scholarly journals Lactoferrin attenuates fatty acid-induced lipotoxicity via Akt signaling in hepatocarcinoma cells

2015 ◽  
Vol 93 (6) ◽  
pp. 566-573 ◽  
Author(s):  
Satoru Morishita ◽  
Keiko Tomita ◽  
Tomoji Ono ◽  
Michiaki Murakoshi ◽  
Kenji Saito ◽  
...  
Keyword(s):  
Cell Viability ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Lactic Dehydrogenase ◽  
Akt Signaling ◽  
Akt Inhibitor ◽  
Nonalcoholic Fatty Liver ◽  
Simple Steatosis

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of lesions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). The excess influx of fatty acids (FAs) into the liver is recognized as a main cause of simple steatosis formation and progression to NASH. Recently, administration of lactoferrin (LF), a glycoprotein present in milk, was suggested to prevent NAFLD development. However, the effect of LF on the contribution of FA to NAFLD development remains unclear. In this study, the effects of LF on FA mixture (FAm)-induced lipotoxicity using human hepatocarcinoma G2 cells were assessed. FAm significantly decreased cell viability and increased intracellular lipid accumulation, whereas LF significantly recovered cell viability without affecting lipid accumulation. FAm-induced lactic dehydrogenase (LDH) and caspase-3/7 activities were significantly decreased by LF and SP600125, a c-Jun N-terminal kinase (JNK) specific inhibitor. We also found that LF added to FAm-treated cells induced Akt phosphorylation, which contributed to inhibition of JNK signaling pathway-dependent apoptosis. Akt inhibitor VIII, an allosteric Akt inhibitor, significantly attenuated the effect of LF on LDH activity and abrogated the ones on cell viability and caspase-3/7 activity. In summary, the present study has revealed that LF has a protective effect on FAm-induced lipotoxicity in a HepG2 model of NAFLD and identified the activation of the Akt signaling pathway as a possibly major mechanism.

scholarly journals Role of TLR4-Mediated PI3K/AKT/GSK-3βSignaling Pathway in Apoptosis of Rat Hepatocytes

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Xian Zhang ◽  
Daorong Jiang ◽  
Wei Jiang ◽  
Min Zhao ◽  
Jianhe Gan
Keyword(s):  
Cell Viability ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Nuclear Translocation ◽  
Rat Hepatocytes ◽  
Akt Inhibitor ◽  
Toll Like Receptor 4 ◽  
Cultured Rat Hepatocytes ◽  
Active Caspase

We investigated the mechanism of the Toll-like receptor 4- (TLR4-) mediated PI3K/AKT/GSK-3βsignaling pathway in rat hepatocytes apoptosis induced by LPS. The cultured rat hepatocytes were treated with LPS alone or first pretreated with TLR4 inhibitor, AKT inhibitor, and GSK-3βinhibitor, respectively, and then stimulated with the same dose of LPS. Cell viability, cell apoptotic rate, and apoptosis morphology were assessed; the level of P-AKTSer473, P-GSK-3βSer9, and active Caspase-3 and the ratio of Bax/Bcl-2 were evaluated. The results indicated that cell viability decreased, while cell apoptotic rate increased with time after LPS stimulation. The expression of P-AKTSer473and P-GSK-3βSer9in the LPS group decreased compared with the control, while the level of active Caspase-3 and the ratio of Bax/Bcl-2 were significantly increased. These effects were attenuated by pretreatment with CLI-095. In addition, the apoptotic ratio decreased after pretreatment with LiCl but increased following pretreatment with LY294002. The expression of P-AKTSer473further decreased following pretreatment with LY294002 and the expression of P-GSK-3βSer9increased following pretreatment with LiCl. Moreover, pretreatment with CLI-095 weakened LPS-induced nuclear translocation of GSK-3β. Our findings suggest that the TLR4-mediated PI3K/AKT/GSK-3βsignaling pathway is present in rat hepatocytes and participates in apoptosis of BRL-3A cells.

Effects of Hydrogen-rich Water on the PI3K/AKT Signaling Pathway in Rats with Myocardial Ischemia-reperfusion Injury

2020 ◽  
Vol 20 (5) ◽  
pp. 396-406 ◽  
Author(s):  
Liangtong Li ◽  
Xiangzi Li ◽  
Zhe Zhang ◽  
Li Liu ◽  
Tongtong Liu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Control Group ◽  
Akt Signaling Pathway ◽  
Expression Levels ◽  
Water Group

Background: The effects of hydrogen-rich water on PI3K/AKT-mediated apoptosis were studied in rats subjected to myocardial ischemia-reperfusion injury (MIRI). Methdos: Sixty rats were divided randomly into a hydrogen-rich water group and a control group. The hearts were removed and fixed in a Langendorff device. Hearts from the control group were perfused with K-R solution, and hearts from the hydrogen-rich water group was perfused with K-R solution + hydrogen-rich water. The two treatment groups were then divided randomly into pre-ischemic period, ischemic period and reperfusion period groups(10 rats per group), which were subjected to reverse perfusion for 10 min, normal treatment for 20 min, and reperfusion for 20 min, respectively. The mRNA and protein expression levels of PI3K, AKT, p-AKT, FoxO1, Bim and Caspase-3 in each group were detected by RT-qPCR, immunohistochemistry (IHC) and Western blotting. Caspase-3 activity was detected by spectrophotometry. Results: Among the hydrogen-rich water group, the PI3K/AKT signaling pathway was significantly activated, and FoxO1, Bim, and Caspase-3 mRNA and protein levels were significantly decreased in ischemia-reperfusion subgroup compared with the preischemic and ischemic subgroups. In the ischemia-reperfusion hydrogen-rich water group, PI3K, AKT and p-AKT mRNA and protein expression levels were increased while the FoxO1, Bim and Caspase-3 expression levels were significantly decreased compared with those in the corresponding control group (p<0.05). Conclusion: Hydrogen-rich water can activate the PI3K/AKT signaling pathway, alleviate ischemia-reperfusion injury in isolated rat hearts, and inhibit cardiomyocyte apoptosis.

scholarly journals Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier

2019 ◽  
Vol 20 (23) ◽  
pp. 6010 ◽  
Author(s):  
Jacopo Junio Valerio Branca ◽  
Mario Maresca ◽  
Gabriele Morucci ◽  
Tommaso Mello ◽  
Matteo Becatti ◽  
...  
Keyword(s):  
Tight Junction ◽  
Er Stress ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Caspase 3 ◽  
Specific Inhibitor ◽  
Brain Barrier ◽  
Oral Exposure ◽  
Blood Brain ◽  
Parkinson’S Diseases

Cadmium (Cd) is a highly toxic environmental pollutant released from the smelting and refining of metals and cigarette smoking. Oral exposure to cadmium may result in adverse effects on a number of tissues, including the central nervous system (CNS). In fact, its toxicity has been related to neurological disorders, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Under normal conditions, Cd barely reaches the brain in adults because of the presence of the blood–brain barrier (BBB); however, it has been demonstrated that Cd-dependent BBB alteration contributes to pathogenesis of neurodegeneration. However, the mechanism underlying Cd-dependent BBB alteration remain obscure. Here, we investigated the signaling pathway of Cd-induced tight junction (TJ), F-actin, and vimentin protein disassembly in a rat brain endothelial cell line (RBE4). RBE4 cells treated with 10 μM cadmium chloride (CdCl2) showed a dose- and time-dependent significant increase in reactive oxygen species (ROS) production. This phenomenon was coincident with the alteration of the TJ zonula occludens-1 (ZO-1), F-actin, and vimentin proteins. The Cd-dependent ROS increase elicited the upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum (ER) stress that induces caspase-3 activation. Further signal profiling by the pannexin-1 (PANX1) specific inhibitor 10Panx revealed a PANX1-independent increase in ATP spillage in Cd-treated endothelial cells. Our results point out that a ROS-dependent ER stress-mediated signaling pathway involving caspase-3 activation and ATP release is behind the BBB morphological alterations induced by Cd.

scholarly journals Cordycepin enhances the chemosensitivity of esophageal cancer cells to cisplatin by inducing the activation of AMPK and suppressing the AKT signaling pathway

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ying Gao ◽  
Dan-Lei Chen ◽  
Mi Zhou ◽  
Zhou-san Zheng ◽  
Mei-Fang He ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Expression Levels ◽  
In Vivo Animal Model ◽  
Esophageal Cancer Cells

Abstract Although cisplatin (cDDP), is a first-line chemotherapy drug for esophageal cancer, it still has the potential to develop drug resistance and side effects. There is increasing evidence that cordycepin can work synergistically with other chemotherapy drugs. Therefore, we investigated whether combination therapy of cordycepin and cDDP may enhance the therapeutic effect of cDDP. We performed a series of functional tests to study the effect of medical treatment on esophageal cancer cells. We then used GO analysis to examine the pathways affected by treatment with cordycepin and cDDP. Next, we observed changes in the abundance of the selected pathway proteins. The in vivo animal model supported the results of the in vitro experiments. Co-treatment with cordycepin and cDDP inhibited cell growth, migration, and metastasis, as well as induced apoptosis. Cordycepin was found to effectively enhance activation of AMPK and inhibited activity of AKT. In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged. Overall, cordycepin was found to enhance the chemical sensitivity of esophageal cancer cells to cisplatin by inducing AMPK activation and inhibiting the AKT signaling pathway. Combination therapy of cordycepin and cisplatin represent a novel potential treatment of esophageal cancer.

scholarly journals Relaxin Attenuates Contrast-Induced Human Proximal Tubular Epithelial Cell Apoptosis by Activation of the PI3K/Akt Signaling Pathway In Vitro

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Xiang-Cheng Xie ◽  
Yizhi Cao ◽  
Xiu Yang ◽  
Qun-Hong Xu ◽  
Wei Wei ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Bax Protein ◽  
Phosphorylated Akt

Background. Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of iatrogenic acute kidney injury (AKI); however, therapeutic strategies for AKI remain limited. This study aims to explore the effect of relaxin (RLX) on contrast-induced HK-2 apoptosis and its underlying mechanisms.Methods. Renal tubular epithelial cells (HK-2) were incubated either with or without ioversol, human H2 relaxin, and LY294002 (the inhibitor of the PI3K/Akt signal pathway). Cell viability was evaluated with a CCK-8 assay. Apoptotic morphologic alterations were observed using the Hoechst 33342 staining method. Apoptosis was detected with Annexin V staining. Western blot analysis was employed to measure the expression of pAkt (S473), Akt, cleaved caspase-3, Bcl-2, Bax, and actin proteins.Results. Ioversol reduced the viability of HK-2 cells. Western blotting results revealed decreased expression of phosphorylated Akt in cells treated with ioversol. The activities of caspase-3 and Bax protein increased, while the expression of Bcl-2 protein decreased. As a result, the Bax/Bcl-2 ratio increased after treatment with ioversol. These effects were reversed when HK-2 cells were cotreated with RLX. However, with preadministration of PI3K/Akt pathway inhibitor LY294002, the effect of RLX was blocked.Conclusion. Our study demonstrates that relaxin attenuates ioversol induced cell apoptosis via activation of the PI3K/Akt signaling pathway, suggesting that RLX might play a protective role in the treatment of CI-AKI.

scholarly journals Inhibition of the SOCS1-JAK2-STAT3 Signaling Pathway Confers Neuroprotection in Rats with Ischemic Stroke

2017 ◽  
Vol 44 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Xiao-Lei Wang ◽  
Chun-Mei Qiao ◽  
Jiong-Ou Liu ◽  
Chun-Yang Li
Keyword(s):  
Ischemic Stroke ◽  
Protein Expression ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Rat Model ◽  
Caspase 3 ◽  
Neuronal Cells ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Mrna And Protein Expression

Background: The present study aims to investigate the protective effects of the SOCS1-JAK2-STAT3 signaling pathway on neurons in a rat model of ischemic stroke. Methods: Our study was conducted using an ischemic stroke rat model. After the microglia were extracted, 40 neonatal Sprague-Dawley (SD) rats were assigned into the blank, AG490, model and negative control (NC) groups. The neurological function of all the rats was evaluated. Histopathological changes were observed. qRT-PCR and western blotting were applied to measure the expression of genes and proteins in the SOCS1-JAK2-STAT3 signaling pathway and related to apoptosis. The TUNEL assay was conducted to calculate the cellular morphology and apoptosis of neuronal cells. Cell viability was detected using the MTT assay. In addition, immunoassays were used to measure the content of superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA) as well as the levels of oxidative stress. Results: Compared with the blank group, the model and NC groups showed higher neurological function scores—the cytoplasm of the neurons were cavitated, the organelles were reduced with unclear margins, some of the neurons were necrotic, and apoptosis was increased. In addition, the NC and model groups exhibited decreased cell viability, lower mRNA and protein expression of SOCS1 SOCS3 and bcl-2 and reduced SOD and GSH levels but higher mRNA and protein expression levels of AK2, STAT3,Bax and caspase-3 as well as increased protein expression of P-JAK2, P-STAT3 and activated caspase-3 (c-caspase-3). Moreover, the MDA levels were up-regulated in the NC and model groups. In contrast, opposing trends were found in the AG490 group compared with the NC and model groups. Conclusion: These data demonstrate that inhibiting the SOCS1-JAK2-STAT3 signaling pathway can reduce the loss of nerve function and apoptosis of neuronal cells, which provides a new target for the clinical treatment of ischemic stroke.

scholarly journals Dietary Blueberry and Bifidobacteria Attenuate Nonalcoholic Fatty Liver Disease in Rats by Affecting SIRT1-Mediated Signaling Pathway

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tingting Ren ◽  
Chao Huang ◽  
Mingliang Cheng
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Control Group ◽  
Nonalcoholic Fatty Liver ◽  
Blueberry Juice ◽  
Group A ◽  
Better Than

NAFLD model rats were established and divided into NAFLD model (MG group), SIRT1 RNAi (SI group), blueberry juice (BJ group), blueberry juice + bifidobacteria (BJB group), blueberry juice + SIRT1 RNAi (BJSI group), and blueberry juice + bifidobacteria + SIRT1 RNAi groups (BJBSI group). A group with normal rats was a control group (CG). BJB group ameliorated NAFLD, which was better than BJ group (P<0.05). The lipid accumulation was lower in CG, BJ, and BJB groups than that in MG, SI, BJSI, and BJBSI groups (P<0.05). The levels of SIRT1 and PPAR-αwere higher in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P<0.05). The levels of SREBP-1c were lower in CG, BJ, and BJB groups than those in MG, SI, BJSI, and BJBSI groups (P<0.05). The biochemical indexes SOD, GSH, and HDL-c were improved from CG to BJB group (P<0.05). Inversely, the levels of AST and ALT, TG, TC, LDL-c, and MDA were decreased from CG to BJB group (P<0.05). These changes enhance antioxidative capability and biochemical index of rats. Blueberry juice and bifidobacteria improve NAFLD by activating SIRTI-mediating signaling pathway.

scholarly journals Phosphatidylinositol 3-kinase/Akt signaling stimulates colonic mucosal cell survival during aging

2006 ◽  
Vol 290 (1) ◽  
pp. G49-G55 ◽  
Author(s):  
Adhip P. N. Majumdar ◽  
Jianhua Du
Keyword(s):  
Cell Survival ◽  
Signaling Pathway ◽  
Colonic Mucosa ◽  
Caspase 3 ◽  
Akt Signaling ◽  
Entire Length ◽  
Mucosal Cell ◽  
Colonic Crypt ◽  
Akt Signaling Pathway ◽  
Age Related

Although aging is shown to be associated with decreased apoptosis and increased survival of cells in the colonic mucosa of Fischer 344 rats, the regulatory mechanisms are poorly understood. The current investigation examines the involvement of phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway in mediating the events of colonic mucosal cell survival during aging. We have observed that aging is associated with activation of PI3K/Akt signaling, as evidenced by the higher levels of phosphorylated forms of p85, the regulatory subunit of PI3K and of Akt in the proximal and distal colonic mucosa, of aged (21–23 mo) than in young (4–7 mo) rats. These increases are accompanied by a concomitant rise in phosphorylation of proapoptotic protein Bad, which is sequestered by the 14-3-3 family of proteins following phosphorylation by Akt, resulting in a reduction in nonphosphorylated Bad. The amount of antiapoptotic Bcl-xL bound to nonphosporylated Bad in the colonic mucosa is found to be substantially lower in aged than in young rats, resulting in a marked rise in the unbound/free form of Bcl-xL in the aging colon. The age-related activation of PI3K and the reduction in caspase-3 activity could be reversed by wortmannin, a specific inhibitor of PI3K. Increased levels of Bcl-xL and phosphorylated forms of Akt and Bad and reduction in caspase-3 activity were observed throughout the entire length of the colonic crypt of aged rats. We conclude that the constitutive activation of the PI3K/Akt-signaling pathway is partly responsible for the age-related increase in colonic mucosal cell survival. This is evident throughout the entire length of the colonic crypt.

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