Norepinephrine-induced oxidative stress causes PC-12 cell apoptosis by both endoplasmic reticulum stress and mitochondrial intrinsic pathway: inhibition of phosphatidylinositol 3-kinase survival pathway

2006 ◽  
Vol 290 (5) ◽  
pp. C1373-C1384 ◽  
Author(s):  
Weike Mao ◽  
Chikao Iwai ◽  
Peter C. Keng ◽  
Raju Vulapalli ◽  
Chang-seng Liang
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cytochrome C ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Pi3 Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Caspase 12 ◽  
Survival Pathway ◽  
Phosphatidylinositol 3

Norepinephrine (NE) induces endoplasmic reticulum (ER) unfolded protein response and reduces maturation and translocation of NE transporter to cell membrane via enhanced formation of reactive oxygen species in PC-12 cells. In the present study, we investigated whether ER stress is also implicated in the proapoptotic effect of NE. We found that the apoptotic effect of NE was associated with increased processing of ER-resident pro-caspase-12, cleavage of caspase-9 and -3, and mitochondrial release of cytochrome c. ER stress was evidenced by upregulation of ER chaperone GRP78 and transcription factor CHOP and the translocation of XBP-1 from the ER to the nucleus by NE. NE also reduced phospho-Akt (Ser473), indicating suppression of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt survival pathway. Similar results were produced by thapsigargin. NGF, which promotes the PI3-kinase/Akt activity, reduced the effects of NE and thapsigargin on apoptosis and activation of caspase-12 and -3. However, the effects of NE, but not of thapsigargin, were abolished by pretreatment with SOD and catalase. In contrast, the PI3-kinase inhibitors LY-294002 and wortmannin abolished the protective effects of both SOD/catalase and NGF on NE-induced apoptosis. The functional importance of caspase-12 activation was supported by the use of Z-ATAD-FMK, which reduced the NE-induced processing of caspase-12 and cell apoptosis, but the caspase-12, -9, and -3 inhibitors had no effects on the increase in cytosolic cytochrome c produced by NE. In contrast, the release of mitochondrial cytochrome c was abolished by SOD/catalase and NGF. These results indicate that NE induced cell apoptosis by both ER stress and a mitochondrial death pathway and that the effects of NE were mediated via oxidative stress and inhibition of the PI3-kinase/Akt survival pathway.

scholarly journals Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells

2003 ◽  
pp. 147-155 ◽  
Author(s):  
S Kang ◽  
J Song ◽  
H Kang ◽  
S Kim ◽  
Y Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Pi3 Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal ◽  
Apoptotic Activity ◽  
Phosphatidylinositol 3

OBJECTIVE: Insulin has well-known activities in controlling energy metabolism, cellular proliferation and biosynthesis of functional molecules to maintain a biological homeostasis. Recently, several studies have suggested that insulin may protect cells from apoptosis in different cell lines; however, little is known about the nature of its anti-apoptotic activity. In many clinical disorders, including type 2 diabetes mellitus, oxidative stress and the production of reactive oxygen species (ROS) is increased. With these facts as a background, we examined here whether insulin protects HepG2 cells from apoptosis by decreasing oxidative stress and, if so, which signaling steps are involved in this process. METHODS: Intracellular DNA content, the degree of nuclear condensation or poly(ADP-ribose) polymerase hydrolysis was measured to verify the occurrence of apoptotic events. Caspase-3 activity and ROS accumulation within cells were also measured. Western blot analysis was performed to identify signaling molecules activated in response to insulin. RESULTS: Serum starvation resulted in a marked accumulation of ROS, activation of caspase-3, and subsequent apoptotic cell death which were, in turn, markedly blocked by the addition of insulin. The anti-apoptotic activity of insulin was sensitive to blockade of two different signaling steps, activations of phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated protein kinase (ERK). CONCLUSION: Insulin exerts an anti-apoptotic activity by suppressing the excessive accumulation of ROS within cells through signaling pathways including stimulation of PI3 kinase and ERK in HepG2 cells.

scholarly journals Oxidative and endoplasmic reticulum stresses are involved in palmitic acid-induced H9c2 cell apoptosis

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Lei Yang ◽  
Gaopeng Guan ◽  
Lanjie Lei ◽  
Jianyun Liu ◽  
Lingling Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Palmitic Acid ◽  
Er Stress ◽  
Cell Apoptosis ◽  
H9c2 Cell ◽  
H9c2 Cells ◽  
Proliferation And Apoptosis ◽  
H9c2 Cardiomyocytes ◽  
Heart Muscle Cells

Abstract Palmitic acid (PA) is the most common saturated long-chain fatty acid that causes damage to heart muscle cells. However, the molecular mechanism of PA toxicity in myocardial cells is not fully understood. In the present study, we explored the effects of PA on proliferation and apoptosis of H9c2 cardiomyocytes, and uncovered the signaling pathways involved in PA toxicity. Our study revealed induction of both oxidative and endoplasmic reticulum (ER) stresses and exacerbation of apoptosis in PA-treated H9c2 cells. Inhibition of oxidative stress by N-acetylcysteine (NAC) reduced apoptosis and decreased ER stress in PA-treated H9c2 cells. Moreover, inhibition of ER stress by 4-phenyl butyric acid decreased apoptosis and attenuated oxidative stress. In summary, the present study demonstrated that oxidative stress coordinates with ER stress to play important roles in PA-induced H9c2 cell apoptosis.

scholarly journals Nicorandil Protects the Heart from Ischemia/Reperfusion Injury by Attenuating Endoplasmic Reticulum Response-induced Apoptosis Through PI3K/Akt Signaling Pathway

2015 ◽  
Vol 35 (6) ◽  
pp. 2320-2332 ◽  
Author(s):  
Hui Wu ◽  
Ming Ye ◽  
Jun Yang ◽  
Jiawang Ding ◽  
Jian Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Infarct Size ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Pi3k Inhibitor ◽  
Myocardial Infarct Size ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Background/Aims: As a vasodilatory drug used to treat angina, nicorandil has been shown to induce an infarct-limiting effect in various experimental animal models of myocardial ischemia-reperfusion (IR). There are multiple mechanisms causing the IR injury, among which, the endoplasmic reticulum (ER) stress and ER stress-initiated apoptosis are implicated to play an important role. However, whether ER stress is involved in nicorandil-induced cardioprotection is unknown. Methods: Post-ischemic functional recovery, lactate dehydrogenase (LDH) release and infarct size in perfused rat hearts subjected to global no-flow I/R were measured to analysis the effect of nicorandil and ER stress inducer of tunicamycin as well as phosphatidylinositol 3-kinase (PI3K) inhibitor of wortmannin on the I/R hearts. The I/R hearts tissue were harvested to evaluate apoptosis ratio with TUNEL assay and protein expression with western blot. Results: We showed that nicorandil ameliorated postischemic contractile recovery, as well as significantly reduced myocardial infarct size at a dose-dependent manner. Furthermore, nicorandil treatment inhibited the IR-induced apoptosis and ER stress. The beneficial effects of nicorandil were blocked by ER stress inducer, tunicamycin and specific phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Concolusion: We conclude that the cardioprotection of nicorandil was at least in part mediated via inhibition of ER stress-induced apoptotic cell death through PI3K/Akt pathway.

Testicular Injury Attenuated by Rapamycin Through Induction of Autophagy and Inhibition of Endoplasmic Reticulum Stress in Streptozotocin- Induced Diabetic Rats

2019 ◽  
Vol 19 (5) ◽  
pp. 665-675 ◽  
Author(s):  
Wenjiao Shi ◽  
Zhixin Guo ◽  
Ruixia Yuan
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Effect ◽  
Er Stress ◽  
B Cell Lymphoma ◽  
Diabetic Rats ◽  
Pathological Changes ◽  
Rapamycin Treatment ◽  
Related Proteins

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

scholarly journals Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4210
Author(s):  
Yan Zhou ◽  
Chunxiu Zhou ◽  
Xutao Zhang ◽  
Chi Teng Vong ◽  
Yitao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Diabetic Mice ◽  
And Oxidative Stress

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

scholarly journals Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

2021 ◽  
Author(s):  
Sinan Xiong ◽  
Wee-Joo Chng ◽  
Jianbiao Zhou
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Fate ◽  
Stress Responses ◽  
Plasma Cells ◽  
Reactive Oxygen Species Generation ◽  
Future Research ◽  
And Oxidative Stress

AbstractUnder physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

Ufmylation regulates granulosa cell apoptosis via ER stress but not oxidative stress during goat follicular atresia

2021 ◽  
Vol 169 ◽  
pp. 47-55
Author(s):  
Xinyan Zhang ◽  
Tong Yu ◽  
Xinyan Guo ◽  
Ruixue Zhang ◽  
Yanni Jia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Granulosa Cell ◽  
Cell Apoptosis ◽  
Follicular Atresia

scholarly journals Role of phosphatidylinositol 3-kinase in oxidative stress-induced disruption of tight junctions. Vol. 278 (2003) 49239-49245

2004 ◽  
Vol 279 (7) ◽  
pp. 6204
Author(s):  
Parimal Sheth ◽  
Shyamali Basuroy ◽  
Chunying Li ◽  
Anjaparavanda P. Naren ◽  
Radhakrishna K. Rao
Keyword(s):  
Oxidative Stress ◽  
Tight Junctions ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals Molecular functions of ASK family in diseases caused by stress-induced inflammation and apoptosis

2020 ◽  
Author(s):  
Kazuki Kojima ◽  
Hidenori Ichijo ◽  
Isao Naguro
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Adverse Effects ◽  
Er Stress ◽  
Inflammatory Diseases ◽  
Family Members ◽  
Disease States ◽  
Molecular Functions ◽  
Critical Responses ◽  
Proper Response

Summary VCells are constantly exposed to various types of stress, and disruption of the proper response lead to a variety of diseases. Among them, inflammation and apoptosis are important examples of critical responses and should be tightly regulated, as inappropriate control of these responses is detrimental to the organism. In several disease states, these responses are abnormally regulated, with adverse effects. Apoptosis signal-regulating kinase (ASK) family members are stress-responsive kinases that regulate inflammation and apoptosis after a variety of stimuli, such as oxidative stress and endoplasmic reticulum (ER) stress. In this review, we summarize recent reports on the ASK family in terms of their involvement in inflammatory diseases, focusing on upstream stimuli that regulate ASK family members.

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