In solid tumours, necrosis is commonly found in the core region in response to metabolic stress that results from oxygen and glucose depletion (OGD) due to insufficient vascularization and has been implicated in tumour progression. We have previously shown that metabolic stress due to glucose depletion (GD) induces necrosis and HMGB1 release through mitochondrial ROS production in A549 lung adenocarcinoma cells. In this study, we examined the effects of hypoxia on GD-induced necrosis and show that hypoxia prevented GD-induced mitochondrial ROS production, HMGB1 release, and necrosis and switched the cell death mode to apoptosis that is dependent on caspase-3 and -9. We further found that inhibition of ERK1/2 by U0126 abolished the effects of hypoxia to switch the cell death mode and to suppress mitochondrial ROS production, indicating an important role(s) of the ERK pathway in cell death mode determination. We also found that during OGD-induced apoptosis the prosurvival protein kinase Akt is activated and inhibition of Akt by the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and wortmannin prevent OGD-induced apoptosis, caspase-3 and -9 activation, and nuclear translocation of AIF and EndoG. Similar inhibitory effects of PI3K inhibitors were observed in A549 cells that underwent apoptosis when treated with GD in the presence of NAC (a general antioxidant) or catalase (a H(2)O(2) scavenger), or in the presence of active PKC by treatment with phorbol-12-myristate-13-acetate, indicating a crucial role(s) of the PI3K-Akt pathway in OGD-indcued apoptosis. In conclusion, our results demonstrate that hypoxia switches GD-induced necrosis to apoptosis and ERK1/2 and PI3K-Akt exert anti-necrotic and pro-apoptotic activities in the cell death, respectively.
"It can be explained by the different HSCs status (intermediate) partly, and why the ability of JNK inhibitor to enhance the HSCs sensitization to induced apoptosis did't display probably is that HMGB1 actually didn't induce apoptosis. Till now,HMGB1 has been found to modulate functions of many cell types, such as human airway epithelial cells, leukemia cells, lung adenocarcinoma cells, through PI3K/Akt signal pathway –. On the other hand, human activated HSCs utilize components of TLR4 signal transduction cascade to stimulate NF-κB and JNK and up-regulate chemokines and adhesion molecules . As to other cell line like Kuffer cells, HMGB1 can induce proinflammatory cytokines production after sever burn injury, largely dependent on TLRs-dependent MAPKs/NF-kB signal pathway. "
[Show abstract][Hide abstract] ABSTRACT: Background
The migration of hepatic stellate cells (HSCs) is essential to the hepatic fibrotic response, and recently High-mobility group box 1 (HMGB1) has been shown up-regulated during liver fibrosis. Nevertheless, whether HMGB1 can modulate the proliferation and migration of HSCs is poorly understood, as well as the involved intracellular signaling. In this study, we examined the effect of HMGB1 on proliferation, migration, pro-fibrotic function of HSCs and investigated whether toll-like family of receptor 4 (TLR4) dependent signal pathway is involved in the intracellular signaling regulation.
Modified transwell chamber system to mimic the space of Disse was used to evaluate the migration of human primary HSCs, and the protein expressions of related signal factors were evaluated by western blot. Cell proliferation was analyzed by MTT assay, the pro-fibrotic functions of HSCs by qRT-PCR and ELISA respectively. Recombinant human HMGB1 could significantly promote migration of HSCs under both haptotactic and chemotactic stimulation, especially the latter. Human TLR4 neutralizing antibody could markedly inhibit HMGB1-induced migration of HSCs. HMGB1 could enhance the phosphorylation of JNK and PI3K/Akt, and TLR4 neutralizing antibody inhibited HMGB1-enhanced phosphorylation of JNK and PI3K/Akt and activation of NF-κB. JNK inhibitor (SP600125) and PI3K inhibitor (LY 294002) significantly inhibited HMGB1-induced proliferation and migration of HSCs, and also reduced HMGB1-enhanced related collagen expressions and pro-fibrotic cytokines production.
HMGB1 could significantly enhance migration of HSCs in vitro, and TLR4-dependent JNK and PI3K/Akt signal pathways are involved in the HMGB1-induced proliferation, migration and pro-fibrotic effects of HSCs, which indicates HMGB1 might be an effective target to treat liver fibrosis.
PLoS ONE 05/2013; 8(5):e64373. DOI:10.1371/journal.pone.0064373 · 3.23 Impact Factor
"We thus hypothesize that, in conditions of serum starvation, rutin could trigger apoptosis of leukemic cells through both their restored Akt and metabolic activities and inhibition of the pro-survival GSK3␤ pathway . Indeed, GSK3␤-induced cytotoxicity has been previously linked to inhibition of NF-B and mitochondrial destabilization   and despite its well-known pro-survival role, the PI3K/Akt pathway could exert pro-apoptotic activity in altered metabolic conditions  . "
[Show abstract][Hide abstract] ABSTRACT: In search for compounds able to reduce cell adhesion-mediated drug resistance (CAM-DR), we studied effects of Hammada scoparia extracts on leukemic cells adherent or in suspension. We show that H. scoparia flavonoidic fraction and its compound rutin induce apoptosis specifically in adherent leukemic cells and abolish CAM-DR. Importantly, rutin inhibited survival of adherent leukemic progenitors (CD34(+)38(-)123(+)) but spared normal progenitors (CD34(+)38(-)). The pro-apoptotic effects of rutin were correlated with a decrease of active GSK3β and inhibitors of GSK3β reproduced rutin-induced cytotoxicity. This study uncovers the potential of H. scoparia flavonoids and rutin to overcome CAM-DR in acute myeloid leukemia.
Leukemia research 08/2011; 35(8):1093-101. DOI:10.1016/j.leukres.2010.12.011 · 2.35 Impact Factor
"Trans resveratrol is a naturally occurring compound and is enriched in grapes, mulberries and in red wine, and possesses a strong antioxidant activity capable of protecting against oxidative damage (Robb and Stuart, 2010; Sakata et al., 2010). In vivo, dietary administration of trans resveratrol to mice (Kim et al., 2010) or rats (Halliwell and Gutteridge, 2000) confers protection against acute brain injury caused by transient middle cerebral artery occlusion or cardiac arrest, respectively. Dietary trans resveratrol supplementation reduces plaque formation in the brains of transgenic mouse model of Alzheimer's disease (Sakata et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: In this study, we determined the protective potential of trans resveratrol against oxygen-glucose deprivation (OGD) induced reactive oxygen species mediated apoptotic damages in PC12 cells. In vitro model of ischemic cerebral stroke was created by keeping cells in an OGD condition for 6h followed by 24h reoxygenation. Cells received biologically safe doses (5, 10, and 25 μM) of trans resveratrol in the following schedules for 24h prior to OGD; during 6h of OGD; for 24h post OGD and whole treatment group which starts from 24h before OGD and lasted to 24h post OGD. Anti-ischemic potential of trans resveratrol was assessed by measuring the regulation of lipid peroxidation, reactive oxygen species production, glutathione content, and expression (mRNA and protein) of apoptotic markers such as Bax, Bcl(2) and Caspase-3. Hypoxia inducible factor-1α (HIF-1α) was also assessed to correlate the changes with ischemic injuries. Significant (P<0.05) restoration in lipid peroxidation, reactive oxygen species, and glutathione content were observed following the treatment of trans resveratrol in cells receiving OGD and re-oxygenation. Changes induced by trans resveratrol could be correlated well with alterations in the expression of Bax, Bcl(2), Caspase-3 and HIF-1α. These results indicate that trans resveratrol administration attenuates free radical formation and mitochondria mediated apoptosis perhaps by regulating the expressions of Bax, Bcl(2,) and Caspase-3 in PC12 cells receiving OGD and re-oxygenation insult.
European journal of pharmacology 05/2011; 666(1-3):5-11. DOI:10.1016/j.ejphar.2011.05.015 · 2.53 Impact Factor
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