scholarly journals Zearalenone Induces Endothelial Cell Apoptosis through Activation of a Cytosolic Ca2+/ERK1/2/p53/Caspase 3 Signaling Pathway

Toxins ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 187
Author(s):  
Hyeon-Ju Lee ◽  
Se-Young Oh ◽  
Inho Jo
Keyword(s):  
Signaling Pathway ◽  
Small Interfering Rna ◽  
Caspase 3 ◽  
Cytosolic Calcium ◽  
Receptor Activation ◽  
Oxygen Species ◽  
Endothelial Cell Apoptosis ◽  
Induced Apoptosis ◽  
Interfering Rna ◽  
Specific Inhibitors

Zearalenone (ZEN) is a mycotoxin that has been reported to damage various types of cells/tissues, yet its effects on endothelial cells (ECs) have never been investigated. Therefore, this study investigates the potential effects of ZEN using bovine aortic ECs (BAECs). In this study, we found that ZEN induced apoptosis of BAECs through increased cleavage of caspase 3 and poly ADP-ribose polymerase (PARP). ZEN also increased phosphorylation of ERK1/2 and p53, and treatment with the ERK1/2 or p53 inhibitor reversed ZEN-induced EC apoptosis. Transfection of BAECs with small interfering RNA against ERK1/2 or p53 revealed ERK1/2 as an upstream target of p53 in ZEN-stimulated apoptosis. ZEN increased the production of reactive oxygen species (ROS), yet treatment with the antioxidant did not prevent EC apoptosis. Similarly, blocking of estrogen receptors by specific inhibitors also did not prevent ZEN-induced apoptosis. Finally, chelation of cytosolic calcium (Ca2+) using BAPTA-AM or inhibition of endoplasmic reticulum (ER) Ca2+ channel using 2-APB reversed ZEN-induced EC apoptosis, but not by inhibiting ER stress using 4-PBA. Together, our findings demonstrate that ZEN induces EC apoptosis through an ERK1/2/p53/caspase 3 signaling pathway activated by Ca2+ release from the ER, and this pathway is independent of ROS production and estrogen receptor activation.

scholarly journals Melatonin Suppresses Iron-Induced Apoptosis by Activating the Nrf2/HO-1 Signaling Pathway in Osteoblast

2021 ◽  
Author(s):  
Hongdong Ma ◽  
Zhiqing Li ◽  
Jiao Chu ◽  
Dali Yin
Keyword(s):  
Signaling Pathway ◽  
Caspase 3 ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Oxygen Species ◽  
Apoptosis Rate ◽  
Excess Iron ◽  
Associated Proteins ◽  
Ferric Ammonium ◽  
Induced Apoptosis

Abstract Objective To investigate the effect of melatonin on the apoptosis of hFOB1.19 cells induced by excess iron. Methods The hFOB1.19 cells were treated with ferric ammonium citrate (300 μmol/L) and melatonin (100 μmol/L) for 24 h. The apoptosis rate and the level of reactive oxygen species (ROS) were analyzed using flow cytometry. Expression of proteins associated with apoptosis, such as Bax and caspase-3, and those associated with the Nrf-2 signaling pathway such as Nrf2 and HO-1 were analyzed using western blotting. Results The level of ROS and the apoptosis rate increased after intervention with excess iron. The levels of Bax in the mitochondria and cleaved caspase-3 in the cytosol increased. However, after pretreatment with melatonin, the level of ROS, apoptosis rate, and expression of apoptosis-associated proteins decreased, and the expression of Nrf2 and HO-1 increased. Conclusion Melatonin inhibits the level of oxidation in osteoblasts via the Nrf2/HO-1 signal pathway, resulting in the reduction of apoptosis induced by excess iron.

scholarly journals β-Elemene Triggers ROS-dependent Apoptosis in Glioblastoma Cells Through Suppressing STAT3 Signaling Pathway

2021 ◽  
Vol 27 ◽  
Author(s):  
Shi-zhong Cai ◽  
Qian-wei Xiong ◽  
Li-na Zhao ◽  
Yi-ting Ji ◽  
Zheng-xiang Luo ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Caspase 3 ◽  
Treatment Strategies ◽  
Oxygen Species ◽  
Glioblastoma Cells ◽  
Western Blot Assay ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Apoptotic Activity ◽  
Induced Apoptosis

Glioblastoma is one of the most aggressive primary brain tumors with few treatment strategies. β-Elemene is a sesquiterpene known to have broad spectrum antitumor activity against various cancers. However, the signaling pathways involved in β-elemene induced apoptosis of glioblastoma cells remains poorly understood. In this study, we reported that β-elemene exhibited antiproliferative activity on U87 and SHG-44 cells, and induced cell death through induction of apoptosis. Incubation of these cells with β-elemene led to the activation of caspase-3 and generation of reactive oxygen species (ROS). Western blot assay showed that β-elemene suppressed phosphorylation of STAT3, and subsequently down-regulated the activation of p-JAK2 and p-Src. Moreover, pre-incubation of cells with ROS inhibitor N-acetyl-L-cysteine (NAC) significantly reversed β-elemene-mediated apoptosis effect and down-regulation of JAK2/Src-STAT3 signaling pathway. Overall, our findings implied that generation of ROS and suppression of STAT3 signaling pathway is critical for the apoptotic activity of β-elemene in glioblastoma cells.

scholarly journals Aleglitazar, a dual peroxisome proliferator-activated receptor-α and -γ agonist, protects cardiomyocytes against the adverse effects of hyperglycaemia

2017 ◽  
Vol 14 (2) ◽  
pp. 152-162 ◽  
Author(s):  
Yan Chen ◽  
Hongmei Chen ◽  
Yochai Birnbaum ◽  
Manjyot K Nanhwan ◽  
Mandeep Bajaj ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Peroxisome Proliferator ◽  
Oxygen Species ◽  
Short Interfering Rna ◽  
Wild Type ◽  
Cytochrome C Release ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Cardiomyocytes ◽  
Induced Apoptosis ◽  
Interfering Rna

Purpose: To assess the effects of Aleglitazar on hyperglycaemia-induced apoptosis. Methods: We incubated human cardiomyocytes, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout or wild-type mice in normoglycaemic or hyperglycaemic conditions (glucose 25 mM). Cells were treated with different concentrations of Aleglitazar for 48 h. We measured viability, apoptosis, caspase-3 activity, cytochrome-C release, total antioxidant capacity and reactive oxygen species formation in the treated cardiomyocytes. Human cardiomyocytes were transfected with short interfering RNA against peroxisome proliferator-activated receptor-α or peroxisome proliferator-activated receptor-γ. Results: Aleglitazar attenuated hyperglycaemia-induced apoptosis, caspase-3 activity and cytochrome-C release and increased viability in human cardiomyocyte, cardiomyocytes from cardiac-specific peroxisome proliferator-activated receptor-γ knockout and wild-type mice. Hyperglycaemia reduced the antioxidant capacity and Aleglitazar significantly blunted this effect. Hyperglycaemia-induced reactive oxygen species production was attenuated by Aleglitazar in both human cardiomyocyte and wild-type mice cardiomyocytes. Aleglitazar improved cell viability in cells exposed to hyperglycaemia. The protective effect was partially blocked by short interfering RNA against peroxisome proliferator-activated receptor-α alone and short interfering RNA against peroxisome proliferator-activated receptor-γ alone and completely blocked by short interfering RNA to both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ. Conclusion: Aleglitazar protects cardiomyocytes against hyperglycaemia-induced apoptosis by combined activation of both peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-γ in a short-term vitro model.

scholarly journals Albendazole Exhibits Anti-Neoplastic Actions against Gastric Cancer Cells by Affecting STAT3 and STAT5 Activation by Pleiotropic Mechanism(s)

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 362
Author(s):  
Min Hee Yang ◽  
In Jin Ha ◽  
Jae-Young Um ◽  
Kwang Seok Ahn
Keyword(s):  
Gastric Cancer ◽  
Reactive Oxygen Species ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Small Interfering Rna ◽  
Oxygen Species ◽  
Gastric Cancer Cells ◽  
Drug Induced ◽  
Cellular Apoptosis ◽  
Interfering Rna

Albendazole (ABZ) has been reported to display anti-tumoral actions against various maliganncies, but possible impact of ABZ on gastric cancer has not been deciphered. As aberrant phosphorylation of STAT3 and STAT5 proteins can regulate the growth and progression of gastric cancer, we postulated that ABZ may interrupt the activation of these oncogenic transcription factors. We found that ABZ exposure abrogated STAT3/5 activation, inhibited phosphorylation of Janus-activated kinases 1/2 and Src and enhanced the levels of SHP-1 protein. Silencing of SHP-1 gene by small interfering RNA (siRNA) reversed the ABZ-promoted attenuation of STAT3 as well as STAT5 activation and cellular apoptosis. In addition, these effects were noted to be driven by an augmented levels of reactive oxygen species caused by drug-induced GSH/GSSG imbalance. Thus, the data indicates that ABZ can modulate the activation of STAT3 and STAT5 by pleiotropic mechanisms in gastric cancer cells.

Abstract 319: Intermedin Attenuates Vascular Calcification by Upregulating Klotho via CRLR/RAMP3 Receptor Complex and cAMP/PKA Signaling Pathway in Rats With Chronic Kidney Disease

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jin-Rui Chang ◽  
Yue-Long Hou ◽  
Wei-Wei Lu ◽  
Jin-Sheng Zhang ◽  
Yan-Rong Yu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Signaling Pathway ◽  
Vascular Calcification ◽  
Small Interfering Rna ◽  
Calcium Deposition ◽  
Alp Activity ◽  
Klotho Protein ◽  
Interfering Rna

Vascular calcification (VC) is highly associated with increased morbidity and mortality in patients with advanced chronic kidney disease(CKD). We previously reported that paracrine/autocrine factor intermedin (IMD) could protect against VC. In the present study we assessed the hypothesis that IMD inhibits VC by upregulating klotho protein. VC in CKD rat was induced by 5/6 nephrectomy plus vitamin D 3 administration and vascular smooth muscle cells (VSMCs) calcification was induced by calcifying media containing β -glycerophosphate and CaCl 2 . IMD (100 ng kg -1 h -1 ) was systemically administered by a mini-osmotic pump. CKD rat aortas showed lower IMD content and increased expression of its receptors (calcitonin receptor-like receptor,CRLR/receptor activity-modifying protein 3, RAMP3), along with increased aortic alkaline phosphatase (ALP) activity and calcium deposition. In vivo administration of IMD significantly reduced aortic ALP activity and calcium deposition in CKD rats when compared with vehicle treatment, which was further confirmed in cultured VSMCs. Concurrently, the loss of smooth muscle lineage markers and klotho protein in aortas was rescued by administering IMD to CKD rats with VC. However, the inhibitory effects of IMD on VC were abolished upon pre-treatment with small interfering RNA to reduce klotho. Moreover, the increased effects of IMD on klotho were abolished upon pretreatment with small interfering RNA to reduce its receptors or with PKA inhibitor H89. These results demonstrated that IMD attenuates VC by upregulating klotho via CRLR/RAMP3-cAMP/PKA signaling pathway in rat with CKD. IMD is an important paracrine/autocrine protective factor for VC.

Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages

2001 ◽  
Vol 280 (1) ◽  
pp. L10-L17 ◽  
Author(s):  
Han-Ming Shen ◽  
Zhuo Zhang ◽  
Qi-Feng Zhang ◽  
Choon-Nam Ong
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Alveolar Macrophages ◽  
Caspase 3 ◽  
Reactive Oxygen ◽  
Parp Cleavage ◽  
Oxygen Species ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Induced Apoptosis

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.

scholarly journals UFL1 Alleviates LPS-Induced Apoptosis by Regulating the NF-κB Signaling Pathway in Bovine Ovarian Granulosa Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 260 ◽  
Author(s):  
Xinling Wang ◽  
Chengmin Li ◽  
Yiru Wang ◽  
Lian Li ◽  
Zhaoyu Han ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Granulosa Cells ◽  
Protein Concentration ◽  
Caspase 3 ◽  
Nuclear Factor Κb ◽  
Ovarian Granulosa Cells ◽  
Induced Apoptosis ◽  
Apoptosis Level ◽  
Lps Treatment

Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) is an E3 ligase of ubiquitin fold modifier 1 (UFM1), which can act together with its target protein to inhibit the apoptosis of cells. Lipopolysaccharides (LPS) can affect the ovarian health of female animals by affecting the apoptosis of ovarian granulosa cells. The physiological function of UFL1 on the apoptosis of bovine (ovarian) granulosa cells (bGCs) remains unclear; therefore, we focused on the modulating effect of UFL1 on the regulation of LPS-induced apoptosis in ovarian granulosa cells. Our study found that UFL1 was expressed in both the nucleus and cytoplasm of bGCs. The results here demonstrated that LPS caused a significant increase in the apoptosis level of bGCs in cows, and also dramatically increased the expression of UFL1. Furthermore, we found that UFL1 depletion caused a significant increase in apoptosis (increased the expression of BAX/BCL-2 and the activity of caspase-3). Conversely, the overexpression of UFL1 relieved the LPS-induced apoptosis. In order to assess whether the inhibition of bGCs apoptosis involved in the nuclear factor-κB (NF-κB) signaling pathway resulted from UFL1, we detected the expression of NF-κB p-p65. LPS treatment resulted in a significant upregulation in the protein concentration of NF-κB p-p65, and knockdown of UFL1 further increased the phosphorylation of NF-κB p65, while UFL1 overexpression significantly inhibited the expression of NF-κB p-p65. Collectively, UFL1 could suppress LPS-induced apoptosis in cow ovarian granulosa cells, likely via the NF-κB pathway. These results identify a novel role of UFL1 in the modulation of bGC apoptosis, which may be a potential signaling target to improve the reproductive health of dairy cows.

scholarly journals Oncolytic H-1 Parvovirus Enters Cancer Cells through Clathrin-Mediated Endocytosis

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1199
Author(s):  
Tiago Ferreira ◽  
Amit Kulkarni ◽  
Clemens Bretscher ◽  
Karsten Richter ◽  
Marcelo Ehrlich ◽  
...  
Keyword(s):  
Viral Entry ◽  
Small Interfering Rna ◽  
Anticancer Agent ◽  
Cell Entry ◽  
Productive Infection ◽  
Acidic Ph ◽  
Coated Pits ◽  
Late Endosomes ◽  
Interfering Rna ◽  
Specific Inhibitors

H-1 protoparvovirus (H-1PV) is a self-propagating virus that is non-pathogenic in humans and has oncolytic and oncosuppressive activities. H-1PV is the first member of the Parvoviridae family to undergo clinical testing as an anticancer agent. Results from clinical trials in patients with glioblastoma or pancreatic carcinoma show that virus treatment is safe, well-tolerated and associated with first signs of efficacy. Characterisation of the H-1PV life cycle may help to improve its efficacy and clinical outcome. In this study, we investigated the entry route of H-1PV in cervical carcinoma HeLa and glioma NCH125 cell lines. Using electron and confocal microscopy, we detected H-1PV particles within clathrin-coated pits and vesicles, providing evidence that the virus uses clathrin-mediated endocytosis for cell entry. In agreement with these results, we found that blocking clathrin-mediated endocytosis using specific inhibitors or small interfering RNA-mediated knockdown of its key regulator, AP2M1, markedly reduced H-1PV entry. By contrast, we found no evidence of viral entry through caveolae-mediated endocytosis. We also show that H-1PV entry is dependent on dynamin, while viral trafficking occurs from early to late endosomes, with acidic pH necessary for a productive infection. This is the first study that characterises the cell entry pathways of oncolytic H-1PV.

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