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

Chronic exposure to peroxisome proliferators (PPs) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis. Transcript profiling showed increased expression of proapoptotic genes and decreased expression of antiapoptotic genes in the livers of mice exposed to the PP WY-14,643 (WY). We tested the hypothesis that prior exposure to WY would increase susceptibility to apoptosis inducers such as Jo2, an antibody which activates the Fas (Apo-1/CD95) death pathway. When compared to their untreated counterparts, wild-type mice pretreated with WY exhibited increased caspase-3 activation and hepatocyte apoptosis following challenge with Jo2. Livers from WY-treated peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice were resistant to the effects of Jo2. In the absence of Jo2 and detectable apoptosis, wild-type mice treated with WY exhibited increases in the activated form of caspase-9. As caspase-9 is a component of the apoptosome, we examined the expression of upstream effectors of apoptosome activity including members of the Bcl-2 family. The levels of the antiapoptotic Mcl-1 transcript and protein were significantly decreased by PPs. PPARalpha-null mice were also resistant to another treatment (concanavalin A) that induces hepatocyte apoptosis. These results (1) indicate that PPARalpha activation increases sensitivity of the liver to apoptosis and (2) identify a mechanism by which PPARalpha could serve as a pharmacological target in diseases where apoptosis is a contributing feature.
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PMID:Activation of peroxisome proliferator-activated receptor alpha enhances apoptosis in the mouse liver. 1668 91

CYP2E1 metabolizes many low-molecular weight toxins and carcinogens. Some in vitro experiments suggest that CYP2E1 may be involved in the metabolic activation of diethylnitrosamine. However, there has been no direct evidence demonstrating a role for CYP2E1 in diethylnitrosamine-mediated carcinogenesis in vivo. To clarify this, we carried out a diethylnitrosamine-induced hepatocarcinogenesis experiment using Cyp2e1-null mice. Male 14-day-old wild-type and Cyp2e1-null mice were treated with diethylnitrosamine (10 mg/kg of body weight) and killed at weeks 24 and 36 after diethylnitrosamine treatment for investigation of tumors and at 6, 24, and 48 h for examination of apoptosis and gene expression. Liver weights of Cyp2e1-null mice were significantly different at weeks 24 and 36 compared with wild-type mice (P < 0.01). Liver tumor incidences of Cyp2e1-null mice were significantly decreased at weeks 24 and 36 compared with wild-type mice (P < 0.01). Cyp2e1-null mice showed significant decrease in the multiplicities of hepatocellular adenoma at weeks 24 and 36 (P < 0.05 and P < 0.01, respectively), and of hepatocellular carcinoma at week 36 (P < 0.01) compared with wild-type mice. Apoptotic index and caspase-3 and/or Bax mRNA expression of Cyp2e1-null mice were significantly different at 6, 24, and 48 h after diethylnitrosamine treatment compared with wild-type mice (P < 0.05). We conclude that Cyp2e1-null mice show lower tumor incidence and multiplicity compared with wild-type mice in diethylnitrosamine-induced hepatocarcinogenesis. It is suggested that CYP2E1 completely participates in diethylnitrosamine-induced hepatocarcinogenesis, and high frequency of tumors in wild-type mice could be associated with the increased apoptosis.
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PMID:Role of CYP2E1 in diethylnitrosamine-induced hepatocarcinogenesis in vivo. 1805 38

Cholangiocarcinoma remains the second most prevalent hepatic neoplasm in the United States with a 5-year survival rate of less than 10%. Currently, no systemic therapy has demonstrated efficacy. Therefore, an urgent need for the identification of molecularly targeted compound(s) remains. The Notch signaling pathway has been shown to be dysregulated in cholangiocarcinoma, exhibiting hyperactivity while also possibly mediating chemotherapeutic resistance. We analyzed the effects of xanthohumol, a prenylated chalcone, on cholangiocarcinoma proliferation utilizing human cholangiocarcinoma cell lines CCLP1, SG-231 and CC-SW-1 while gaining insight into the associated mechanism. Xanthohumol potently reduced cellular proliferation, colony formation, and cell confluency in all three cell lines. Xanthohumol induced cell cycle arrest as well as apoptosis through the reduction of cell cycle regulatory proteins as well as an increase in pro-apoptotic markers (cleaved poly ADP ribose polymerase, cleaved caspase-3) and a decrease in anti-apoptotic markers (X-linked inhibitor of apoptosis and survivin). At the molecular level, xanthohumol reduced Notch1 and AKT expression in a step-wise and time-dependent fashion, with Notch1 reductions preceding AKT. Additionally, xanthohumol reduced cholangiocarcinoma growth in both CCLP-1 and SG-231 derived mice xenografts. In summary, we show that xanthohumol significantly reduced cholangiocarcinoma growth through the Notch1/AKT signaling axis. Furthermore, known pharmacokinetics and bioavailability of XN supports continued development of treatment for cholangiocarcinoma.
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PMID:Antiproliferative and apoptotic effects of xanthohumol in cholangiocarcinoma. 2915 42