scholarly journals Insulin Protects Liver Cells from Saturated Fatty Acid-Induced Apoptosis via Inhibition of c-Jun NH2 Terminal Kinase Activity

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3338-3345 ◽  
Author(s):  
M. J. Pagliassotti ◽  
Y. Wei ◽  
D. Wang
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Saturated Fatty Acid ◽  
Caspase 3 ◽  
Kinase Activity ◽  
Liver Cells ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Induced Apoptosis

Hepatocyte apoptosis is increased in patients with nonalcoholic steatohepatitis and correlates with disease severity. Long-chain saturated fatty acids, such as palmitate and stearate, induce apoptosis in liver cells. The present study examined insulin-mediated protection against saturated fatty acid-induced apoptosis in the rat hepatoma cell line, H4IIE, and primary rat hepatocytes. Cells were provided a control media (no fatty acids) or the same media containing 250 μmol/liter of albumin-bound oleate or palmitate for 16 h. Insulin concentrations were 0, 1, 10, or 100 nmol/liter (n = 4–6/treatment). Palmitate, but not oleate, activated caspase-3 and induced DNA fragmentation in the absence of insulin. Insulin reduced palmitate-mediated activation of caspase-3 and DNA fragmentation in a dose-dependent manner. Phosphatidylinositol 3-kinase inhibitors abolished these effects of insulin. Insulin-mediated inhibition of palmitate-induced apoptosis was not due to an augmentation in the unfolded protein response or increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate, but not oleate, increased c-Jun NH2 terminal kinase activity in the absence of insulin. Insulin or SP600125, a chemical inhibitor of c-Jun NH2 terminal kinase, blocked palmitate-mediated activation of c-Jun NH2 terminal kinase and reduced apoptosis. These data suggest that insulin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in insulin-deficient and/or -resistant states.

Biologic sequelae of nuclear factor–κB blockade in multiple myeloma: therapeutic applications

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4079-4086 ◽  
Author(s):  
Nicholas Mitsiades ◽  
Constantine S. Mitsiades ◽  
Vassiliki Poulaki ◽  
Dharminder Chauhan ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Inhibitor Of Apoptosis ◽  
Caspase 8 ◽  
Nuclear Factor ◽  
Inhibitor Of Apoptosis Protein ◽  
Tnf Α ◽  
Apoptosis Protein ◽  
Induced Apoptosis

The transcription factor nuclear factor–κB (NF-κB) confers significant survival potential in a variety of tumors. Several established or novel anti–multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-κB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-κB activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-κB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome–linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochromec release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor–α (TNF-α) is present locally in the bone marrow microenvironment and induces NF-κB–dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-α alone induced NF-κB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-α–induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-α family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-α–induced expression of another NF-κB target gene, intercellular adhesion molecule–1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-κB pathways. Our results therefore demonstrate that NF-κB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-κB activity in novel biologically based therapies for MM.

scholarly journals Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

2021 ◽  
Vol 8 ◽  
Author(s):  
Mingjuan Deng ◽  
Xingqi Li ◽  
Weiwei Li ◽  
Jiahui Gong ◽  
Xiaoying Zhang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Short Chain Fatty Acids ◽  
Uremic Toxins ◽  
Short Chain ◽  
Liver Carcinoma ◽  
Apoptosis Protein ◽  
Induced Apoptosis ◽  
Chain Fatty Acids

Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 μM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 μM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.

scholarly journals Diablo Promotes Apoptosis by Removing Miha/Xiap from Processed Caspase 9

2001 ◽  
Vol 152 (3) ◽  
pp. 483-490 ◽  
Author(s):  
Paul G. Ekert ◽  
John Silke ◽  
Christine J. Hawkins ◽  
Anne M. Verhagen ◽  
David L. Vaux
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Caspase 3 ◽  
Direct Interaction ◽  
Inhibitor Of Apoptosis ◽  
Caspase 9 ◽  
Inhibitor Of Apoptosis Protein ◽  
Grim Reaper ◽  
Apoptosis Protein ◽  
Mammalian Protein

MIHA is an inhibitor of apoptosis protein (IAP) that can inhibit cell death by direct interaction with caspases, the effector proteases of apoptosis. DIABLO is a mammalian protein that can bind to IAPs and antagonize their antiapoptotic effect, a function analogous to that of the proapoptotic Drosophila molecules, Grim, Reaper, and HID. Here, we show that after UV radiation, MIHA prevented apoptosis by inhibiting caspase 9 and caspase 3 activation. Unlike Bcl-2, MIHA functioned after release of cytochrome c and DIABLO from the mitochondria and was able to bind to both processed caspase 9 and processed caspase 3 to prevent feedback activation of their zymogen forms. Once released into the cytosol, DIABLO bound to MIHA and disrupted its association with processed caspase 9, thereby allowing caspase 9 to activate caspase 3, resulting in apoptosis.

scholarly journals X-linked inhibitor of apoptosis protein and active caspase-3 expression patterns in antral follicles in the sheep ovary

Reproduction ◽  
2011 ◽  
Vol 142 (6) ◽  
pp. 855-867 ◽  
Author(s):  
Hollian R Phillipps ◽  
Ilona C Kokay ◽  
David R Grattan ◽  
Peter R Hurst
Keyword(s):  
Mrna Expression ◽  
Caspase 3 ◽  
Expression Patterns ◽  
Inhibitor Of Apoptosis ◽  
Mrna Levels ◽  
Follicular Atresia ◽  
Inhibitor Of Apoptosis Protein ◽  
Antral Follicles ◽  
Apoptosis Protein ◽  
Active Caspase

X-linked inhibitor of apoptosis protein (XIAP) interacts with caspases to inhibit their activity, thereby providing a potential mechanism for regulation of granulosa cell apoptosis occurring during follicular atresia. The aim of this study was to determine the presence and localization of XIAP mRNA and protein content in the sheep ovary and compare these expression patterns with active caspase-3 protein in the same antral follicles. Romney ewe estrous cycles (n=25) were synchronized with 2–3 Estrumate injections and ovarian tissue collected during the luteal and follicular phases of the cycle. The presence ofXIAPmRNA was confirmed by RT-PCR using laser capture microdissected ovarian cell samples.XIAPmRNA was subsequently localized byin situhybridization histochemistry and XIAP and active caspase-3 protein visualized by immunohistochemistry. In antral follicles extensive XIAP localization was evident in both granulosa and thecal cells. In contrast, mRNA expression was widespread in granulosa cells and only detected in thecal tissue from a small proportion of antral follicles. Active caspase-3 and XIAP comparative expression analysis showed positiveXIAPmRNA expression in all late luteal phase (day 14) follicles, despite varying levels of active caspase-3 protein. A proportion of follicular phase (days 15 and 16) follicles, however, showed an inverse expression relationship at the protein and mRNA levels in both granulosa and thecal tissue, as did XIAP protein in day 14 follicles. These results suggest high XIAP may prevent activation of caspase-3, thereby regulating follicular atresia in antral follicles and could potentially be utilized as a marker of follicular health.

Resistance of bone marrow-derived macrophages to apoptosis is associated with the expression of X-linked inhibitor of apoptosis protein in primary cultures of bone marrow cells

2001 ◽  
Vol 353 (2) ◽  
pp. 299-306 ◽  
Author(s):  
Hong LIN ◽  
Catheryne CHEN ◽  
Ben D.-M. CHEN
Keyword(s):  
Bone Marrow ◽  
Caspase 3 ◽  
Bone Marrow Cells ◽  
Primary Cultures ◽  
Precursor Cells ◽  
Inhibitor Of Apoptosis ◽  
Caspase 9 ◽  
Prolonged Incubation ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

In this study we investigated the underlying mechanisms that confer resistance on mature macrophages with the use of macrophage colony-stimulating factor (M-CSF)-induced bone marrow-derived macrophages (BMDM). In the presence of M-CSF, immature precursor cells were induced to undergo proliferation and differentiation into mature macrophages in vitro with cell morphology similar to that of tissue macrophages by day 7Ő10. Immunoblot analyses showed that bone marrow precursors express appreciable levels of caspase-3 and caspase-9 but no or very low levels of c-fms (M-CSF receptor) and the apoptosis regulators X-linked inhibitor of apoptosis protein (XIAP), c-IAP-1, Bcl-2 and Bax. The differentiation of BMDM is associated with a steady and gradual increase in the levels of c-fms, XIAP, c-IAP-1, Bcl-2 and Bax, reaching maximal levels by day 7. However, the levels of caspase-3 and caspase-9 stayed essentially unchanged even after prolonged incubation (more than 10 days) with M-CSF. Unlike bone marrow precursor cells, mature BMDM (day 7Ő10) were resistant to apoptosis induced by M-CSF depletion, which includes the activation of caspase-3 and caspase-9 and the degradation of XIAP, Bcl-2 and Bax proteins in the process. Treatment of day 7 BMDM with XIAP anti-sense oligonucleotides (oligos), but not sense oligos, partly abolished their resistance to apoptosis. By using a gel-shift assay and a specific nuclear factor κB (NF-κB) inhibitor, we demonstrated that NF-κB activity is responsible for the up-regulation of XIAP in M-CSF-treated macrophages. In addition, treatment of starved macrophages with M-CSF induced a rapid phosphorylation of Akt kinase before the activation of NF-κB. Our results showed that XIAP is one of the anti-apoptotic regulators that confer resistance on mature macrophages by M-CSF.

scholarly journals α-bisabolol enhances radiotherapy-induced apoptosis in endometrial cancer cells by reducing the effect of XIAP on inhibiting caspase-3

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Dongmei Fang ◽  
Hongxin Wang ◽  
Min Li ◽  
Wenwen Wei
Keyword(s):  
Endometrial Cancer ◽  
Caspase 3 ◽  
Migration And Invasion ◽  
Inhibitor Of Apoptosis ◽  
Downstream Effectors ◽  
Apoptosis Protein ◽  
Ec Cells ◽  
Cox 2 ◽  
Matrix Metalloproteinases 9 ◽  
Induced Apoptosis

Abstract Endometrial cancer (EC) is one of the most common cancers in females. Although the diagnosis and treatment in early stages can greatly improve the survival rate of patients, the advanced EC still is lethal. Radiotherapy is widely used against EC, and it is a great challenge to find an effective way to overcome the resistance of EC during radiotherapy. α-bisabolol is a promising drug, which has already exhibited its anti-tumor effect in some malignancies. Here we reported that α-bisabolol could inhibit the proliferation of EC cells. It is also shown that their abilities of migration and invasion were effectively reduced by α-bisabolol. Furthermore, our results also demonstrated that α-bisabolol could improve sensitivity of EC cells in radiotherapy and further inhibited the growth of EC cells. By Western blot, we found the expression of matrix metalloproteinases-9 (MMP-9) and cyclin E were significantly decreased, which indicated that EC cells can be further suppressed by using α-bisabolol and radiotherapy. It is also demonstrated in our study that the rate of apoptotic cells is markedly increased in EC by using these two treatments. The significant decrease in X-linked inhibitor of apoptosis protein (XIAP) and increase in caspase-3 detected in our study suggested that the enhancement of apoptosis is mediated by XIAP/caspase-3 pathway, which was further confirmed by examining the downstream effectors of caspase-3, COX-2, PARP and cleaved PARP. In the present study, we demonstrated that α-bisabolol could enhance the sensitivity of EC cells to radiotherapy, which provide a novel alternative for overcoming radioresistance of EC cells and achieving a better outcome in radiotherapy.

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