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ABSTRACT: Adiponectin (APN), a circulating adipose-derived hormone that regulates inflammation and energy metabolism, has beneficial effects on the cardiovascular disorders. Serum APN levels are lower in patients with coronary artery disease and higher in patients with chronic kidney disease. However, the precise role of APN in acute reno-vascular disease is not clear. Results of the present study show that serum APN concentration decreased after renal ischemia reperfusion (I/R) injury in mice. In addition, I/R-induced renal dysfunction (elevated serum creatinine and urea levels), inflammation (number of infiltrating neutrophils, myeloperoxidase activity), and apoptotic responses (apoptotic cell number and caspase-3 activation) were attenuated in APN-treated compared to control mice. Molecular and biochemical analysis revealed that APN up-regulates heme oxygenase-1 (HO-1) via peroxisome-proliferator-activated-receptor-α (PPARα) dependent pathway which is mediated through the enhancement of COX-2 and 6-keto PGF1α expression. Chromatin immune-precipitation assay demonstrated that APN increases the binding activity of PPARα to PPRE region of HO-1 promoter. Furthermore, APN induced HO-1 expression was only found in wild-type but not in PPARα gene deleted mice. This provides in vivo evidence that APN mediated HO-1 expression depends on PPARα regulation. In conclusion, our results provide a novel APN mediated prostacyclin-PPARα-HO-1 signaling pathway in protecting renal I/R injury.
Journal of Cellular Physiology 03/2011; 227(1):239-49. · 3.87 Impact Factor
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ABSTRACT: An overproduction of proinflammatory mediators in severe acute pancreatitis contributes to the systemic inflammatory response, which may lead to multiorgan damage and even death. Thus, inflammatory cytokines, e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β, may be novel targets for the treatment of acute pancreatitis. The aim of this study was to investigate the therapeutic effects of pomalidomide (or CC-4047), a thalidomide analog and immunomodulatory agent, in acute pancreatitis.
Acute pancreatitis was induced in C57BL/6 mice by intraperitoneal administration of cerulein (100 μg/kg/h × 8). Pomalidomide was administered (0.5 mg/kg orally) 1 h before the first or 1 h after the last cerulein administration. The severity of the acute pancreatitis was evaluated biochemically and morphologically.
Pretreatment with pomalidomide significantly reduced the plasma levels of amylase and lipase; the histological injury; and the expression of TNF-α, IL-1β, monocyte chemotactic protein-1 (MCP-1), and inducible nitric oxide synthase (iNOS) in cerulein-induced acute pancreatitis. Post-treatment with pomalidomide also decreased the cerulein-induced elevation of plasma amylase and lipase and decreased the pancreatic damage.
Treatment with pomalidomide ameliorated the severity of cerulein-induced acute pancreatitis in mice. Our data suggest that pomalidomide may become a new therapeutic agent in future clinical trials for the treatment of acute pancreatitis.
Journal of Gastroenterology 03/2011; 46(6):822-33. · 4.16 Impact Factor
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Shih-Yen Weng,
Chia-Yu Yang,
Chao-Chin Li,
Te-Ping Sun,
Shu-Yun Tung,
Jeffrey Jong-Young Yen,
Ting-Fen Tsai,
Chun-Ming Chen, Sung Ho Chen,
Michael Hsiao,
Pei-Hsin Huang,
Hsin-Fang Yang-Yen
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ABSTRACT: Mcl-1-deficient hepatocytes are prone to undergo apoptosis. The tumor suppressor protein p53 plays an important role in apoptosis control as well as other cellular responses. This study was initially aimed to examine whether p53 was involved in Mcl-1 deficiency-induced apoptosis of hepatocytes.
Hepatocyte-specific Mcl-1 knockout (Alb-Mcl-1(-/-)) mice and Alb-Mcl-1(-/-) mice in wild-type or p53-deficient background were generated and characterized.
Alb-Mcl-1(-/-) mice were viable, but their liver cells were prone to undergo apoptosis and manifested a slightly elevated level of p53. To examine the role of p53 in Alb-Mcl-1(-/-) livers, Alb-Mcl-1(-/-) mice without p53 (DKO mice) were characterized. Unexpectedly, although p53-deficient mice appeared to be developmentally normal, DKO mice were highly susceptible to neonatal death (∼60%). Further analysis revealed that such an early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. Moreover, those DKO mice that did survive to adulthood manifested more severe liver damage than Alb-Mcl-1(-/-) mice, suggesting that p53 was activated in Alb-Mcl-1(-/-) livers to promote cell survival. Microarray followed by quantitative PCR analysis suggested that p21(Waf1/Cip1), one p53 target gene with apoptosis-inhibitory function, is likely involved in the protective role of p53 in Alb-Mcl-1(-/-) livers. Moreover, we demonstrated that loss of p53 promoted liver fibrosis and tumor development in Alb-Mcl-1(-/-) mice.
This study revealed an unexpected synergism between Mcl-1 and p53 in protecting from hepatic injury, fibrosis, and cancer.
Journal of Hepatology 09/2010; 54(4):685-94. · 9.26 Impact Factor
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ABSTRACT: Translationally controlled tumor protein (TCTP) is expressed throughout T cell development and prominently induced following T cell activation. However, its function(s) during these processes is unclear. Here, we demonstrated that conditional deletion of TCTP before the beta selection checkpoint resulted into a partial block of thymocyte development at the double-negative (DN) 3 stage. Deletion of TCTP in the double-positive (DP) stage did not cause any significant phenotype in the thymus except a slight increase of mature CD8 single-positive (SP) thymocytes. In contrast to the very modest phenotype observed in the thymus, a significant reduction of mature T cells was observed in the peripheral lymphoid organs of these two conditional null TCTP mutant mice. Detailed analysis revealed that the latter phenotype (peripheral T cell lymphopenia) was largely due to a decreased viability of mature TCTP-deficient (TCTP(-/-)) T cells. Transgenic expression of the anti-apoptotic protein Bcl-2 rescued the partial block of early thymocyte development, but not peripheral T cell lymphopenia of T-lineage-specific TCTP(-/-) mice, suggesting that the signaling networks of TCTP in these two processes are not identical. Last, we demonstrated that TCTP(-/-) T cells manifested a significant defect in T cell Ag receptor (TCR)-mediated cell proliferation. Further analysis revealed that such defect was due to a marked delay in the initial cell-cycle entry of TCTP(-/-) T cells following TCR stimulation. Together, these results indicate that TCTP plays a very modest role in thymocyte development, but is critical for peripheral T cell maintenance and TCR-mediated cell proliferation.
The Journal of Immunology 09/2009; 183(4):2373-81. · 5.79 Impact Factor
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ABSTRACT: Pyrrolidine dithiocarbamate (PDTC) is a metal chelator. Biologically, slight toxic affects EC50, 100+/-5.9 microM are observed when added to cultured HL-60 cells. CuCl2 at a physiological concentration (1 microM), but not FeCl2, Pb potentiated the cytotoxic effect of PDTC by 700 fold (EC50, 0.14+/-0.02 microM). Furthermore, results indicated that the PDTC/Cu complex induced an apoptotic process, evidenced by apoptotic bodies, DNA ladder and hypodiploidy cells. Additional studies showed that PDTC/Cu complex significantly decreased mitochondrial membrane potential, increased cytochrome c release, and reactive oxygen species production, and depleted reduced non-protein thiols in a time-dependent manner. Following oxidative stress, the PDTC/Cu complex sequentially activated JNK, NF-kappaB and AP-1 signaling pathways while IkappaB kinase activity was enhanced. The apoptotic process was eventually induced by caspase 3 activation and PARP degradation. The non-permeable copper-specific chelator-bathocuproine disulfonate (BCPS) and vitamin C were able to inhibit apoptosis and the elevation of intracellular Cu. Based on these findings; we conclude that PDTC/Cu complex-induced apoptosis is mediated by activation of JNK, NF-kappaB, AP-1 and caspase 3. Due to its high potency, PDTC may be useful as a therapeutic anti-cancer drug.
European Journal of Pharmacology 11/2008; 594(1-3):9-17. · 2.52 Impact Factor
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ABSTRACT: Astrocytes play a critical neurotrophic and neuroprotective role in the brain, and improper function of these cells may contribute to the onset of neurodegenerative diseases. Because astrocytes are known to be enriched with Cu chaperone proteins, it is important to understand the factors that may lead to cytotoxic effects of Cu on astrocytes. In this report, we demonstrated a dramatic potentiating effect of neocuproine (NCP), a membrane permeable metal chelator, on Cu, but not Fe or Pb, in inducing apoptosis of cultured astrocytes. It was estimated that individually, CuCl2 and NCP only weakly exhibited cytotoxic effects on astrocytes, with EC50 of 180 and 600 microM, respectively. However, NCP at a nontoxic concentration of 10 microM markedly reduced EC50 of Cu to 0.35 microM (physiological concentration) and Cu (10 microM) reduced EC50 of NCP down to 0.06 microM. The mechanisms underlying these dramatic potentiation effects are elucidated. NCP increased the intracellular concentration of Cu in astrocytes and a nonpermeable Cu chelator, bathocuproine disulfonate was able to abolish all of the apoptotic signaling. Cell death was determined to be via apoptosis due to increased reactive oxygen species production, mitochondrial dysfunction, depletion of glutathione and adenosine triphosphate, cytochrome c release, c-Jun N-terminal kinase, and caspase-3 activation, and poly-ADP-ribose polymerase degradation. This finding, coupled with our previous reports, suggests that metal chelators (NCP, dithiocarbamate and disulfiram) should be cautiously used as they may potentiate a cytotoxic effect of endogenous Cu on astrocytes. Their clinical implications in the etiology of neurodegenerative diseases deserve further investigation.
Toxicological Sciences 04/2008; 102(1):138-49. · 4.65 Impact Factor
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ABSTRACT: Translationally controlled Tumor Protein (TCTP) is an evolutionally highly conserved protein which has been implicated in many cellular functions that are related to cell growth, death, and even the allergic response of the host. To address the physiological roles of TCTP, we generated TCTP knockout mice by targeted gene disruption. Heterozygous mutants appeared to be developmentally normal. However, homozygous mutants (TCTP(-/-)) were embryonic lethal. TCTP(-/-) embryos were smaller in size than the control littermates at all postimplantation stages examined. Although TCTP is widely expressed in both extraembryonic and embryonic tissues, the most prominent defect of the TCTP(-/-) embryo at embryonic stage day 5.5 (E5.5) was in its epiblast, which had a reduced number of cells compared with wild-type controls. The knockout embryos also suffered a higher incidence of apoptosis in epiblast starting about E6.5 and subsequently died around E9.5-10.5 with a severely disorganized structure. Last, we demonstrated that TCTP(-/-) and control mouse embryonic fibroblasts manifested similar proliferation activities and apoptotic sensitivities to various death stimuli. Taken together, our results suggest that despite that TCTP is widely expressed in many tissues or cell types, it appears to regulate cell proliferation and survival in a tissue- or cell type-specific manner.
Molecular Biology of the Cell 08/2007; 18(7):2525-32. · 4.94 Impact Factor
