Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetaminophen hepatotoxicity is the leading cause of drug-induced liver failure. Despite substantial efforts in the past, the mechanisms of acetaminophen-induced liver cell injury are still incompletely understood. Recent advances suggest that reactive metabolite formation, glutathione depletion, and alkylation of proteins, especially mitochondrial proteins, are critical initiating events for the toxicity. Bcl-2 family members Bax and Bid then form pores in the outer mitochondrial membrane and release intermembrane proteins, e.g., apoptosis-inducing factor (AIF) and endonuclease G, which then translocate to the nucleus and initiate chromatin condensation and DNA fragmentation, respectively. Mitochondrial dysfunction, due to covalent binding, leads to formation of reactive oxygen and peroxynitrite, which trigger the membrane permeability transition and the collapse of the mitochondrial membrane potential. In addition to the diminishing capacity to synthesize ATP, endonuclease G and AIF are further released. Endonuclease G, together with an activated nuclear Ca2+,Mg2+-dependent endonuclease, cause DNA degradation, thereby preventing cell recovery and regeneration. Disruption of the Ca2+ homeostasis also leads to activation of intracellular proteases, e.g., calpains, which can proteolytically cleave structural proteins. Thus, multiple events including massive mitochondrial dysfunction and ATP depletion, extensive DNA fragmentation, and modification of intracellular proteins contribute to the development of oncotic necrotic cell death in the liver after acetaminophen overdose. Based on the recognition of the temporal sequence and interdependency of these mechanisms, it appears most promising to therapeutically target either the initiating event (metabolic activation) or the central propagating event (mitochondrial dysfunction and peroxynitrite formation) to prevent acetaminophen-induced liver cell death.
 ...
PMID:Intracellular signaling mechanisms of acetaminophen-induced liver cell death. 1617 35

This study investigated the effects of the in vitro co-culture of mouse embryos with non-polarized or polarized uterine epithelial cells, using sequential culture media, on their development to blastocysts, blastocyst quality (blastocyst diameter and cell number), apoptosis, Bcl-2 and Bax gene expression. There were three treatments, all of which used sequential culture media. The treatments were no co-culture (control), non-polarized or polarized epithelial cell monolayer co-culture in 24-well tissue culture plates. Mouse uterine epithelial cells were isolated enzymatically and were seeded either on the surface of the culture plate (non-polarized monolayer) or on a Millipore filter insert coated with extra-cellular matrix extract (polarized monolayer) that was then placed in the culture plate. Two-cell mouse embryos were cultured in G-1 ver3 medium to the eight-cell stage when they were randomly assigned to the treatments. The culture medium was G-2 ver3 during the treatment phase of the study. Significances of differences were evaluated by the one-way analysis of variance for continuous data. The epithelial cells cultured on Millipore filters became polarized and their morphology compared favorably with those cultured on the surface of the culture plate and in vivo uterine epithelial cells. After 96 h on the treatments, the polarized monolayer had supported the development of significantly more hatched blastocysts (80.0%; P<0.05) than the non-polarized monolayer (63.4%) or the control (61.4%) culture treatments. Co-culture resulted in the production of blastocysts with significantly more cells (non-polarized monolayer 56.7+/-2.1, polarized monolayer 61.9+/-2.1) than the control culture (42.8+/-2.6; P<0.05) but the diameter and shape of the blastocysts were not significantly different. The proportion of blastocysts with apoptotic blastomere was higher for the control culture (94.4%) than for the non-polarized (68.2%) or polarized (66.7%) co-culture systems (P<0.05). Moreover, the apoptotic index was significantly higher in control blastocysts (5.6+/-0.9; P<0.05) than in non-polarized (1.7+/-0.3) or polarized (1.5+/-0.3) co-culture. In the control, Bax mRNA was strongly expressed when compared to co-culture treatments (P<0.05), whereas, the relative abundance of Bcl-2 mRNA to the beta-tubulin was lower than co-culture treatments (P<0.05). It is concluded that a co-culture system involving polarized uterine epithelial cells and sequential culture media is a promising method of producing mouse embryos.
 ...
PMID:Development of mouse embryos co-cultured with polarized or non-polarized uterine epithelial cells using sequential culture media. 1687 44

Leflunomide, a disease-modifying anti-rheumatic drug, protects against T-cell-mediated liver injury by poorly understood mechanisms. The active metabolite of leflunomide, A77 1726 (teriflunomide) has been shown to inhibit stress-activated protein kinases (JNK pathway), which are key regulators of mitochondria-mediated cell death. Therefore, we hypothesized that leflunomide may protect from drugs that induce the mitochondrial permeability transition (mPT) by blocking the JNK signaling pathway. To this end, we exposed cultured immortalized human hepatocytes (HC-04) to the standard protoxicant drug acetaminophen (APAP), which induces CsA-sensitive mPT-mediated cell death. We determined the effects of leflunomide on the extent of APAP-induced hepatocyte injury and the upstream JNK-mediated mitochondrial signaling pathways. We found that leflunomide or A77 1726 concentration-dependently protected hepatocytes from APAP (1 mM)-induced mitochondrial permeabilization and lethal cell injury. This was not due to proximal inhibition of CYP-catalyzed APAP bioactivation to its thiol-reactive metabolite. Instead, we demonstrate that leflunomide (20 microM) inhibited the APAP-induced early (3 h) activation (phosphorylation) of JNK1/2, thus inhibiting phosphorylation of the anti-apoptotic protein Bcl-2 and preventing P-Bcl-2-mediated induction of the mPT. This greatly attenuated mitochondrial cytochrome c release, which we used as a marker for mitochondrial permeabilization. The specific JNK2 inhibitor SP600125 similarly protected from APAP-induced cell death. In conclusion, these findings are consistent with our hypothesis that leflunomide protects from protoxicant-induced hepatocyte injury by inhibiting JNK signaling and preventing mPT induction.
 ...
PMID:Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes. 1697 4

Stem cell factor (SCF) and its receptor c-kit are important in hematopoiesis and cellular proliferation. c-kit has also been identified as a cell surface marker for progenitor cells. We have previously shown that there is a large reservoir of hepatic SCF, and this molecule plays a significant role in liver regeneration after 70% hepatectomy. In the current study, we further examined the expression of SCF and c-kit in acetaminophen (APAP)-induced liver injury in C57BL/6J mice or SCF-deficient sl-sld mice and their appropriate wild-type controls. Following APAP-induced liver injury, c-kit mRNA expression increased, with peak levels detected 48 h postinjury. Hepatic SCF mRNA levels after APAP injury were also increased, with peak levels seen 16 h post-APAP. The mortality rate in SCF-deficient mice treated with APAP was significantly higher than that of wild-type mice; furthermore, administration of exogenous SCF significantly reduced the mortality of APAP-treated wild-type mice. Bromodeoxyuridine incorporation experiments showed that SCF significantly increased hepatocyte proliferation at 48 and 72 h in APAP-treated mice. SCF inhibited APAP-induced hepatocyte apoptosis and increased Bcl-2 and Bcl-xL expression, suggesting that this decrease in hepatocyte apoptosis is mediated through Bcl-2 and Bcl-xL. In summary, SCF and c-kit expression was increased after APAP-induced liver injury. Administration of exogenous SCF reduces mortality in APAP-treated mice, increases hepatocyte proliferation, and prevents hepatocyte apoptosis induced by APAP, suggesting that these molecules are important in the liver's recovery from these injuries.
 ...
PMID:Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice. 1846 6

Ganoderma lucidum is known as a medicinal mushroom used in traditional Chinese medicine. In the present study, the effect of lucidenic acids (A, B, C, and N) isolated from a new G. lucidum (YK-02) on induction of cell apoptosis and the apoptotic pathway in HL-60 cells were investigated. The results demonstrated that lucidenic acids decreased cell population growth of HL-60 cells, assessed with the MTT assay. The cell cycle assay indicated that treatment of HL-60 cells with lucidenic acid A, C, and N caused cell cycle arrest in the G 1 phase. Lucidenic acid B (LAB) did not affect the cell cycle profile; however, it increased the number of early and late apoptotic cells but not necrotic cells. Treatment of HL-60 cells with LAB caused loss of mitochondria membrane potential. Moreover, the ratio of expression levels of pro- and antiapoptotic Bcl-2 family members was changed by LAB treatment. LAB-induced apoptosis involved release of mitochondria cytochrome c and subsequently induced the activation of caspase-9 and caspase-3, which were followed by cleavage of poly(ADP-ribose) polymerase (PARP). Pretreatment with a general caspase-9 inhibitor (Z-LEHD-FMK) and caspase-3 inhibitor (Z-DEVD-FMK) prevented LAB from inhibiting cell viability in HL-60 cells. Our finding may be critical to the chemopreventive potential of lucidenic acid B.
 ...
PMID:Lucidenic acid B induces apoptosis in human leukemia cells via a mitochondria-mediated pathway. 1848 62

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug and is safe at therapeutic doses but its overdose frequently causes liver injury. In earlier studies, we demonstrated that arjunolic acid (AA) has a protective effect against chemically induced hepatotoxicity. The purpose of this study was to explore whether AA plays any protective role against APAP-induced acute hepatotoxicity and, if so, what molecular pathways it utilizes for the mechanism of its protective action. Exposure of rats to a hepatotoxic dose of acetaminophen (700 mg/kg, ip) altered a number of biomarkers (related to hepatic oxidative stress), increased reactive oxygen species production, reduced cellular adenosine triphosphate level, and induced necrotic cell death. Arjunolic acid pretreatment (80 mg/kg, orally), on the other hand, afforded significant protection against liver injury. Arjunolic acid also prevented acetaminophen-induced hepatic glutathione depletion and APAP metabolite formation although arjunolic acid itself did not affect hepatic glutathione levels. The results suggest that this preventive action of arjunolic acid is due to the metabolic inhibition of specific forms of cytochrome P450 that activate acetaminophen to N-acetyl-p-benzoquinone imine. In addition, administration of arjunolic acid 4 h after acetaminophen intoxication reduced acetaminophen-induced JNK and downstream Bcl-2 and Bcl-xL phosphorylation, thus protecting against mitochondrial permeabilization, loss of mitochondrial membrane potential, and cytochrome c release. In conclusion, the data suggest that arjunolic acid affords protection against acetaminophen-induced hepatotoxicity through inhibition of P450-mediated APAP bioactivation and inhibition of JNK-mediated activation of mitochondrial permeabilization.
 ...
PMID:Arjunolic acid, a triterpenoid saponin, prevents acetaminophen (APAP)-induced liver and hepatocyte injury via the inhibition of APAP bioactivation and JNK-mediated mitochondrial protection. 1996 75

Oxidative stress is an important factor in drug induced hepatotoxicity and antioxidants from natural sources have potential to ameliorate it. The present study was aimed to investigate cyto-protective potential of probiotic Enterococcus lactis IITRHR1 (El(SN)) and Lactobacillus acidophilus MTCC447 (La(SN)) lysate against acetaminophen (APAP) induced hepatotoxicity. Cultured rat hepatocytes pretreated with El(SN)/La(SN) showed higher cell viability under APAP stress. Pre-treatment with El(SN,) restored glutathione level and reduced ROS generation significantly which are major biomarkers of oxidative stress. It also reduced NO level, MDA formation and enhanced SOD activity. Pre-treatment with probiotic lysates significantly inhibited the translocation of pro-apoptotic protein (Bax), enhanced anti-apoptotic (Bcl-2) protein levels and prevented release of cyt c to cytosol; suggesting involvement of mitochondrial proteins in protection against APAP induced oxidative cellular damage. Loss in mitochondrial membrane potential due to APAP treatment was prevented in the presence of probiotic lysates. Protective action of El(SN)/La(SN) pretreatment was further supported by prevention of procaspase-3 activation, DNA fragmentation and chromatin condensation, in turn inhibiting APAP induced apoptotic cell death. The results indicate that probiotic preparations modulate crucial end points of oxidative stress induced apoptosis and may be used for management of drug induced liver injury.
 ...
PMID:Modulation of Bax/Bcl-2 and caspases by probiotics during acetaminophen induced apoptosis in primary hepatocytes. 2113 Aug 31

Acetaminophen (N-acetyl-para-aminophenol (APAP), paracetamol) is a commonly used analgesic and antipyretic agent. Although considered safe at therapeutic doses, accidental or intentional overdose causes acute liver failure characterized by centrilobular hepatic necrosis with high morbidity and mortality. Although many molecular aspects of APAP-induced cell death have been described, no conclusive mechanism has been proposed. We recently identified TNF-related apoptosis-inducing ligand (TRAIL) and c-Jun kinase (JNK)-dependent activation of the pro-apoptotic Bcl-2 homolog Bim as an important apoptosis amplification pathway in hepatocytes. In this study, we, thus, investigated the role of TRAIL, c-JNK and Bim in APAP-induced liver damage. Our results demonstrate that TRAIL strongly synergizes with APAP in inducing cell death in hepatocyte-like cells lines and primary hepatocyte. Furthermore, we found that APAP strongly induces the expression of Bim in a c-JNK-dependent manner. Consequently, TRAIL- or Bim-deficient mice were substantially protected from APAP-induced liver damage. This study identifies the TRAIL-JNK-Bim axis as a novel target in the treatment of APAP-induced liver damage and substantiates its general role in hepatocyte death.
 ...
PMID:Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage. 2165 29

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.
 ...
PMID:Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation. 2209 18

Alzheimer's disease is a devastating neurodegenerative disorder, the most common among the dementing illnesses. Acetaminophen has gaining importance in neurodegenerative diseases by attenuating the dopaminergic neurodegeneration in Caenorhabditis elegans model, decreasing the chemokines and the cytokines and increasing the anti apoptotic protein such as Bcl-2 in neuronal cell culture. The low concentration acetaminophen improved the facilitation to find the hidden platform in Morris Water Maze Test. Also some data suggest that acetaminophen could contribute in neurodegeneration. The present study was aimed to evaluate the effect of acetaminophen against colchicine induced cognitive impairment and oxidative stress in wistar rats. The cognitive learning and memory behaviour was assessed using step through passive avoidance paradigm and acetylcholine esterase activity. The parameters of oxidative stress were assessed by measuring the malondialdehyde, reduced glutathione and catalase levels in the whole brain homogenates. There was a significant memory improvement in the rats received acetaminophen treatment and it has also decreased the acetylcholine esterase enzyme level, confirming its nootropic activity. Acetaminophen neither increases nor decreases the reduced glutathione and catalase in the whole brain homogenates, showing that acetaminophen is devoid of any adverse effect on brain antioxidant defense system.
 ...
PMID:Nootropic activity of acetaminophen against colchicine induced cognitive impairment in rats. 2257 28


1 2 3 4 5 Next >>