Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Caspase-3 was activated in apoptotic L-MAT cells by treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Treatment with tributyltin, which has been reported to induce apoptosis in rat thymocytes, also activated caspase-3 and led to cell death in L-MAT cells. Blocking caspase-3 activity with the peptide inhibitor, DEVE-CHO, prevented TCDD from inducing subsequent apoptotic changes. The potent Ah receptor ligand, 2,3,7,8-tetrachlorodibenzofuran (TCDF), the low acute toxicity compound, 1,2,3,4,6,7,9-heptachlorodibenzo-p-dioxin (HCDD), and one of the major contaminants in human milk, 3,3',4,4',5-pentachlorobiphenyl (PCBP), increased the activation level of caspase-3, each in a dose-dependent manner. Thus, we propose that measuring caspase-3 activation in the human T-lymphoblastic cell line, L-MAT, is a useful evaluation method for the immunotoxicity of dioxin compounds.
 ...
PMID:Method for evaluation of immunotoxicity of dioxin compounds using human T-lymphoblastic cell line, L-MAT. 1137 70

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants and many of their toxic effects, including their immunotoxicities, are mediated by the activation of aryl hydrocarbon receptor (AhR). We previously reported that Aroclor 1254, one of the most widely used PCB mixtures, increased DNA fragmentation in mouse spleen cells, suggesting that apoptosis was correlated with the immunotoxicity of PCB (Yoo et al., Toxicol. Lett. 91, 83-89, 1997). In the present study we investigated the mechanism by which PCB induces apoptosis and the involvement of AhR in the PCB-mediated apoptosis of mouse spleen cells. Aroclor 1254 induced DNA fragmentation without AhR activation, and the apoptosis was unaffected by alpha-naphtoflavone, a well-known antagonist of AhR. Moreover, the PCB congeners (PCB 47, 52, 128, and 153), which have little affinity for AhR, induced DNA fragmentation, whereas congeners (PCB 77, 126, and 169) that have high affinity for AhR did not induce fragmentation. The di-ortho form of PCB (PCB 153) and Aroclor 1254 induced DNA fragmentation in the spleen cells of both AhR knockout mice and Ah low-response mice, whereas the non-ortho form of PCB (PCB 126) did not induce DNA fragmentation. In the light of these findings, it is evident that AhR is not involved in PCB-mediated apoptosis. PCB 153 significantly increased caspase-3 activity in both spleen cells and human leukemia cells, and z-VAD-fmk, a general inhibitor of caspases, prevented PCB-induced DNA fragmentation. Based on our findings, the most likely mechanism that can account for this biological effect involves the induction of caspase-dependent apoptotic cell death.
 ...
PMID:Polychlorinated biphenyl-induced apoptosis of murine spleen cells is aryl hydrocarbon receptor independent but caspases dependent. 1205 90

Tri-n-butyltin (TBT), a biocide, is known for its immunotoxicity and hepatotoxicity and is a well-characterised mitochondrial toxin. This report investigates the mechanisms involved in induction of apoptosis by TBT in primary cultures of rat hepatocytes. Release of cytochrome c from mitochondria into the cytosol was apparent after 15 min of exposure to 2.5 microM TBT. In addition, activity of initiator caspase-9 increased after 30 min, representing activation of the mitochondrial pathway in hepatocytes. The death receptor pathway was also activated by TBT, as indicated by recruitment of the adaptor protein FADD from the cytosol to the membrane as soon as 15 min after treatment. In addition, levels of the pro-apoptotic protein Bid decreased in the cytosol, while there was an increase in levels of the cleaved form tBid, in TBT-treated hepatocytes. Activity of initiator caspase-8 increased after 30 min. The principal effector caspase-3 was activated following 30 min of treatment with TBT. Activation was confirmed by immunodetection of a 17-kDa cleaved fragment. Apoptotic substrates such as Poly(ADP-ribose) polymerase and DNA fragmentation factor-45 are cleaved by caspase-3 to ensure the dismantlement of the cell. Cleavage of Poly(ADP-ribose) polymerase into a 85-kDa fragment appeared after 30 min of TBT treatment. DNA fragmentation factor-45 disappeared in TBT-exposed rat hepatocytes. This is the first detailed study reporting the involvement of initiator and effector caspases, cleavage of their intracellular substrates and activation of both death receptor and mitochondrial pathways in TBT-induced apoptosis in rat hepatocytes. The comprehension of molecular events of apoptosis is important for the evaluation of the risk to humans and animals.
 ...
PMID:Involvement of mitochondrial and death receptor pathways in tributyltin-induced apoptosis in rat hepatocytes. 1527 21

The halogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to induce immunotoxicity, but relatively little is known regarding its effects on B-lymphocytes, and on avian B-cells in particular. In this study, the avian bursal pre-B-cell line DT40 was exposed to TCDD ranging from 1 to 500 nM for 1 and 6 h. At 100 nM, TCDD caused a significant increase in the number of apoptotic cells, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay, and induced the expression of the chicken cytochrome P450 1A4 (CYP1A4) mRNA, a hallmark of TCDD exposure. TCDD induced transient upregulation of aryl hydrocarbon receptor (AhR) mRNA. At 100 nM, both caspase 3 and caspase 9 were transiently upregulated after 1 h, but returned to normal levels after 6 h of exposure. Challenge with TCDD after AhR blockade with resveratrol, a competitive AhR antagonist, prevented changes in caspases 3 and 9 and in the AhR message itself, suggesting that the effects of TCDD were mediated via the AhR. TCDD did not cause significant changes in the relative gene expression of caspase 8, Bcl-2 and Bcl-xL. We conclude that avian DT40 pre-B-cells exposed to TCDD are susceptible to apoptosis, likely through activation of executioner caspase 3.
 ...
PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin elicits aryl hydrocarbon receptor-mediated apoptosis in the avian DT40 pre-B-cell line through activation of caspases 9 and 3. 1553 54

Cadmium is a nonessential heavy metal and a well-known persistent environmental pollutant. It causes a variety of toxic effects, including immunotoxicity. The exact mechanism of its cellular effects still is unclear. Cell-cycle regulation is an important factor that modulates cell death; however, cadmium-mediated cell-cycle arrest leading to cell death in murine macrophages has not been investigated. Cadmium at 20 microM induced both apoptotic and necrotic death in murine macrophage (J774A.1) cultures at 24 h. Cadmium at 20 microM triggered re-entry of G0/G1 to the next phase and increased the number of cells in the G2/M phase at 24 h. Phosphorylation of extracellular signal-regulated kinase (ERK) correlated with the cyclin-dependent kinase inhibitor p21WAF1/CIP1 induction. Inhibition of ERK activation by PD98059 resulted in G0/G1 arrest and partially released the cadmium-mediated G2/M arrest. Inhibition of ERK phosphorylation by PD98059 strongly attenuated cadmium-induced necrotic cell death, but did not prevent caspase-3 activation and DNA fragmentation. Necrosis rather than apoptosis was caused by cadmium-induced ERK signaling in J774A.1 cells. A scavenger of reactive oxygen species (ROS), N-acetylcystein, decreased cadmium-induced ERK activation and necrotic cell death, suggesting that cadmium induces the ROS-ERK-p21WAF1/CIP1 signaling pathway, leading to G2/M arrest and cell death. These findings may be important in further understanding the cellular mechanisms of cadmium toxicity to provide information to assess objectively risk for this metal.
 ...
PMID:Extracellular signal-regulated kinase-signaling-dependent G2/M arrest and cell death in murine macrophages by cadmium. 1644 87

We have recently shown that the actinobacterium Streptomyces californicus and the fungus Stachybotrys chartarum originating from moisture damaged buildings possess both immunotoxic and immunostimulatory characteristics, which are synergistically potentiated by microbial interaction. In the search for the causative agent(s) behind the immunotoxicity, the cytostatic effects of the co-cultivated spores of S. californicus and S. chartarum were compared to those caused by widely used cytostatic agents produced by streptomycetes. The RAW264.7 macrophages were exposed to four doses of doxorubicin (DOX), actinomycin D (AMD), mitomycin C (MMC) or phleomycin (PHLEO) for 24 h. Kinetics of the spores of the co-cultivated and the separately cultivated microbes (1x10(6) spores/ml) was compared to DOX (0.15 muM). Apoptotic responses were analyzed by measuring DNA content and mitochondria membrane depolarization with flow cytometer, and by the fluorometric caspase-3 assay. The present data indicate that interactions during co-cultivation of S. californicus and S. chartarum stimulate the production of an unidentified cytostatic compound(s) capable of inducing mitochondria mediated apoptosis and cell cycle arrest at S-G(2)/M. The spores of co-cultivated microbes caused a 4-fold collapse of mitochondrial membrane potential and an almost 6-fold caspase-3 activation and DNA fragmentation when compared to control. Similar responses were induced by DNA cleaving compounds, especially DOX and AMD, at the relatively low concentrations, but not the spores of the same microbes when they were grown separately. These data suggest that when growing in the same habitat, interactions between S. californicus and S. chartarum stimulates the production of an unknown cytostatic compound(s) which evoke immunotoxic effects similar to those by chemotherapeutic drugs.
 ...
PMID:Co-cultivation of Streptomyces californicus and Stachybotrys chartarum stimulates the production of cytostatic compound(s) with immunotoxic properties. 1709 29

Cadmium immunotoxicity in rodents is primarily characterized by marked thymic damage and splenomegaly. To understand the toxicity of Cd on lymphoid cells in vivo, a single dose of Cd as CdCl2 (1.8 mg/kg, i.p.) was administered to male BALB/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) were assessed in thymic and splenic single cell suspensions, at various time intervals. Lowering of body weight gain and cellularity and a loss in cell viability was seen in the Cd treated mice. The earliest significant increase in ROS at 18 h, followed by mitochondrial membrane depolarization, caspase-3 activation and GSH depletion at 24h in spleen and later at 48 h in thymus, strongly implicate the possible involvement of ROS. A pronounced inhibition of cell proliferative response at 48 h and 72 h may also be linked to Cd induced apoptosis. The morphological alterations including thymic cortical cell depletion and an increase in red pulp with diminished white pulp in spleen were observed at 48 h and beyond. The splenic cells appeared more susceptible than thymus cells to the adverse effects of Cd. The present study, therefore, demonstrates potentiation of oxidative stress followed by mitochondrial-caspase dependent apoptotic pathway. This may, in part, be responsible for causing suppression of cell proliferative response, thymic atrophy and splenomegaly.
 ...
PMID:Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice. 1726 44

Six 1-month-old piglets were intravenously injected with deoxynivalenol (DON) at the concentration of 1 mg/kg body weight, with three pigs each necropsied at 6 and 24 h post-injection (PI) for investigation of hepatotoxicity and immunotoxicity with special attention to apoptotic changes and cytokine mRNA expression. Histopathological examination of the DON-injected pigs revealed systemic apoptosis of lymphocytes in lymphoid tissues and hepatocytes. Apoptosis of lymphocytes and hepatocytes was confirmed by the TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method and immunohistochemical staining against singlestranded DNA and cleaved caspase-3. The number of TUNELpositive cells in the thymus and Peyer's patches of the ileum was increased at 24 h PI compared to 6 h PI, but the peak was at 6 h PI in the liver. The mRNA expression of interleukin (IL)-1beta, IL-6, IL-18, and tumor necrosis factor (TNF)-alpha in the spleen, thymus and mesenteric lymph nodes were determined by semi-quantitative RT-PCR, and elevated expression of IL-1beta mRNA at 6 h PI and a decrease of IL-18 mRNA at 24 h PI were observed in the spleen. IL-1beta and IL-6 mRNA expressions increased significantly at 6 h PI in the thymus, but TNF-alpha decreased at 6 h PI in the mesenteric lymph nodes. These results show the apoptosis of hepatocytes suggesting the hepatotoxic potential of DON, in addition to an immunotoxic effect on the modulation of proinflammatory cytokine genes in lymphoid organs with extensive apoptosis of lymphocytes induced by acute exposure to DON in pigs.
 ...
PMID:Induction of apoptotic lesions in liver and lymphoid tissues and modulation of cytokine mRNA expression by acute exposure to deoxynivalenol in piglets. 2045 50

3,3'-Diindolylmethane (DIM), a major product of indole-3-carbinol derived from vegetables of the genus Brassica, exhibits chemotherapeutic activity and various immune modulatory effects in animal models and in vitro studies. Although extensive studies have only focused on DIM's beneficial effects, the toxic effects of DIM on the immune systems have not been clearly elucidated. The aim of this study was to explore the immunotoxic effects of DIM in a neonatal mouse and to further evaluate whether DIM administration affects rotavirus (RV)-induced gastroenteritis. Interestingly, multiple immunotoxic effects were observed in the DIM treated group, including decreases in various immune cells (F4/80(+), CD11c(+), CD19(+), and CD3(+) cells) in the spleen, induction of splenic white pulp atrophy, an increase in immune cell apoptosis, and decreased expression of various toll-like receptors (TLRs) in the spleen and small intestine. Apoptosis was notably promoted by up-regulating caspase-3 activity and by the change in the ratio of Bcl-2/Bax activities. Finally, oral administration of DIM led to deterioration of RV-induced intestinal disease and delayed viral clearance in the intestine and MLNs. Our results indicate that oral administration of DIM in neonatal mice induces immunotoxicity and hampers efficient RV clearance in the intestine. This new information about the immunotoxic roles of DIM in a newborn mouse model may provide valuable clues for the development of a safe supplement, especially one designed for human infants.
 ...
PMID:3,3'-Diindolylmethane induces immunotoxicity via splenocyte apoptosis in neonatal mice. 2182 Apr 97

The authors investigated the toxic effects of simazine on mice spleen immune cells and the underlying mechanisms. Mice were given simazine at 0, 90, 200, or 400 mg/kg by gastric gavage for 3 weeks. The authors then measured immune cell proliferation and the expressions of apoptosis-related proteins (Bcl-2, Bax, Fas, and caspase-3), spleen cell intracellular [Ca(2+)], cellular oxidative stress level, and immune functions. After 3 weeks, mice exposed to simazine had reduced proliferation of both spleen T and B cells. The number of spleen CD4(+) T lymphocytes decreased with simazine exposure, while CD8(+) T cells remained unchanged. Exposure to simazine resulted in reduced immune function, higher intracellular [Ca(2+)], and oxidative stress. Finally, simazine induced spleen immune cells apoptosis by reducing Bcl-2, while increasing Fas and Caspase-3 level. Overall, the immunotoxicity of simazine may involve the induction of immune cell apoptosis and alterations in the immune and physiological functions of spleen cells.
 ...
PMID:Oral exposure to the herbicide simazine induces mouse spleen immunotoxicity and immune cell apoptosis. 2276 72


1 2 3 4 5 Next >>