Cisplatin-mediated c-myc overexpression and cytochrome c (cyt c) release result in the up-regulation of the death receptors DR4 and DR5 and the activation of caspase 3 and caspase 9, likely responsible for the TRAIL-sensitizing effect of cisplatin

Background: Sepsis is a life-threatening condition often associated with a high incidence of multiple organs injury. Several papers suggested the immune response by itself, with the production of humoral inflammatory mediators, is crucial in determining organ injury. However, little is known of how sepsis directly induces organ injury at the cellular levels. To assess this point, we set up an in vitro study to investigate the response of renal tubular cells (RTCs), monocytes (U937) and hepatocytes (HepG2) after 24 h-incubation with septic patients’ plasma. Methods: We enrolled 26 septic patients (“test” group). We evaluated cell viability, apoptosis and necrosis by flow cytometer. Caspase-3,-8,-9 and cytochrome-c concentrations have been analyzed using the Human enzyme-linked immunosorbent assay kit. Results: We found that a decrease of cell viability in all cell lines tested was associated to the increase of apoptosis in RTCs and U937 (p < 0.0001) and increase of necrosis in HepG2 (p < 0.5). The increase of apoptosis in RTCs and U937 cells was confirmed by higher levels of caspase-3 (p < 0.0001). We showed that apoptosis in both RTCs and U937 was triggered by the activation of the intrinsic pathway, as caspase-9 and cytochrome-c levels significantly increased (p < 0.0001), while caspase-8 did not change. This assumption was strengthened by the significant correlation of caspase-9 with both cytochrome-c (r = 0.73 for RTCs and r = 0.69 for U937) and caspase-3 (r = 0.69 for RTCs and r = 0.63 for U937). Conclusion: Humoral mediators in septic patients’ plasma induce apoptosis. This fact suggests that apoptosis inhibitors should be investigated as future strategy to reduce sepsis-induced organ damages.

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Silica nanoparticles inducing the apoptosis of spermatocyte cell through microRNA-450b-3p targeting MTCH2-mediating mitochondrial signaling pathway

10.21203/rs.3.rs-24673/v1 ◽

2020 ◽

Author(s):

Guiqing Zhou ◽

Jianhui Liu ◽

Xiangyang Li ◽

Yujian Sang ◽

Yue Zhang ◽

...

Keyword(s):

Cytochrome C ◽

Silica Nanoparticles ◽

Caspase 3 ◽

Reproductive Toxicity ◽

Control Group ◽

Caspase 9 ◽

Protein Expressions ◽

Underlying Mechanisms

Abstract Background: Silica nanoparticles (SiNPs) are found in environmental particulate matter and are proven to have adverse effects on fertility. The relationship and underlying mechanisms between miRNAs and apoptosis induced by SiNPs during spermatogenesis is currently ambiguous. Experimental design: The present study was designed to investigate the role of miRNA-450b-3p in the reproductive toxicity caused by SiNPs. In vivo, 40 male mice were randomly divided into control and SiNPs groups, 20 per group. The mice in the SiNPs group were administrated 20 mg/kg SiNPs by tracheal perfusion once every 5 days, for 35 days, and the control group were given the equivalent of a normal luminal saline. In vitro, spermatocyte cells were divided into 0 and 5 μg/mL SiNPs groups, after passaged for 30 generations, the GC-2spd cells in 5 μg/mL SiNPs groups were transfected with miRNA-450b-3p and its mimic and inhibitor. Results: In vivo, the results showed that SiNPs damaged tissue structures of testis, decreased the quantity and quality of the sperm, reduced the expression of miR-450b-3p, and increased the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, and Caspase-3 in the testis. In vitro, SiNPs obviously repressed the viability and increased the LDH level and apoptosis rate, decreased the levels of the miR-450b-3p, significantly enhanced the protein expressions of the MTCH2, BID, BAX, Cytochrome C, Caspase-9, Caspase-3; while the mimic of miR-450b-3p reversed the changes induced by SiNPs, but inhibitor further promoted the effects induced by SiNPs.Conclusion: The result suggested that SiNPs could induce the spermatocyte apoptosis by inhibiting the miR-450b-3p expression to target promoting the MTCH2 resulting in activating mitochondrial apoptotic signaling pathways in the spermatocyte cells.

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LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00406.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. G821-G829 ◽

Cited By ~ 54

Author(s):

Wenlin Deng ◽

De-An Wang ◽

Elvira Gosmanova ◽

Leonard R. Johnson ◽

Gabor Tigyi

Keyword(s):

Epithelial Cells ◽

Cytochrome C ◽

Protein Expression ◽

Caspase 3 ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Caspase 9 ◽

Cytochrome C Release ◽

Apoptotic Pathway ◽

Antiapoptotic Activity

We previously showed ( Gastroenterology 123: 206–216, 2002) that lysophosphatidic acid (LPA) protects and rescues rat intestinal epithelial cells (IEC-6) from apoptosis. Here, we provide evidence for the LPA-elicited inhibition of the mitochondrial apoptotic pathway leading to attenuation of caspase-3 activation. Pretreatment of IEC-6 cells with LPA inhibited campothecin-induced caspase-9 and caspase-3 activation and DNA fragmentation. A caspase-9 inhibitor peptide mimicked the LPA-elicited antiapoptotic activity. LPA elicited ERK1/ERK2 and PKB/Akt phosphorylation. The LPA-elicited antiapoptotic activity and inhibition of caspase-9 activity were abrogated by pertussis toxin, PD 98059, wortmannin, and LY 294002. LPA reduced cytochrome c release from mitochondria and prevented activation of caspase-9. LPA prevented translocation of Bax from cytosol to mitochondria and increased the expression of the antiapoptotic Bcl-2 mRNA and protein. LPA had no effect on Bcl-xl, Bad, and Bak mRNA or protein expression. These data indicate that LPA protects IEC-6 cells from camptothecin-induced apoptosis through Gi-coupled inhibition of caspase-3 activation mediated by the attenuation of caspase-9 activation due to diminished cytochrome c release, involving upregulation of Bcl-2 protein expression and prevention of Bax translocation.

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Mechanism of Heshouwuyin inhibiting the Cyt c/Apaf-1/Caspase-9/Caspase-3 pathway in spermatogenic cell apoptosis

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-020-02904-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Hongjie Wang ◽

Juan Zhu ◽

Liping Jiang ◽

Boying Shan ◽

Peihan Xiao ◽

...

Keyword(s):

Cell Apoptosis ◽

Caspase 3 ◽

Spermatogenic Cell ◽

Caspase 9 ◽

Cyt C

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

The Journal of Cell Biology ◽

10.1083/jcb.152.3.483 ◽

2001 ◽

Vol 152 (3) ◽

pp. 483-490 ◽

Cited By ~ 128

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.

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JS-K, a Novel Nitric Oxide (NO) Generator, Induces Cytochrome c Release and Caspase Activation in HL-60 Myeloid Leukemia Cells.

Blood ◽

10.1182/blood.v104.11.3415.3415 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3415-3415

Author(s):

Paul J. Shami ◽

Vidya Udupi ◽

Margaret Yu ◽

Swati Malaviya ◽

Joseph E. Saavedra ◽

...

Keyword(s):

Cytochrome C ◽

Caspase 3 ◽

Myelogenous Leukemia ◽

Leukemia Cells ◽

Caspase 8 ◽

Caspase 9 ◽

Cytochrome C Release ◽

Dose Dependent Fashion ◽

Acute Myelogenous ◽

Dose Dependent

Abstract NO induces differentiation and apoptosis in Acute Myelogenous Leukemia (AML) cells. Glutathione S-Transferases (GST) play an important role in multidrug resistance and are upregulated in 90% of AML cells. We have designed a novel prodrug class that releases NO on metabolism by GST. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antileukemic activity. We have previously shown that JS-K induces apoptosis in HL-60 cells by a caspase dependent mechanism (Molecular Cancer Therapeutics2:409-417,2003). The purpose of this study was to determine the pathway through which JS-K induces apoptosis. Western blot analysis showed that treatment of HL-60 cells with JS-K (0 – 1 μM) for 6 hours results in release of Cytochrome c from mitochondria in a dose dependent fashion. Treatment with JS-K resulted in a dose dependent activation of Caspase 9. Sixteen and 24 hours after exposure to 1 μM JS-K, Caspase 9 activity was induced by 393 ± 93% and 237 ± 13% of control, respectively (p = 0.03 at the 24 hours time point). Treatment with JS-K resulted in a dose dependent activation of Caspase 3. Twenty four hours after exposure to 1 μM JS-K, Caspase 3 activity was 208 ± 3.4 % of control (p = 0.02). Treatment with JS-K also resulted in a dose dependent activation of Caspase 8, but to a lesser extent than Caspase 9 and 3. Twenty four hours after exposure to 1 μM JS-K, Caspase 8 activity was 144 ± 5.3 % of control (p = 0.04). We conclude that JS-K activates the intrinsic pathway of apoptosis in leukemia cells by inducing the release of Cytochrome c from mitochondria. (NO1-CO-12400).

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Omi/HtrA2 and XIAP are components of platelet apoptosis signalling

Thrombosis and Haemostasis ◽

10.1160/th12-06-0404 ◽

2013 ◽

Vol 109 (03) ◽

pp. 532-539 ◽

Cited By ~ 13

Author(s):

Jeannine Winkler ◽

Margaret Rand ◽

Markus Schmugge ◽

Oliver Speer

Keyword(s):

Cytochrome C ◽

Caspase 3 ◽

Transmembrane Potential ◽

Signalling Pathway ◽

Ionophore A23187 ◽

Caspase 9 ◽

Cytochrome C Release ◽

Thrombin Inhibition ◽

Induction Of Apoptosis ◽

Apoptotic Proteins

SummaryAlthough platelets possess the hallmarks of apoptosis such as activation of caspases, cytochrome c release and depolarisation of the mitochondrial transmembrane potential (ΔΨm), their entire apoptotic-signalling pathway is not totally understood. Therefore we studied the expression of various apoptotic proteins and found that platelets contain the pro-apoptotic proteins Omi/HtrA2 and Smac/Diablo, as well as their target the X-linked inhibitor of apoptosis XIAP. Omi/HtrA2 and Smac/Diablo were released from mitochondria into the platelet cytosol together with cytochrome c after induction of apoptosis by the Ca2+ ionophore A23187 or the BH3 mimetic ABT-737, and to a lesser extent, after platelet stimulation with collagen and thrombin. Inhibition of Omi/HtrA2 led to decreased levels of activated caspase-3/7 and caspase-9, but did not abolish loss of ΔΨm or prevent release of Omi/HtrA2 from mitochondria. These results indicate that platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease Omi/HtrA2 and its target protein XIAP.

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PO-298 Effect of exercise and Siyeshen upon hippocampal cytochrome c and caspase-3 of diabetic rats

Exercise Biochemistry Review ◽

10.14428/ebr.v1i5.13453 ◽

2018 ◽

Vol 1 (5) ◽

Author(s):

Dongmei Wang ◽

Jinming Zhang ◽

Haibin Liu ◽

Rongmei Wang

Keyword(s):

Cytochrome C ◽

Protein Expression ◽

Caspase 3 ◽

Diabetic Control ◽

Exercise Group ◽

Diabetic Rats ◽

Control Group ◽

Diabetic Control Group ◽

Mrna And Protein Expression ◽

Cyt C

Objective To observe the effects of aerobic exercise and Siyeshen water extract on cytochrome c (Cyt c) and caspase-3 in hippocampus of diabetic rats and to explore the possible mechanism of improving diabetes. Methods Healthy male Wister rats fed with high fat and high sugar and combined with streptozotocin to establish type II diabetes model. They were randomly divided into 4 groups: diabetic control group, exercise group, Siyeshen group and exercise+Siyeshen group, and another normal control group, with 6 rats in each group. After aerobic exercise (15m/min, 5°slope, 60min, every other day) or/and Siyeshen (200mg/kg) gastrointestinal administration for 8w, the expression of Cyt c and caspase-3 in hippocampus of each group were detected by immunoblotting, and mRNA expressions were detected by RT-PCR. Results Compared with the normal control group, the mRNA and protein expressions of Cyt c and caspase-3 in the hippocampus of the diabetic control group were significantly increased (P<0.05). Compared with the diabetic control group, the blood glucose level of exercise group and exercise+ Siyeshen group decreased (P<0.05), the mRNA and protein expression of Cyt c and caspase-3 decreased significantly (P<0.05), but there were no significant changes in the mRNA and protein expression of Cyt c and caspase-3 between Siyeshen group and diabetic control group (P﹥0.05). Conclusions Exercise and exercise combined with Siyeshen can inhibit cytochrome c release and reduce caspase-3 protein expression, which may be related to the improvement of blood glucose levels in diabetic rats.

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Ameliorative Effects of Nano-Selenium Against Fluoride Stress Induced Hepatocytes Autophagy and Apoptosis in Mice

10.21203/rs.3.rs-44205/v1 ◽

2020 ◽

Author(s):

Yajing Wang ◽

Bingxian Liu ◽

Qingyue Han ◽

Khalid Mehmood ◽

Fazul Nabi ◽

...

Keyword(s):

Caspase 3 ◽

Beclin 1 ◽

Protective Effects ◽

Human Beings ◽

Caspase 9 ◽

Nano Material ◽

Cyt C ◽

Hepatocyte Damage

Abstract Background: Fluorine is widespread in the environment, and the injurious impacts of fluoride underscore its significance for public health. The long-term presence of fluorine in environment could be a risk in hepatotoxicity for both human beings and animals. Important role of selenium in mitigation of heavy metal toxicity via regulating autophagy and apoptosis is well-known. Further, nano-Se is a common artificial nano material, with higher biological activity and lower toxicity. The aim of the current study was to examine whether nano-Se supplementation can reduce the effects of fluoride-induced hepatocytes autophagy and apoptosis. Results: Here, we report that fluoride exposure induces apoptosis and autophagy with nucleus broken, dissolved and disappeared of hepatocyte, contributing to its hepatotoxicity. More importantly, Cyt-C and Beclin-1/Bcl-2 pathways are involved in the regulation of autophagy and apoptosis via targeting Caspase-9, Caspase-3, P53, Bax, LC3, ATG-5, P62 and mTOR expressions. Conclusion: Nano-Se is capable to alleviate fluoride-induced hepatocyte damage, that selenium can be prefer to prevent chronic fluorosis-induced autophagy and apoptosis by regulating Cyt-C and Beclin-1/Bcl-2 signaling pathway. In precisely, NaF-induced the liver injury by activating autophagy and apoptosis, which indicate that fluorine exposure, pose an ecological risk to human beings and animals. Nano-Se has protective effects against fluoride-induced hepatocytes.

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Polyamine depletion prevents camptothecin-induced apoptosis by inhibiting the release of cytochromec

AJP Cell Physiology ◽

10.1152/ajpcell.00351.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. C1290-C1297 ◽

Cited By ~ 46

Author(s):

Qing Yuan ◽

Ramesh M. Ray ◽

Leonard R. Johnson

Keyword(s):

Cytochrome C ◽

Mammalian Cells ◽

Caspase 3 ◽

Intestinal Epithelial ◽

Caspase 9 ◽

Cytochrome C Release ◽

Polyamine Synthesis ◽

Antiapoptotic Proteins ◽

Induced Apoptosis ◽

Rate Limiting

C1297, 2002; 10.1152/ajpcell.00351.2001.We have shown previously that depletion of polyamines delays apoptosis induced by camptothecin in rat intestinal epithelial cells (IEC-6). Mitochondria play an important role in the regulation of apoptosis in mammalian cells because apoptotic signals induce mitochondria to release cytochrome c. The latter interacts with Apaf-1 to activate caspase-9, which in turn activates downstream caspase-3. Bcl-2 family proteins are involved in the regulation of cytochrome c release from mitochondria. In this study, we examined the effects of polyamine depletion on the activation of the caspase cascade, release of cytochrome cfrom mitochondria, and expression and translocation of Bcl-2 family proteins. We inhibited ornithine decarboxylase, the first rate-limiting enzyme in polyamine synthesis, with α-difluoromethylornithine (DFMO) to deplete cells of polyamines. Depletion of polyamines prevented camptothecin-induced release of cytochrome c from mitochondria and decreased the activity of caspase-9 and caspase-3. The mitochondrial membrane potential was not disrupted when cytochrome c was released. Depletion of polyamines decreased translocation of Bax to mitochondria during apoptosis. The expression of antiapoptotic proteins Bcl-xL and Bcl-2 was increased in DFMO-treated cells. Caspase-8 activity and cleavage of Bid were decreased in cells depleted of polyamines. These results suggest that polyamine depletion prevents IEC-6 cells from apoptosis by preventing the translocation of Bax to mitochondria, thus preventing the release of cytochrome c.

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