomy (group 3); sham operated (group 4). At the end of the third month, all rats were sacrificed in estrous cycle, as determined by the vaginal smear test, and their right eyes were enucleated. Enucleated eyes were analyzed by immunohistochemical methods for the expression of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end (TUNEL), caspase-3, and bcl-2 labeling. The TUNEL, caspase-3, and bcl-2 staining scores were found to increase in group 3 rats following the ovariectomy compared to the sham-operated group. The ERT decreased these scores in rats with or without the ovariectomy; however, these differences were not statistically significant. These data suggest that estrogen does not significantly affect lens epithelial cell apoptosis. Further studies are needed to gain a better understanding of the protective mechanism of estrogen and to provide new ideas for the treatment and prevention of cataract.
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PMID:Effect of estrogen replacement therapy on lens epithelial cell apoptosis in an experimental rat model. 1996 48


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