Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chlorophyllin (CHL), an antimutagenic and anticarcinogenic water-soluble derivative of chlorophyll, was recently found to be highly effective as a chemopreventive agent in a high-risk population exposed unavoidably to aflatoxin B(1) in the diet (P. A. Egner et al., Proc. Natl. Acad. Sci. USA, 98: 14601-14606, 2001). The current study examined the response of HCT116 human colon cancer cells to CHL treatment. Cells exposed to concentrations in the range 0.0625-0.5 mM CHL underwent growth arrest and apoptosis after 24 h, with the formation of a sub-G(1) peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (deltapsi(m)) without the release of cytochrome c or activation of the caspase-9/caspase-3/poly(ADP-ribose) polymerase pathway. However, apoptosis-inducing factor was released from mitochondria into the cytosol and translocated to the nucleus, leading to concentration-dependent cleavage of nuclear lamins. The upstream mediators of this CHL-induced apoptosis pathway were identified as caspase-8/caspase-6 and truncated Bid, acting in conjunction with other proapoptotic members of the Bcl-2 family, such as Bak. These findings suggest that CHL might trigger apoptosis via interaction with putative "death receptors" in the plasma membrane of cancer cells, leading to initial cleavage of procaspase-8 and activation of subsequent downstream events, resulting in the destruction of nuclear lamins. Importantly, E-cadherin and alkaline phosphatase, which are indicators of cell differentiation, were strongly induced at all concentrations of CHL. Thus, in addition to being an effective blocking agent during the initiation phase, these findings support a role for CHL as a suppressing agent and as a possible novel therapeutic strategy directed toward aberrant cell proliferation in the colon.
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PMID:Caspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin. 1264 85

Wikyungtang, an oriental herbal formulation, has been known to exert anti-inflammatory and anti-tumoral activity. However, its molecular mechanism of action is not understood. The purpose of the present study was to examine the effect of the water extract of Wikyungtang (WKT) on the growth of A549 human lung cancer cells. Treatment with WKT resulted in a dose-dependent growth inhibition coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of WKT induced caspase-3 and caspase-9 activation accompanied by proteolytic degradation of poly(ADP-ribose)-polymerase and phospholipase C-gamma1. In addition, WKT-induced apoptosis in A549 cells was associated with a decreased expression of the anti-apototic Bcl-XL expression. WKT treatment also inhibited the expression of cyclooxygenase (COX)-2 and the accumulation of prostaglandin E2 without significant changes in the levels of COX-1. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of WKT.
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PMID:Wikyungtang inhibits proliferation of A549 human lung cancer cells via inducing apoptosis and suppressing cyclooxygenase-2 activity. 1501 Aug 84

The effect of water-soluble chitosan, a natural polymer used as a dietary supplement, on human bladder-tumor cells was investigated. Apoptotic morphological change was demonstrated by nuclear staining. Chitosan-treated cells showed elevation of caspase-8-like activity, but no significant elevation of caspase-9-like activity, which suggest that proapoptotic effect of chitosan is attributable to death receptor activation and not to activation of the mitochondria-cytochrome c pathway. Chitosan increased expression of TNF-R1, but decreased Fas expression. Use of monoclonal antibodies to inhibit death-receptor signal transduction did not attenuate the proapoptotic activity of chitosan. Examination of death-ligands revealed that TNFalpha mRNA expression was markedly increased by chitosan treatment while FasL mRNA was not affected. Although the direct interaction of chitosan with death receptors remains unidentified, the results suggest that its proapoptotic effect might be related to interaction with TNFalpha or TNF-R1.
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PMID:Proapoptotic effect of a dietary supplement: water soluble chitosan activates caspase-8 and modulating death receptor expression. 1549 73

The role of apoptotic signaling proteins for long-lived neurons in the mature brain is poorly understood. Recently, we have shown that water deprivation leads to the activation of vasopressin (VP) secretion and expression of Bcl-2 and caspase-9 apototic proteins in the hypothalamus of the rat brain. In the present work, we continued to study a possible relationship between the functional activity of neurosecretory cells of the hypothalamus and apoptosis related proteins. We found that water deprivation leads to simultaneous activation of synthesis of VP and p53 and Bcl-2 apoptotic proteins in the mouse brain. To study a possible effect of apoptotic proteins on the functional state of hypothalamic neurons, the VP and tyrosine hydroxylase (TH) synthesis were analyzed in p53, p21(Waf1/Cip1) and Bcl-2 deficient mice. Loss of p53 and Bcl-2 significantly reduced VP synthesis in paraventricular and supraoptic nuclei and TH expression in arcuat, periventricular and zona incerta nuclei of the hypothalamus. Surprisingly, in contrast with the loss of p53, the inactivation of p21(Waf1/Cip1) up-regulates the expression of VP and TH. These data indicate that p53, p21(Waf1/Cip1) and Bcl-2 proteins, besides affecting cell cycle, tumor suppression and apoptosis, may act as modulators of neurosecretory activity of hypothalamic neurons; however, this problem remains to be determined more detailed.
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PMID:Apoptotic signaling proteins: possible participation in the regulation of vasopressin and catecholamines biosynthesis in the hypothalamus. 1613 24

To understand antitumor activity of Albizzia julibrissin Durazz (Leguminosae), which has been used as a traditional oriental medicine, the mechanism underlying cytotoxic effect of its extract on human acute leukemia Jurkat T cells were investigated. The methanol extract of the stripped barks (3kg) of Albizzia julibrissin was evaporated, dissolved in water, and then sequentially extracted by chloroform, ethyl acetate, and n-butanol. The substance in the butanol extract containing the most cytotoxic activity was further purified by a series of preparative column chromatography. The active substance obtained (723mg) was designated as HaBC18. When Jurkat T cells were treated with HaBC18 (0.5-2microg/ml), apoptosis along with several biochemical events such as mitochondrial cytochrome c release, activation of caspase-9 and -3, degradation of PARP, and DNA fragmentation was induced in a dose-dependent manner. However, the HaBC18-induced apoptosis was abrogated by an ectopic overexpression of Bcl-xL, which is known to block mitochondrial cytochrome c release. Primary cultures of human PBMC were less sensitive to the cytotoxicity relative to Jurkat T cells. These results demonstrate that the cytotoxicity of HaBC18 toward Jurkat T cells is attributable to apoptosis mediated by mitochondria-dependent death-signaling pathway regulated by Bcl-xL.
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PMID:Induction of apoptosis in human acute leukemia Jurkat T cells by Albizzia julibrissin extract is mediated via mitochondria-dependent caspase-3 activation. 1653 81

The pathobiology of traumatic brain injury (TBI) includes activation of multiple caspases followed by cell death with a spectrum of apoptotic phenotypes. There are initiator (e.g. caspase-2, -8, and -9) and effector (e.g. caspase-3 and -7) caspases. Recently, caspase-2 and -8 have been shown to regulate cell death via provoking cytochrome c release from the mitochondria upstream of caspase-9. Here, we show that an intracerebral injection of the pan-caspase inhibitor boc-Aspartyl(OMe)-fluoromethylketone (BAF; 1 micromol) 1 min after TBI in rats reduces caspase-3-like activity, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and tissue damage, and cytochrome c release in ipsilateral cortex at 24 h versus vehicle. To investigate whether either caspase-2 and/or caspase-8 activation may contribute to cytochrome release, the effect of BAF treatment on caspase-2 and caspase-8 proteolysis was also examined. boc-aspartyl(OMe)-fluoromethylketone treatment inhibited proteolysis of caspase-2 but not caspase-8 24 h after TBI in rats versus vehicle. However, BAF with or without nerve growth factor (12.5 ng/h x 14 days intracerebrally via osmotic pump) did not result in differences in motor function, Morris water maze performance, hippocampal neuron survival, nor contusion volume at 14 days. These data suggest that BAF treatment reduces acute cell death after TBI by inhibiting mitochondrial release of cytochrome c, possibly via a mechanism involving initiator caspases; however, BAF appears to delay cell death, rather than result in permanent protection.
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PMID:boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats. 1673 44

Increasing evidence suggests that apoptosis is a contributing factor to neuronal cell death in traumatic brain injury (TBI). There is increased expression, cleavage and activation of caspases as well as other proteins known to regulate apoptosis in neurons after TBI. These proteins include the proto-oncogene Bcl-2 which belongs to a family of proteins with both pro- and anti-apoptotic properties. To investigate the role of apoptosis in TBI and the importance of Bcl-2 protein on the severity and outcome of injury, Bcl-2 overexpressing transgenic and wild-type control mice were subjected to the controlled cortical impact model of TBI. There was no significant difference in the cleavage of caspase-3 or caspase-9 detected by Western blotting of hippocampal samples from transgenic or wild-type mice after TBI. Bcl-2 transgenic mice had smaller contusion volumes and increased numbers of surviving neurons in CA2 but not other regions of hippocampus compared to wild-type controls. By contrast, there was no difference in motor function determined by the round beam balance and wire grip tests between transgenic and wild-type mice after TBI. Cognitive function assessed by the Morris water maze was also not different between groups. These results suggest that overexpression of Bcl-2 is only partially neuroprotective and other members of this protein family may prove to be more important in protecting neurons from cell death.
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PMID:Transgenic mice that overexpress the anti-apoptotic Bcl-2 protein have improved histological outcome but unchanged behavioral outcome after traumatic brain injury. 1678 76

Chronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this review, we provide and discuss the pathomechanisms of arsenic skin cancer and the relationship to its characteristic figures. Such information is critical for understanding the molecular mechanism for arsenic carcinogenesis in other internal organs.
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PMID:Arsenic carcinogenesis in the skin. 1680 64

Novel substituted triptycene bisquinones and 1, 4-anthracenediones were synthesized and screened for their anti-cancer activities. A number of analogs were synthesized utilizing various synthetic transformations and found to elicit interesting antitumor effects. Analogs included water-soluble pro-drugs and ammonium salts. These potent antitumor drugs are DNA topoisomerase inhibitors that induce DNA strand breaks, inhibit DNA, RNA and protein syntheses and reduce tumor cell proliferation in the nanomolar range in vitro. They induce cytochrome c release, caspase-9, -3 and -8 activities, poly(ADP)-ribose polymerase-1 (PARP) cleavage, and internucleosomal DNA fragmentation by a mechanism which involves caspase-2 activation but not Fas signaling. Moreover, these drugs remain effective in multidrug-resistant tumor cells and have the advantage of blocking nucleoside transport and inducing a rapid loss of mitochondrial transmembrane potential. Based on their effects in tumor cells and isolated mitochondria, it is hypothesized that these drugs might, directly and indirectly, target components of the permeability transition pore to induce mitochondrial permeability transition and the release of proapoptotic factors. This review provides a summary of synthetic efforts and mechanistic endeavor.
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PMID:Syntheses, molecular targets and antitumor activities of novel triptycene bisquinones and 1,4-anthracenedione analogs. 1684 33

American ginseng root displays the ability to achieve glucose homeostasis both experimentally and clinically but the unknown mechanism used by ginseng to achieve its therapeutic effects on diabetes limits its application. Disruption in the insulin secretion of pancreatic beta cells is considered the major cause of diabetes. A mitochondrial protein, uncoupling protein-2 (UCP-2) has been found to play a critical role in insulin synthesis and beta cell survival. Our preliminary studies found that the extracts of American ginseng inhibit UCP-2 expression which may contribute to the ability of ginseng protecting beta cell death and improving insulin synthesis. Therefore, we hypothesized that ginseng extracts suppress UCP-2 in the mitochondria of pancreatic beta cells, promoting insulin synthesis and anti-apoptosis (a programmed cell-death mechanism). To test the hypothesis, the serum-deprived quiescent beta cells were cultured with or without interleukin-1beta (IL-1beta), (200 pg ml(-1), a cytokine to induce beta cell apoptosis) and water extracts of American ginseng (25 mug per 5 mul administered to wells of 0.5 ml culture) for 24 h. We evaluated effects of ginseng on UCP-2 expression, insulin production, anti-/pro-apoptotic factors Bcl-2/caspase-9 expression and cellular ATP levels. We found that ginseng suppresses UCP-2, down-regulates caspase-9 while increasing ATP and insulin production/secretion and up-regulates Bcl-2, reducing apoptosis. These findings suggest that stimulation of insulin production and prevention of beta cell loss by American ginseng extracts can occur via the inhibition of mitochondrial UCP-2, resulting in increase in the ATP level and the anti-apoptotic factor Bcl-2, while down-regulation of pro-apoptotic factor caspase-9 occurs, lowering the occurrence of apoptosis, which support the hypothesis.
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PMID:American ginseng stimulates insulin production and prevents apoptosis through regulation of uncoupling protein-2 in cultured beta cells. 1695 21


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