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)

Tacrolimus (FK506) has been widely used as an immunosuppressant. We examined the effects of FK506 on expression of apoptotic signal transduction pathway proteins of Jurkat human T lymphocytes. We investigated the effects of FK506 on apoptosis, cell viability, caspase family protein activity, Western blotts of Bcl-2, Bak, Fas, Fas-L, CDK4, and cyclin D1, as well as reactive oxygen species (ROS) generation and mitochondrial membrane potential transition. Cells were cultured in the presence or absence of FK506. Flow cytometric analysis was performed after staining with propidium iodide. Viability of Jurkat cells was decreased by the addition of FK506 in dose- and time- dependent manner. FK506-induced cytotoxicity was characterized by G0/G1 phase cell cycle arrest. FK506-induced cell death was confirmed by apoptosis characterized by nuclear fragmentation and caspase-3 protease activation. FK506 induced no change in catalytic activity of caspase-6, -8, and -9 proteases. No change in expression of Bcl-2 protein was noted but we confirmed increased expression of Bak protein. No changes of expressions of Fas and Fas-L were seen. Increased expressions of CDK4 and cyclin D1 were identified. In addition, pharmacological scavenging study of ROS, including H2O2, revealed that cytotoxicity was achieved by generation of ROS, which might modulate Bak protein expression and mitochondrial dysfunction. In conclusion, FK506-induced cell death was apoptotic, characterized by nuclear fragmentation and caspase-3 activation. FK506 induced G0/G1 phase cell cycle arrest via expression of CDK4 and cyclin D1. Apoptosis was also achieved by generation of H2O2, which modulated Bak protein expression and mitochondrial dysfunction.
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PMID:Tacrolimus-induced apoptotic signal transduction pathway. 1892 48

Our goal was to investigate whether previously related antiapoptotic and anti-inflammatory effects of tacrolimus could be useful in protecting human islets cultured in the presence of several proinflammatory mediators. Human islets obtained from cadaveric donors after intraductal infusion with collagenase, mechanical digestion, and continuous Ficoll gradient purification were cultured in RPMI-1640 medium for 24 h. Escherichia coli lipopolysaccharide (10 microg/ml) or interleukin-1 (50 UI/ml) + gamma-IF (1000 UI/ml) and low-dose tacroliumus (5 ng/ml) were added. Homogenized samples (300 IE) from five different donors where assigned to four different experimental groups (control, treatment, cytokines, and cytokines + treatment). To evaluate islet damage and apoptotic response, nucleosome content, Bcl-2 protein levels, caspase-3, -8, and -9 levels, and insulin concentration were measured. Also, TNF-alpha and IL-6 levels where assessed as indicators of the inflammatory response. All proapoptotic markers, TNF-alpha, and IL-6 levels were augmented after both LPS and cytokine stimulation. Tacrolimus reduced significantly all of them and restored baseline values of nucleosome and caspase-9 in both experiments and Bcl-2 and caspase-3 when IL-1 + gamma-IF was added. Twenty-four-hour insulin concentration diminished when LPS or IL-1 + gamma-IF were present. Tacrolimus treatment restored insulin levels in both experiments. These results suggest that in vitro apoptotic events and media insulin concentration decrease after proinflammatory stimulation can be reverted using low-dose tacrolimus.
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PMID:Antiapoptotic effect of tacrolimus on cytokine-challenged human islets. 1966 Jan 76