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Chen, Yang, Nasui Wang, Qiongjing Yuan, Jiao Qin, Gaoyun Hu, Qianbin Li, Lijian Tao, Yanyun Xie, and Zhangzhe Peng. "The Protective Effect of Fluorofenidone against Cyclosporine A-Induced Nephrotoxicity." Kidney and Blood Pressure Research 44, no. 4 (2019): 656–68. http://dx.doi.org/10.1159/000500924.
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Background/Aims: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. Methods: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-β1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-β1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 μmol/L), AKF-PD (400 μg/mL), PFD (400 μg/mL), and GW788388 (5 μmol/L). Results: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-β1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 μg/mL) significantly decreased TGF-β1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. Conclusion: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.
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Okinaga, Toshinori, Hironori Kasai, Toshiyuki Tsujisawa, and Tatsuji Nishihara. "Role of caspases in cleavage of lamin A/C and PARP during apoptosis in macrophages infected with a periodontopathic bacterium." Journal of Medical Microbiology 56, no. 10 (October 1, 2007): 1399–404. http://dx.doi.org/10.1099/jmm.0.47193-0.
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The periodontopathic bacterium Actinobacillus actinomycetemcomitans has been implicated in the pathogenesis of periodontal diseases. It has been reported previously that infection with the organism induced apoptosis in the mouse macrophage cell line J774.1. In the present study, the role of caspases during apoptosis in A. actinomycetemcomitans-infected J774.1 cells was examined. A large number of apoptotic cells was detected by flow cytometric analysis in infected J774.1 cells; however, inhibitors of caspase-9, -6 and -3/7 completely blocked the induction of apoptosis. Expression of the cleaved forms of caspase-6 and -7 was detected during apoptosis in infected J774.1 cells. Immunoblot analysis revealed that the caspase-9 inhibitor blocked expression of the cleaved forms of caspase-6 and -7, whilst the caspase-3 inhibitor blocked expression of the cleaved form of caspase-7, but not caspase-6. It is known that lamin A/C and poly(ADP-ribose) polymerase (PARP) are essential nuclear components for maintaining normal cell function and viability, and both were found to be cleaved in the infected J774.1 cells. Immunoblot analysis also revealed that the caspase-6 inhibitor blocked the cleavage of lamin A/C, whilst the caspase-3/7 inhibitor blocked the cleavage of PARP. Taken together, these results suggest that activation of caspases and the subsequent cleavage of lamin A/C and PARP are involved in the morphological changes of apoptotic macrophages infected with A. actinomycetemcomitans.
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Gao, Hongwei, Wen Sun, Wenwen Zhao, Wenhui Hao, Chung-Hang Leung, Jinjian Lu, and Xiuping Chen. "Total Tanshinones-Induced Apoptosis and Autophagy Via Reactive Oxygen Species in Lung Cancer 95D Cells." American Journal of Chinese Medicine 43, no. 06 (January 2015): 1265–79. http://dx.doi.org/10.1142/s0192415x1550072x.
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Tanshinones are a group of bioactive constituents isolated from Salvia miltiorrhiza Bunge, a widely prescribed traditional Chinese herb. In the current study, the anticancer properties of total tanshinones (TDT) were evaluated using 95D lung cancer cells. Tanshinone IIA was identified as the main component of TDT. Compared with tanshinone IIA, TDT showed more cytotoxic effects on the 95D cells. Annexin V/7-AAD double staining, the depolarization of mitochondrial membrane potential (MMP) (Δψ), the up-regulation of pro-apoptotic proteins, such as cleaved-PARP, cleaved-caspase-3, Bax, and Bad, and the down-regulation of anti-apoptotic protein Bcl-2 were evidence of TDT-induced apoptosis. Furthermore, TDT-induced autophagy as demonstrated by monodansylcadaverine (MDC) staining and the up-regulation of autophagy-associated proteins, such as LC3-II, Beclin-1, Atg3, Atg5, Atg7, and Atg12. Autophagy inhibitors, 3-methyladenine (3-MA) and bafilomycin A1, enhanced TDT-induced cell death. 3-MA pretreatment enhanced the TDT-induced up-regulation of Bax and cleaved-PARP. In addition, TDT induced the generation of reactive oxygen species (ROS), which was reversed by N-acetylcysteine (NAC). NAC also reversed TDT-induced depolarization of Δψ, MDC staining, up-regulation of Bax, cleaved-PARP, Beclin-1, LC3-II, and cell viability. In conclusion, our findings showed that TDT-induced apoptosis and protective autophagy in 95D cells mediated by increasing intracellular ROS production.
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Lai, Shiue-Wei, Oluwaseun Adebayo Bamodu, Jia-Hong Chen, Alexander TH Wu, Wei-Hwa Lee, Tsu-Yi Chao, and Chi-Tai Yeh. "Targeted PARP Inhibition Combined with FGFR1 Blockade is Synthetically Lethal to Malignant Cells in Patients with Pancreatic Cancer." Cells 9, no. 4 (April 8, 2020): 911. http://dx.doi.org/10.3390/cells9040911.
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The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines.
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Meng, Fan Yi, Yun-bi Fu, Qi-xin Sun, Jun Xie, and Guang-biao Zhou. "Bortezomib Combined with Harringtonine or Arsenious Acid Induced Apoptosis in HL-60 Cells and Its Mechanism." Blood 108, no. 11 (November 16, 2006): 4412. http://dx.doi.org/10.1182/blood.v108.11.4412.4412.
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Abstract Objective: To explore the apoptosis effect induced by bortezomib combined with harringtonine or arsenious acid in HL60 cell line and the mechanism. Methods: Cell’s apoptosis was demonstrated by MTT assay and Hoechst33342 staining. Expression of Bcl-2, Caspase-9, Caspase-3 and PARP protein was detected by western blotting. Results: HL60 cells’ apoptosis could be induced by bortezomib, harringtonine and arsenious acid respectively, and the apoptosis effect was inhanced significantly when bortezomib combined with harringtonine or arsenious acid. Western blotting showed Bcl-2 protein was down-regulated and Caspase-9, Caspase-3 and PARP proteins were all cleaved activation when cells were treated by 15uM arsenious acid alone, but only cleaved activation of PARP and down-regulation of Bcl-2 protein be detected when cells were treated with 30nM harringtonine alone, expression of Caspase-9 and Caspase-3 has no change compared with the control. The changes of associated proteins were paralleled with the cell’s apoptosis when treated with combined drugs. Conclusion: HL60 cells’ apoptosis could be inhanced significantly when treated by bortezomib combined with harringtonine or arsenious acid compared with treated by bortezomib alone. Arsenious acid and bortezomib can inhibit caspase signaling pathway and down-regulate the expression of Bcl-2 protein together, but harringtonine and bortezomib can only down-regulate the expression of Bcl-2 protein and induce cleaved activation of PARP together.
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Casao, A., M. Mata-Campuzano, L. Ordás, JA Cebrián-Pérez, T. Muiño-Blanco, and F. Martínez-Pastor. "Cleaved PARP-1, an Apoptotic Marker, can be Detected in Ram Spermatozoa." Reproduction in Domestic Animals 50, no. 4 (June 2, 2015): 688–91. http://dx.doi.org/10.1111/rda.12549.
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Barral, Paola M., Juliet M. Morrison, Jennifer Drahos, Pankaj Gupta, Devanand Sarkar, Paul B. Fisher, and Vincent R. Racaniello. "MDA-5 Is Cleaved in Poliovirus-Infected Cells." Journal of Virology 81, no. 8 (January 31, 2007): 3677–84. http://dx.doi.org/10.1128/jvi.01360-06.
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ABSTRACT Infections with RNA viruses are sensed by the innate immune system through membrane-bound Toll-like receptors or the cytoplasmic RNA helicases RIG-I and MDA-5. It is believed that MDA-5 is crucial for sensing infections by picornaviruses, but there have been no studies on the role of this protein during infection with poliovirus, the prototypic picornavirus. Beginning at 4 h postinfection, MDA-5 protein is degraded in poliovirus-infected cells. Levels of MDA-5 declined beginning at 6 h after infection with rhinovirus type 1a or encephalomyocarditis virus, but the protein was stable in cells infected with rhinovirus type 16 or echovirus type 1. Cleavage of MDA-5 is not carried out by either poliovirus proteinase 2Apro or 3Cpro. Instead, degradation of MDA-5 in poliovirus-infected cells occurs in a proteasome- and caspase-dependent manner. Degradation of MDA-5 during poliovirus infection correlates with cleavage of poly(ADP) ribose polymerase (PARP), a hallmark of apoptosis. Induction of apoptosis by puromycin leads to cleavage of both PARP and MDA-5. The MDA-5 cleavage product observed in cells treated with puromycin is ∼90 kDa, similar in size to the putative cleavage product observed in poliovirus-infected cells. Poliovirus-induced cleavage of MDA-5 may be a mechanism to antagonize production of type I interferon in response to viral infection.
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Tfayli, A. H., M. Cherry, J. Yang, K. Kojouri, M. Jafari, A. Thor, and H. Ozer. "Effect of celecoxib, a specific cyclooxygenase 2 inhibitor, on the apoptotic and mitotic indexes of breast cancer in patients with early stage disease." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14132. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14132.
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14132 Background: To assess whether the administration of celecoxib, a specific cyclooxegenease-2 (COX-2) inhibitor, to patients with breast cancer alters the proliferative and apoptotic indexes of their tumors. Methods: Women newly diagnosed with non metastatic breast cancer were enrolled into the study after undergoing a diagnostic core needle biopsy. Patients received celecoxib treatment at 400 mg orally twice a day for 14 days, and then underwent surgical excision of their tumor. Core biopsies obtained at the time of initial diagnostic procedure and surgical excision specimens were stained for Ki-67, as well as COX-2 and cleaved poly (ADP-ribose) polymerase (PARP) expression (as an apoptosis marker). Appropriate negative and positive controls were included. We assessed the difference in Ki- 67, COX-2 and cleaved PARP expression levels, before and after treatment using the Wilcoxon’s matched-pair ranks test and the McNemar’s test. Results: 16 patients were enrolled. The median age was 54.6 years. ER and/or PR expression was present in 81% of tumors; Her-2 neu overexpression was present in 25%. No significant change in COX-2 or cleaved PARP expression was noticed in the post intervention specimen compared to the core biopsies. Surprisingly, there was a significant increase in the Ki-67 expression (p < 0.009). Conclusions: we have conducted a short term prospective study to assess the effects of celecoxib, on the proliferative and apoptotic indexes in patients with early stage breast cancer. We have found an increase in the Ki-67 activity, with no significant down regulation of COX-2 or increase in cleaved PARP expression with 14 days of therapy. This could be partly due to the small sample size. [Table: see text]
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Khan, RB, A. Phulukdaree, and AA Chuturgoon. "Concentration-dependent effect of fumonisin B1 on apoptosis in oesophageal cancer cells." Human & Experimental Toxicology 37, no. 7 (October 13, 2017): 762–71. http://dx.doi.org/10.1177/0960327117735570.
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The geographical distribution of oesophageal cancer is linked to the exposure of fumonisin B1 (FB1), a mycotoxin produced by fungi that contaminates staple food worldwide. Non-genotoxic carcinogens like FB1 disturb homeostasis through increased cell proliferation or suppression of apoptosis. This study investigated the involvement of FB1 (0–20 μM) in spindle-shaped N-cadherin (+) CD45 (−) osteoblastic (SNO) cell death. Cell viability and death were assessed using the MTS and Annexin V-Fluos assays, respectively. Caspase activities were determined luminometrically and the comet assay assessed DNA damage. Induction of oxoguanine glycosylase 1 (OGG1) was measured using quantitative Polymerase Chain Reaction (qPCR), while cleaved poly (ADP-ribose) polymerase 1 (PARP-1) and Bax were determined by western blotting. Cell viability and PARP-1 cleavage were not affected by 1.25 μM FB1, but phosphatidylserine externalization, Bax protein expression, caspase activity, comet tail length and OGG1 transcripts were increased. The reduced cell viability in 10 μM FB1-treated cells was accompanied by corresponding increases in externalized phosphatidylserine, Bax, caspase-3/7 activity and cleaved PARP-1. The OGG1 transcripts were not significantly increased, but comet tails were increased. Bax, caspase-3/7 activities and cleaved PARP-1 were inhibited at 20 μM FB1. In addition, the OGG1 transcript levels were decreased ( p < 0.0001) along with comet lengths ( p < 0.0001). This study showed that FB1-induced apoptosis in SNO cells may be caspase-dependent or caspase-independent; the pathway used depends on the exposure concentration.
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Mohammad, Ghulam, Mohammad Mairaj Siddiquei, and Ahmed M. Abu El-Asrar. "Poly (ADP-Ribose) Polymerase Mediates Diabetes-Induced Retinal Neuropathy." Mediators of Inflammation 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/510451.
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Retinal neuropathy is an early event in the development of diabetic retinopathy. One of the potential enzymes that are activated by oxidative stress in the diabetic retina is poly (ADP-ribose) polymerase (PARP). We investigated the effect of the PARP inhibitor 1,5-isoquinolinediol on the expression of the neurodegeneration mediators and markers in the retinas of diabetic rats. After two weeks of streptozotocin-induced diabetes, rats were treated with 1,5-isoquinolinediol (3 mg/kg/day). After 4 weeks of diabetes, the retinas were harvested and the levels of reactive oxygen species (ROS) were determined fluorometrically and the expressions of PARP, phosporylated-ERK1/2, BDNF, synaptophysin, glutamine synthetase (GS), and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, PARP-1/2, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expressions of BDNF synaptophysin and GS were significantly decreased in the retinas of diabetic rats, compared to nondiabetic rats. Administration of 1,5-isoquinolinediol did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of PARP, ROS, ERK1/2phosphorylation, and cleaved caspase-3 and downregulation of BDNF, synaptophysin, and GS. These findings suggest a beneficial effect of the PARP inhibitor in increasing neurotrophic support and ameliorating early retinal neuropathy induced by diabetes.
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Liu, Wei, Mengling Yang, Xuejian Chen, Li Li, Aijun Zhou, Shuhe Chen, Pengtao You, and Yanwen Liu. "Mechanisms of Antiulcer Effect of an Active Ingredient Group of Modified Xiao Chaihu Decoction." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/5498698.
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The present study aimed to investigate the antiulcer activities and mechanisms of action of an active ingredient group (AIG) of Modified Xiao Chaihu Decoction (MXCD). The gastroprotective action of the AIG was studied in ethanol-induced, pylorus ligature-induced, and acetic acid-inducedin vivogastric ulcer models. The enzyme-linked immunoadsorbent assay (tumor necrosis factor-α(TNF-α), prostaglandin E2(PGE2), and epidermal growth factor (EGF)), nitrate reductase assay (nitric oxide (NO)), western blot analysis (Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP (poly (ADP-Ribose) polymerase)), histological analysis (HE), and immunohistochemical analysis (HSP-70, p-AKT, and PCNA) were used to evaluate the anti-inflammatory, antiapoptotic, and healing properties of AIG. Numerous mechanisms are involved in the antiulcer activity of AIG, including the increase of PGE2, NO, and EGF content and a reduction in TNF-αlevels. The upregulation of HSP-70, p-AKT, and PCNA seems to be directly linked to the healing effect of AIG. Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP also play a key role in this process. The AIG exerted gastroprotective effects by reducing antisecretory, anti-inflammatory, and antiapoptotic mechanisms. In addition, it promotes cell proliferation. Therefore, activation of the PI3K/AKT signaling pathway may play an important role in cell proliferation.
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Zhang, Shengbin, Baoqin Liu, Changcheng Dong, and Bing Li. "Mechanism of apoptosis induced by Mcl-1 inhibitor UMI-77 on gallbladder carcinoma GBC-SD cells." Discussion of Clinical Cases 6, no. 1 (March 10, 2019): 1. http://dx.doi.org/10.5430/dcc.v6n1p1.
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Objective: To investigate the mechanism of apoptosis induced by myeloid cell leukemia-1 (Mcl-1) inhibitor UMI-77 on gallbladder carcinoma GBC-SD cells.Methods: GBC-SD cells were treated with different concentrations of UMI-77. GBC-SD cell proliferation and apoptosis were detected by MTT assay and Annexin V/PI. The expressions of Mcl-1, Bcl-2, Bcl-xL, Bax, Bak, cleaved-caspase 9, cleaved-caspase 3 and cleaved-PARP proteins in GBC-SD cells treated with UMI-77 were detected by Western blotting.Results: The results of MTT showed that different concentrations of UMI-77 had different inhibitory effects on cell proliferation of GBC-SD cells in a dose-dependent and time-dependent manner. Annexin V/PI results showed that the apoptosis rate was increasing gradually with the increase of UMI-77 concentration in a dose-dependent manner. Western blotting results showed that the expression of anti-apoptotic protein Mcl-1 was significantly decreased (p < .05), and the expressions of Bax and Bak proteins were significantly increased respectively (p < .05), but there were no significant changes in the expressions of Bcl-2 and Bcl-xL proteins, and the expression levels of cleaved-caspase 9, cleaved-caspase 3 and cleaved-PARP proteins were significantly increased (p < .05) in 24 h after GBC-SD cells were treated with 10 μmol/L of UMI-77.Conclusions: Mcl-1 inhibitor UMI-77 can induce the apoptosis of GBC-SD cells in a dose-dependent manner through the caspase-mediated endogenous apoptosis pathway. Therefore, Mcl-1 may become a new therapeutic target in the research on gallbladder cancer.
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Tsai, Tsen-Ni, Jia-Jing Ho, Maw-Shung Liu, Tzu-Ying Lee, Mei-Chin Lu, Chia-Jen Liu, Li-Ju Huang, Sheng-I. Lue, and Rei-Chen Yang. "Role of Exogenous Hsp72 on Liver Dysfunction during Sepsis." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/508101.
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This study examined the role of exogenous heat shock protein 72 (Hsp72) in reversing sepsis-induced liver dysfunction. Sepsis was induced by cecal ligation and puncture. Liver function was determined on the basis of the enzymatic activities of serum glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT). Apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3 and caspase-9, and cleaved poly (ADP-ribose) polymerase (PARP) protein expressions were analyzed using Western blotting. Results showed GOT and GPT levels increased during sepsis, and levels were restored following the administration of human recombinant Hsp72 (rhHsp72). Increased liver tissue apoptosis was observed during sepsis, and normal apoptosis resumed on rhHsp72 administration. The Bcl-2/Bax ratio, cleaved caspase-3, caspase-9, and PARP protein expressions in the liver tissues were upregulated during sepsis and normalized after rhHsp72 treatment. We conclude that, during sepsis, exogenous Hsp72 restored liver dysfunction by inhibiting apoptosis via the mitochondria-initiated caspase pathway.
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Xie, Yi, Linbo Wang, Mohammad A. Khan, Anne W. Hamburger, Wei Guang, Antonino Passaniti, Kashif Munir, Douglas D. Ross, Michael Dean, and Arif Hussain. "Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells." Cancers 13, no. 4 (February 5, 2021): 633. http://dx.doi.org/10.3390/cancers13040633.
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We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.
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Lim, Eu Jin, Korri El Khobar, Ruth Chin, Linda Earnest-Silveira, Peter W. Angus, C. Thomas Bock, Ueli Nachbur, John Silke, and Joseph Torresi. "Hepatitis C virus-induced hepatocyte cell death and protection by inhibition of apoptosis." Journal of General Virology 95, no. 10 (October 1, 2014): 2204–15. http://dx.doi.org/10.1099/vir.0.065862-0.
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Chronic hepatitis C virus (HCV) infection results in progressive liver fibrosis leading to cirrhosis and liver cancer. The mechanism for this remains unclear but hepatocyte apoptosis is thought to play a major role. Hepatocyte apoptosis in human liver tissue was determined by immunohistochemistry for cytokeratin 18 (M30 CytoDEATH) and cleaved poly(ADP-ribose) polymerase (PARP). In vitro studies were performed with replication-defective recombinant adenoviruses expressing HCV proteins (rAdHCV) to study the effects of HCV on cell death in Huh7 cells, primary mouse hepatocytes (PMoHs) and primary human hepatocytes (PHHs). Cell viability and apoptosis were studied using crystal violet assays and Western blots probed for cleaved caspase-3 and cleaved PARP, with and without treatment with the pan-caspase inhibitor Q-VD-OPh and necrostatin-1. Liver tissue of HCV-infected patients expressed elevated levels of apoptotic markers compared with HCV-negative patients. rAdHCV infection reduced cell viability compared with uninfected controls and cells infected with control virus (rAdGFP). Huh7, PMoHs and PHHs infected with rAdHCV showed significantly increased levels of apoptotic markers compared with uninfected controls and rAdGFP-infected cells. In rAdHCV-infected Huh7, treatment with Q-VD-OPh and necrostatin-1 both improved cell viability. Q-VD-Oph also reduced cleaved PARP in rAdHCV-infected Huh7 and PMoHs. Hepatocyte apoptosis is known to be increased in the livers of HCV-infected patients. HCV promoted cell death in primary and immortalized hepatocytes, and this was inhibited by Q-VD-OPh and necrostatin-1. These findings indicate that HCV-induced cell death occurs by both apoptosis and necroptosis, and provide new insights into the mechanisms of HCV-induced liver injury.
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Huang, Shiying, Sekar Karthik, Qi Lin, YuChen Du, Ching C. Lau, Adesina Adekunle, Jack M. F. Su, et al. "EMBR-23. KIF11 DEPENDENCY ON P53 MUTATIONAL STATUS IN MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i10—i11. http://dx.doi.org/10.1093/neuonc/noab090.041.
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Abstract Introduction KIF11, a mitotic kinesin, is a component responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11. Inhibition of KIF11 results monopolar spindle formation, resulting in monoastral mitosis in cells. This activates the spindle assembly checkpoint, cells are arrested and prevented from entering cell cycle, resulting in cell death via apoptosis or necrosis, cell division with aneuploidy or mitotic slippage without division into tetraploid G1 phase. Methods We hypothesized that the effect of KIF11 inhibition on medulloblastoma (MB) is dependent of its p53 mutational status. Results Our findings on Hoechst staining demonstrated a small molecule inhibitor of KIF11 which induced apoptosis in p53-wildtype MB cells at 48h (p<0.0001), was able to trigger mitotic catastrophe (p = 0.0010) in p53-mutant MB cells at 24h and subsequent necrosis (p=0.0039) at 48h. KIF11 inhibitor exerted anti-proliferative effects on five MB cell lines at nanomolar concentration range, independent of its p53 mutational status. Cells treated with KIF11 inhibitor were arrested in G2/M phase. Apoptosis was observed on Annexin V flow cytometry 24h after treatment, followed by necrosis after 48h in p53-wildtype cells. In contrast, treated p53-mutant cells underwent necrosis at 24h. Differences in cell death mechanisms upon KIF11 inhibition was confirmed on immunoblotting by upregulated p53 expression and presence of cleaved-PARP and DNA-damage marker in p53-wildtype cells, indicative of apoptosis. While inhibition of KIF11 and increased p53 expression were observed only after 48h, cleaved-PARP expression was detected as early as 24h in p53-wildtype, suggesting KIF11-independent, cleaved-PARP-mediated cell death at 24h. In contrast, treated p53-mutant cells showed decreased p53 expression and absence of cleaved-PARP and DNA-damage marker after 24h. Conclusions Our results suggest that when mitotic arrest is induced, p53-mutant MB cells undergo mitotic catastrophe and necrosis while p53-wildtype MB cells predominantly undergo apoptosis.
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Holubec, Hana, Claire M. Payne, Harris Bernstein, Katerina Dvorakova, Carol Bernstein, Caroline N. Waltmire, James A. Warneke, and Harinder Garewal. "Assessment of Apoptosis by Immunohistochemical Markers Compared to Cellular Morphology in Ex Vivo-stressed Colonic Mucosa." Journal of Histochemistry & Cytochemistry 53, no. 2 (February 2005): 229–35. http://dx.doi.org/10.1369/jhc.4a6386.2005.
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Apoptosis competence is central to the prevention of cancer. Frequency of apoptotic cells, after a sample of colonic tissue is stressed, can be used to gauge apoptosis competence and, thus, possible susceptibility to colon cancer. The gold standard for assessment of apoptosis is morphological evaluation, but this requires an experienced microscopist. Easier-to-use immunohistochemical markers of apoptosis, applicable in archived paraffin-embedded tissue, have been commercially developed. Potentially useful apoptosis markers include cleaved cytokeratin-18 (c-CK18), cleaved caspase-3 (c-cas-3), cleaved lamin A (c-lam-A), phosphorylated histone H2AX (γH2AX), cleaved poly(ADP ribose) polymerase (c-PARP), and translocation of apoptosis-inducing factor (AIF). When tissue samples from freshly resected colon segments were challenged ex vivo with the bile acid deoxycholate, ∼50% of goblet cells became apoptotic by morphologic criteria. This high level of morphologic apoptosis allowed quantitative comparison with the usefulness and specificity of immunohistochemical markers of apoptosis. The antibody to c-CK18 was almost as useful and about as specific as morphology for identifying apoptotic colonic epithelial cells. Antibodies to c-cas-3, c-lam-A, and γH2AX, though specific for apoptotic cells, were less useful. The antibody to c-PARP, though specific for apoptotic cells, had low usefulness, and the antibody to AIF was relatively nonspecific, under our conditions.
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Yin, Feng, Xiaoxia Huang, and Yi Xuan. "Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Cancer Progression via Activating PI3K/AKT/mTOR Pathway." Disease Markers 2021 (September 1, 2021): 1–11. http://dx.doi.org/10.1155/2021/9950663.
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Aim. The aim of this study was to investigate the effect and underlying pathway of pyrroline-5-carboxylate reductase-2 (PYCR2) on colorectal cancer (CRC). Methods. The Cancer Genome Atlas (TCGA) database was used to analyze PYCR2 expression levels and clinical information. Cell proliferation was evaluated using colony forming and EdU assay. Cell apoptosis rate was determined using flow cytometry. Cell migration and invasion were measured by performing a Transwell assay, and PYCR2, MMP-2, MMP-9, Bax, cleaved caspase-3, Bcl-2, cleaved PARP, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR protein levels were detected by Western blot. Results. A review of the TCGA database revealed that PYCR2 was highly expressed in CRC patients and that high PYCR2 expression was associated with advanced stage, adenocarcinoma, nodal metastasis, and poor survival rate. Moreover, PYCR2 knockdown reduced cell viability, proliferation, migration, and invasion and increased apoptosis. Additionally, PYCR2 knockdown increased Bax, cleaved caspase-3, and cleaved PARP levels and decreased Bcl-2, MMP-2, MMP-9, p-PI3K, p-AKT, and p-mTOR levels in CRC cells. Effects of silencing PYCR2 on proliferation, migration, invasion, apoptosis, and the PI3K/AKT/mTOR pathway in CRC cells were all reversed using a PI3K activator (740Y-P). Conclusion. PYCR2 was highly expressed in CRC, and its knockdown suppressed CRC tumorigenesis via inhibiting the activation of PI3K/AKT/mTOR pathway. This finding provides a new theoretical foundation for the treatment of CRC.
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Shan, Qunqun, Ning Li, Fan Zhang, Peng Yu, and Qingxi Meng. "Resveratrol Suppresses Annulus Fibrosus Cell Apoptosis through Regulating Oxidative Stress Reaction in an Inflammatory Environment." BioMed Research International 2021 (September 27, 2021): 1–6. http://dx.doi.org/10.1155/2021/9100444.
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During disc degeneration, the increase of inflammatory cytokines and decrease of disc cell density are two prominent features. Enhanced inflammatory reaction contributes to disc annulus fibrosus (AF) cell apoptosis. In this study, we investigated whether resveratrol can suppress AF cell apoptosis in an inflammatory environment. Rat disc AF cells were cultured in medium with or without tumor necrosis factor-α (TNF-α). Resveratrol was added along with the culture medium supplemented with TNF-α. Caspase-3 activity, cell apoptosis ratio, expression of apoptosis-associated molecules (Bcl-2, Bax, caspase-3, cleaved PARP, and cleaved caspase-3), reactive oxygen species (ROS) content, and the total superoxide dismutase (SOD) activity were measured. Our results showed that TNF-α significantly increased caspase-3 activity and AF cell apoptosis ratio and upregulated gene/protein expression of Bax, caspase-3, cleaved caspase-3, and cleaved PARP, whereas it downregulated the expression of Bcl-2. Moreover, TNF-α significantly increased ROS content but decreased the total SOD activity. Further analysis demonstrated that resveratrol partly attenuated the effects of TNF-α on AF cell apoptosis-associated parameters, decreased ROS content, and increased the total SOD activity in the AF cells treated with TNF-α. In conclusion, resveratrol attenuates inflammatory cytokine TNF-α-induced AF cell apoptosis through regulating oxidative stress reaction in vitro. This study sheds a new light on the protective role of resveratrol in alleviating disc degeneration.
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Addioui, Anissa, Assila Belounis, Sonia Cournoyer, Carine Nyalendo, Rose Marie Brito, Mona Beaunoyer, Pierre Teira, and Hervé Sartelet. "Preclinical study of a PARP inhibitor in neuroblastoma." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 9570. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.9570.
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9570 Background: Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In spite of many therapeutic improvements, only 60% survive long term despite aggressive combinations of multi-agent chemotherapy. In previous studies, we have demonstrated that tumor initiating cells (TIC) expressing CD133 (CD133high) in NB are more resistant to chemotherapy. Moreover, these cells express higher levels of PARP-1, a central protein involved in DNA repair. PARP-1 expression is significantly lower in NB usually showing spontaneous regression than in standard NB, suggesting an implication of PARP-1 in NB progression. The objective of this study is to determine the efficacy in vitro of AG-014699 (AG), a PARP- inhibitor, used in monotherapy or in combination to cisplatine (CP) and doxorubicine (DR), classical chemotherapeutic agents used in NB treatment, on NB cell survival. Methods: Six NB cell lines (parental or CD133high purified by flow cytometry (FACS)) were treated with AG alone or in association to CP or DR. PARP-1 ELISA protein assay was used to determine the optimal drug concentration needed to inhibit the protein. Cell survival was measured by MTT test. Western Blots were done to evaluate any apoptotic or autophagic pathway modulations. Quantification of DNA damage in treated cell was done by immunofluorescence of H2A-X protein. Results: We showed that a 4µM concentration of AG is sufficient for PARP-1 inhibition. One third of celllines presented a sensitivity to AG when used in monotherapy with an IC50 lower than 5µM. However, AG demonstrated synergistic effects when associated to DR, decreasing the IC50 by half, although none is observed when combined to CP. Sentitivity of the TIC did not appear to be more important than the bulk cells. With increasing concentration of AG, our WB showed no increase in cleaved Caspase-3 suggesting no modulation of the apoptotic pathway. However, autophagy seemed to be upregulated confirmed by an increase in cleaved LC3 II protein. Double strand breaks increased 2.5 folds when 4µM AG is added to the IC50 of DR. Conclusions: AG used in combination at potentially therapeutic doses shows promising results in NB. These results will allow for the improvement of NB treatments by introducing a new therapeutic strategy.
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Uddin, Md Hafiz, Yiwei Li, Husain Yar Khan, Irfana Muqbil, Amro Aboukameel, Rachel E. Sexton, Shriya Reddy, et al. "Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6676. http://dx.doi.org/10.3390/ijms22136676.
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Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes BAX, TP53 and CASPASE 9. Mechanistically, KPT-8602-PARPi suppressed AR, ARv7, PSA and AR targets FOXA1 and UBE2C. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.
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Xu, Yichun, Hui Yao, Qiyou Wang, Wenbin Xu, Kaihua Liu, Junbin Zhang, Huiqing Zhao, and Gang Hou. "Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway." Cellular Physiology and Biochemistry 50, no. 5 (2018): 1687–97. http://dx.doi.org/10.1159/000494788.
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Background/Aims: Previous studies have shown that oxidative damage is a main contributor to disc nucleus pulposus (NP) cell apoptosis. Aquaporin-3 (AQP-3) facilitates reactive oxygen species (ROS) scavenging and thus alleviates oxidative injury in other cells. This study aims to investigate the role and mechanism of AQP-3 in regulating NP cell apoptosis under oxidative damage. Methods: Rat NP cells were treated with H2O2 for 48 hours, while control NP cells were free of H2O2. Recombinant AQP-3 lentiviral vectors were used to investigate the effect of enhanced AQP-3 expression levels in NP cells. NP cell apoptosis was assessed by flow cytometry, caspase-3 activity, gene expression of apoptosis-related molecules (Bax, Bcl-2 and caspase-3), and protein expression of cellular apoptosis markers (cleaved PARP and cleaved caspase-3). Additionally, intracellular ROS content and activity of the p38 MAPK pathway were evaluated. Results: Compared with the control NP cells, oxidative damage in the treatment cells significantly increased cell apoptosis ratios and caspase-3 activity, upregulated gene expression of Bax and caspase-3, downregulated gene expression of Bcl-2, and increased protein expression of cleaved PARP and cleaved caspase-3, as well as increased intracellular ROS content and activity of the p38 MAPK pathway. However, AQP-3 overexpression partly alleviated cell apoptosis, decreased intracellular ROS content, and inhibited the p38 MAPK pathway in NP cells under oxidative damage. Conclusion: Oxidative damage can significantly downregulate AQP-3 expression. Enhancing AQP-3 expression in NP cells partly attenuates cellular apoptosis through regulating the p38 MAPK pathway under oxidative damage.
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Golbaz, Rezvan, Samideh Khoei, Sepideh Khoee, Sakine Shirvalilou, Majid Safa, Seied R. Mahdavi, and Mohammad R. Karimi. "Apoptosis pathway in the combined treatment of x-ray and 5-FU-loaded triblock copolymer-coated magnetic nanoparticles." Nanomedicine 15, no. 23 (August 2020): 2255–70. http://dx.doi.org/10.2217/nnm-2020-0119.
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Aim: In this study, the effects of ionizing radiation and 5-fluorouracil (5-FU)-loaded triblock copolymer-coated magnetic nanoparticles (NPs) on the induction of apoptosis in HT-29 and HCT-116 were investigated. Materials & methods: The percentage of apoptotic cells and alteration of the expression of apoptotic-related proteins were evaluated in treated cells by flow cytometry and western blot analysis, respectively. Results: Combination treatment with 5-FU and radiation had a stronger effect on decreasing Bcl-2 expression and increasing expression of Bax, cleaved caspase-9, cleaved caspase-3, cleaved PARP compared with each treatment alone. Conclusion: The combination of radiation and triblock copolymer-coated magnetic NPs as 5-FU drug carriers works by triggering apoptosis to improve in vitro treatment efficacy. Additional study may present the NPs as an effective approach for the treatment of colon cancer.
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Kim, RJ, SH An, JY Gwark, and HB Park. "Antioxidant effects on hypoxia-induced oxidative stress and apoptosis in rat rotator cuff fibroblasts." European Cells and Materials 41 (June 11, 2021): 680–93. http://dx.doi.org/10.22203/ecm.v041a44.
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Most cells, highly sensitive to oxygen levels, undergo apoptosis under hypoxia. Therefore, the involvement of hypoxia in rotator cuff tendon degeneration has been proposed. While previous studies have reported that hypoxia induces apoptosis in rotator cuff fibroblasts (RCFs), little research has investigated whether antioxidants have cytoprotective effects against RCF apoptosis. The present study aimed at determining whether the antioxidant N-acetylcysteine (NAC) exerted cytoprotective effects against hypoxia-induced RCF apoptosis. Third-passage rat RCFs were divided into normoxia, NAC, hypoxia and NAC-hypoxia groups. The hypoxia inducer was 1,000 µmol/L cobalt chloride (CoCl2); the antioxidant was 20 mmol/L NAC. Expressions of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1), cell viability, intracellular reactive oxygen species (ROS) production, apoptosis rates as well as expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors-β (VEGF-β) and matrix metalloproteinase-2 (MMP-2) were evaluated. Expression of HIF-1α and HO-1 was significantly higher in the hypoxia group than in the normoxia group (p < 0.001). Cell viability was significantly lower in the hypoxia group than in the normoxia group (p < 0.001). Intracellular ROS production, apoptosis rate and expressions of cleaved caspase-3, cleaved PARP-1, VEGF-β and MMP-2 were significantly higher in the hypoxia group than in the normoxia group (p < 0.001). All these responses were significantly attenuated by pre-treatment with NAC (p ≤ 0.001). ROS were involved in hypoxic RCF apoptosis induced by CoCl2; NAC, an ROS scavenger, inhibited hypoxia-induced RCF apoptosis by inhibiting ROS production.
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Lu, Justin Y. D., Ping Su, James E. M. Barber, Joanne E. Nash, Anh D. Le, Fang Liu, and Albert H. C. Wong. "The neuroprotective effect of nicotine in Parkinson’s disease models is associated with inhibiting PARP-1 and caspase-3 cleavage." PeerJ 5 (October 19, 2017): e3933. http://dx.doi.org/10.7717/peerj.3933.
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Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.
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Wang, Yan, Adi S. Virji, Paul Howard, Yaseen Sayani, Jianghong Zhang, Paul Achu, and Carole McArthur. "Detection of cleaved α-fodrin autoantigen in Sjögren's syndrome: Apoptosis and co-localisation of cleaved α-fodrin with activated caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) in labial salivary glands." Archives of Oral Biology 51, no. 7 (July 2006): 558–66. http://dx.doi.org/10.1016/j.archoralbio.2005.11.008.
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Xi, Song-yang, Yu-hao Teng, Yan Chen, Jie-ping Li, Ying-ying Zhang, Shen-lin Liu, Xi Zou, Jin-yong Zhou, Jian Wu, and Rui-ping Wang. "Jianpi Huayu Decoction Inhibits Proliferation in Human Colorectal Cancer Cells (SW480) by Inducing G0/G1-Phase Cell Cycle Arrest and Apoptosis." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/236506.
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Jianpi Huayu Decoction (JHD), a Chinese medicine formula, is a typical prescription against multiple tumors in the clinical treatment, which can raise quality of life and decrease complications. The aim of this study is to assess the efficacy of JHD against human colorectal carcinoma cells (SW480) and explore its mechanism. MTT assay showed that JHD decreased the cellular viability of SW480 cells in dose-dependent and time-dependent manner. Flow cytometry analysis revealed that JHD induced G0/G1-phase cell cycle arrest in SW480 cells and had a strong apoptosis-inducing effect on SW480 cells. Meanwhile it enhanced the expression of p27, cleaved PARP, cleaved caspase-3, and Bax and decreased the levels of PARP, caspase-3, Bcl-2, CDK2, CDK4, CDK6, cyclin D1, cyclin D2, cyclin D3, and cyclin E1, which was evidenced by RT-qPCR and Western blot analysis. In conclusion, these results indicated that JHD inhibited proliferation in SW480 cells by inducing G0/G1-phase cell cycle arrest and apoptosis, providing a practicaltherapeutic strategy against colorectal cancer.
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Tber, Zahira, Mohammed Loubidi, Jabrane Jouha, Ismail Hdoufane, Mümin Alper Erdogan, Luciano Saso, Güliz Armagan, and Sabine Berteina-Raboin. "Pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as Potential Cytotoxic Agents against Human Neuroblastoma." Pharmaceuticals 14, no. 8 (July 30, 2021): 750. http://dx.doi.org/10.3390/ph14080750.
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We report herein the evaluation of various pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multicomponent Groebke–Blackburn–Bienaymé reaction to yield various pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer potential of these pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5-amine derivatives in the human neuroblastoma cell line, the cytotoxicity was examined using the WST-1 assay after 72 h drug exposure. A clonogenic assay was used to assess the ability of treated cells to proliferate and form colonies. Protein expressions (Bax, bcl-2, cleaved caspase-3, cleaved PARP-1) were analyzed using Western blotting. The colony number decrease in cells was 50.54%, 37.88% and 27.12% following exposure to compounds 2d, 2g and 4b respectively at 10 μM. We also show that treating the neuroblastoma cell line with these compounds resulted in a significant alteration in caspase-3 and PARP-1 cleavage.
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Zhang, Yu-chen, Xiao-li Qin, Xiao-ling Ma, Hui-qin Mo, Shi Qin, Cheng-xi Zhang, Xiao-wei Wei, et al. "CLDN1 regulates trophoblast apoptosis and proliferation in preeclampsia." Reproduction 161, no. 6 (June 1, 2021): 623–32. http://dx.doi.org/10.1530/rep-20-0677.
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Preeclampsia is a gestational hypertensive disease; however, preeclampsia remains poorly understood. Bioinformatics analysis was applied to find novel genes involved in the pathogenesis of preeclampsia and identified CLDN1 as one of the most differentially expressed genes when comparing patients with preeclampsia and healthy controls. The results of the qRT-PCR, Western blotting and immunohistochemistry experiments demonstrated that CLDN1 was significantly downregulated in the chorionic villi in samples from patients with preeclampsia. Furthermore, knockdown of CLDN1 in HTR-8/SVneo cells resulted in the inhibition of proliferation and induction of apoptosis, and overexpression of CLDN1 reversed these effects. In addition, RNA-seq assays demonstrated that the gene BIRC3 is potentially downstream of CLDN1 and is involved in the regulation of apoptosis. Knockdown of CLDN1 confirmed that the expression level of BIRC3 was obviously decreased and was associated with a significant increase in cleaved PARP. Interestingly, the apoptotic effect in CLDN1 knockdown cells was rescued after BIRC3 overexpression. Overall, these results indicate that a decrease in CLDN1 inhibits BIRC3 expression and increases cleaved PARP levels thus participating in the pathogenesis of preeclampsia.
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Mahfouz, R., R. Jha, R. Sharma, U. Paasch, S. Grunewald, and A. Agarwal. "Evaluation of poly (ADP-ribose) polymerase cleavage (cleaved-PARP) in sperm fractions after sperm apoptosis induction." Fertility and Sterility 88 (September 2007): S385—S386. http://dx.doi.org/10.1016/j.fertnstert.2007.07.1281.
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Lee, Dahae, Sanghee Shim, and Kisung Kang. "4,6′-Anhydrooxysporidinone from Fusarium lateritium SSF2 Induces Autophagic and Apoptosis Cell Death in MCF-7 Breast Cancer Cells." Biomolecules 11, no. 6 (June 11, 2021): 869. http://dx.doi.org/10.3390/biom11060869.
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Previous studies have reported that 4,6′-Anhydrooxysporidinone (SSF2-2), isolated from Fusarium lateritium SSF2, has neuroprotective effects on the HT-22 hippocampal neuronal cell line. However, the anti-cancer effect of SSF2-2 remains unclear. Here, we examined the viability of MCF-7 human breast cancer cells treated with SSF2-2 or left untreated using a cell viability assay kit. The underlying molecular mechanism was further investigated by Western blotting and immunocytochemistry studies. The results demonstrated that SSF2-2 inhibited the viability of MCF-7 cells. Treatment with SSF2-2 increased the levels of cleaved caspase-9, cleaved caspase-7, poly (ADP-ribose) polymerase (PARP), and LC3B. Additionally, SSF2-2 significantly increased the conversion of LC3-I to LC3II and LC3-positive puncta in MCF-7 cells.
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Lee, Eunji, Ah-Reum Han, Bomi Nam, Ye-Ram Kim, Chang Hyun Jin, Jin-Baek Kim, Young-Gyu Eun, and Chan-Hun Jung. "Moscatilin Induces Apoptosis in Human Head and Neck Squamous Cell Carcinoma Cells via JNK Signaling Pathway." Molecules 25, no. 4 (February 18, 2020): 901. http://dx.doi.org/10.3390/molecules25040901.
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Dendrobii Herba is an herbal medicine that uses the stems of Dendrobium species (Orchidacea). It has been traditionally used to treat fever, hydrodipsomania, stomach disorders, and amyotrophia. In our previous study, a bibenzyl compound, moscatilin, which is isolated from Dendrobii Herba, showed potent cytotoxicity against a FaDu human pharyngeal squamous carcinoma cell line. Prompted by this finding, we performed additional studies in FaDu cells to investigate the mechanism of action. Moscatilin induced FaDu cell death by using 5 μM of concentration and by mediating apoptosis, whereas cell proliferation following treatment with 1 μM of moscatilin was not suppressed to the same levels as by the anti-cancer agent, cisplatin. Apoptosis-related protein expression (cleaved caspase-8, cleaved caspase-7, cytochrome c, cleaved caspase-9, cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP) was increased by treating with 5 μM of moscatilin. This suggests that moscatilin-mediated apoptosis is associated with the extrinsic and intrinsic apoptotic signaling pathways. In addition, moscatilin-induced apoptosis was mediated by the c-Jun N-terminal kinase (JNK) signaling pathway. Overall, this study identified additional biological activity of moscatilin derived from natural products and suggested its potential application as a chemotherapeutic agent for the management of head and neck squamous cell carcinoma.
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Qu, Yibai, Chunxiu Yang, Xueyang Li, Haihua Luo, Shan Li, Mengwei Niu, Peng Chen, Zhengzheng Yan, and Yong Jiang. "CpG-Oligodeoxynucleotides Alleviate Tert-Butyl Hydroperoxide-Induced Macrophage Apoptosis by Regulating Mitochondrial Function and Suppressing ROS Production." Oxidative Medicine and Cellular Longevity 2020 (May 9, 2020): 1–19. http://dx.doi.org/10.1155/2020/1714352.
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Oxidative stress and mitochondrial dysfunction are related to disease pathogenesis. Oligodeoxynucleotide containing CpG motifs (CpG ODN) demonstrate possibilities for immunotherapy applications. The aim of the present work is to explore the underlying mechanism of the cytoprotective function of CpG ODN by employing the oxidative stress modulation in immune cells. We used the imaging flow cytometry to demonstrate that tert-butyl hydroperoxide (t-BHP) induces mitochondrial-mediated apoptosis and ROS production in RAW264.7 cells. After pretreatment with CpG ODN, the percentage of apoptotic cells and ROS production was both markedly reduced. The decrease in mitochondrial membrane potential (MMP) induced by t-BHP was partially reversed by CpG ODN. The t-BHP induced upregulation of the expression of apoptosis-related proteins (cleaved-caspase 3, cleaved-caspase 9, cleaved-PARP, and bax) was notably decreased in the presence of CpG ODN. Furthermore, we found that CpG ODN enhanced phosphorylation of ERK1/2 and Akt to inhibit ROS production. In conclusion, the protective effect of CpG ODN in mitigation of t-BHP-induced apoptosis is dependent on the reduction of ROS.
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Beneke, Ralph, Christoph Geisen, Branko Zevnik, Thomas Bauch, Wolfgang-Ulrich Müller, Jan-Heiner Küpper, and Tarik Möröy. "DNA Excision Repair and DNA Damage-Induced Apoptosis Are Linked to Poly(ADP-Ribosyl)ation but Have Different Requirements for p53." Molecular and Cellular Biology 20, no. 18 (September 15, 2000): 6695–703. http://dx.doi.org/10.1128/mcb.20.18.6695-6703.2000.
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ABSTRACT Poly(ADP-ribose) polymerase (PARP) is a DNA binding zinc finger protein that catalyzes the transfer of ADP-ribose residues from NAD+ to itself and different chromatin constituents, forming branched ADP-ribose polymers. The enzymatic activity of PARP is induced upon DNA damage and the PARP protein is cleaved during apoptosis, which suggested a role of PARP in DNA repair and DNA damage-induced cell death. We have generated transgenic mice that lack PARP activity in thymocytes owing to the targeted expression of a dominant negative form of PARP. In the presence of single-strand DNA breaks, the absence of PARP activity correlated with a strongly increased rate of apoptosis compared to cells with intact PARP activity. We found that blockage of PARP activity leads to a drastic increase of p53 expression and activity after DNA damage and correlates with an accelerated onset of Bax expression. DNA repair is almost completely blocked in PARP-deficient thymocytes regardless of p53 status. We found the same increased susceptibility to apoptosis in PARP null mice, a similar inhibition of DNA repair kinetics, and the same upregulation of p53 in response to DNA damage. Thus, based on two different experimental in vivo models, we identify a direct, p53-independent, functional connection between poly(ADP-ribosyl)ation and the DNA excision repair machinery. Furthermore, we propose a p53-dependent link between PARP activity and DNA damage-induced cell death.
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Peng, Yuan, Junliang Pu, Chengyong Tang, and Zhongjun Wu. "Curcumin Inhibits Heat-Induced Apoptosis by Suppressing NADPH Oxidase 2 and Activating the Akt/mTOR Signaling Pathway in Bronchial Epithelial Cells." Cellular Physiology and Biochemistry 41, no. 5 (2017): 2091–103. http://dx.doi.org/10.1159/000475444.
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Background: Heat causes bronchial epithelial cell apoptosis, which is a known factor contributing to airway damage during inhalation injury. Accumulating evidence has shown the effect of curcumin on inhibiting apoptosis. In this study, we investigated whether curcumin suppresses heat-induced apoptosis in bronchial epithelial cells and the underlying mechanism. Methods: Bronchial epithelial cell line 16HBE140 cells were incubated at either 42 °C, 47 °C, 52 °C, or 57 °C for 5 min in a cell incubator and then returned back to normal culture conditions (37 °C). An in vivo thermal inhalation injury rat model was established with a heat gun blowing hot air into the airway of rats. 16HBE140 cells and lung tissue were obtained for further study with or without curcumin treatment. Cell viability was determined by measuring the absorbance of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). 2',7'-dichlorofluorescein diacetate fluorescence was used as a measure of reactive oxygen species (ROS) production. Levels of Bcl2, Bax, α-ATP, cleaved Poly (ADP-ribose) polymerase (PARP), cleaved caspase-3, gp91phox, p47phox, p67phox, p22phox, p40phox, and Rac were determined by Western blotting. TUNEL staining was used to determine apoptosis. Results: Heat treatment triggered the apoptosis of 16HBE140 cells as shown by the increase in apoptosis molecular markers, including Bcl-2, Bax, cleaved PARP, and cleaved caspase-3. Administration of curcumin significantly inhibited apoptosis of 16HBE140 cells and suppressed the membrane translocation of NADPH oxidase 2 cytosolic components, as well as ROS production. Downregulation of Akt and mTOR phosphorylation induced by heat was also reversed by curcumin. Furthermore, we demonstrated that NADPH oxidase 2 is upstream of Akt/mTOR in heat-induced apoptosis. The protective role of curcumin on bronchial epithelia apoptosis was also confirmed in vivo by a rat inhalation injury model. Conclusion: This study demonstrates that one of the critical mechanisms underlying curcumin inhibiting heat-induced apoptosis is through suppressing NADPH Oxidase 2 and activating the Akt/mTOR signaling pathway in bronchial epithelial cells.
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Xu, Jianjun, Cai Lin, Tingting Wang, Peng Zhang, Zhengjun Liu, and Caijiao Lu. "Ergosterol Attenuates LPS-Induced Myocardial Injury by Modulating Oxidative Stress and Apoptosis in Rats." Cellular Physiology and Biochemistry 48, no. 2 (2018): 583–92. http://dx.doi.org/10.1159/000491887.
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Background/Aims: Ergosterol (ER) is the primary sterol found in fungi and is named after the ergot fungus. A variety of pharmacological activities have been reported for ER, including antioxidative, anti-proliferative, and anti-inflammatory effects, although its role in sepsis remains unclear. Methods: The protective effect of ER on lipopolysaccharide (LPS)-induced sepsis myocardial injury was evaluated both in vivo and in vitro. Rats were pretreated with ER and then with LPS. Histopathology of heart tissues was first performed. Subsequently, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), creatine kinase MB fraction (CK-MB), and lactate dehydrogenase (LDH) in serum and heart tissues were assessed by enzyme-linked immunosorbent assay kits. Western blotting was further used to evaluate the expression of antioxidant proteins (HO-1 and cytochrome c) and apoptosis associated proteins (Bcl-2, Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP). In addition, the effects of ER on oxidative stress biomarkers and apoptosis proteins were also detected in LPS-treated H9C2 cells. Moreover, small interfering Nrf2 RNA was transfected to H9C2 cells to study the role of Nrf2 signaling in connection with the protective effects of ER. Results: Pretreatment with ER ameliorated the histopathological changes in heart tissue induced by LPS injection, increased SOD activity, and reduced MDA content, and CK-MB and LDH levels. Furthermore, ER restored the expression of Nrf-2 and HO-1 in rat hearts, attenuating apoptotic damage via up-regulation of Bcl-2 in combination with the inhibition of Bax, cytochrome c, cleaved-caspase-3 and 9, and PARP, as revealed by western blot. When Nrf2 was blocked by siRNA, the effects of ER on SOD and MDA activity, as well as the expression of the antioxidant proteins and apoptosis-associated proteins were abolished. Conclusions: We demonstrated that ER has a cardioprotective effect in LPS-induced sepsis model through modulation of the antioxidant activity and anti-apoptosis effects and this process might be regulated by Nrf2 signaling.
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Cao, Peng, Xueting Cai, Wuguang Lu, Fei Zhou, and Jiege Huo. "Growth Inhibition and Induction of Apoptosis in SHG-44 Glioma Cells by Chinese Medicine Formula “Pingliu Keli”." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/958243.
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The present study was carried out to evaluate the effects of the water extract of Chinese medicine “Pingliu Keli” (PK) on human glioma cell viability and apoptosis and to investigate its mechanisms of action in SHG-44 cells. MTT assay showed that PK had a strong cytotoxic effect on SHG-44 cells. The number of live cells was less than 20% after exposure to 90 μg/mL PK for 24 h. PK increased cytotoxicity of SHG-44 cells in a dose-dependent manner. PK caused arrest of SHG-44 cells in G1 phase at low concentration and in G2 phase at high concentration. The percentage of apoptotic cells by flow cytometric analysis of the DNA-stained cells increased to 38% and 52% after treatment with 72 and 108 μg/mL PK, respectively. In addition, PK increased the expression of proapoptotic protein (Bax) and decreased antiapoptotic protein (Bcl-2), with a concomitant increase in the levels of cleaved caspase-3, cleaved caspase-9 and cleaved poly-ADP-ribose polymerase (PARP). These results suggest that PK has a significant apoptosis inducing effect on SHG-44 glioma cellsin vitroand caspase-3 may act as a potential mediator in the process.
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Lee, Shou-Lun, Ting-Yu Chin, Ching-Long Lai, and Wen-Han Wang. "Sedum mexicanumBritt. Induces Apoptosis of Primary Rat Activated Hepatic Stellate Cells." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/194373.
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Background. Liver fibrosis is a significant liver disease in Asian countries.Sedum mexicanumBritt. (SM) has been claimed to have antihepatitis efficacy. In traditional folk medicine, a solution of boiling water-extracted SM (SME) is consumed to prevent and treat hepatitis. However, its efficacy has not yet been verified. The purpose of this study was to investigate the in vitro effect of SME on hepatoprotection.Methods. Hepatic stellate cells (HSCs) and hepatocytes (HCs) were isolated from the livers of the rats by enzymatic digestion and density gradient centrifugation.Results. Treating the HCs and aHSCs with SME caused a dose-dependent decrease in the viability of aHSCs but not that of HCs. In addition, treatment with SME resulted in apoptosis of aHSCs, as determined by DAPI analysis and flow cytometry. SME also increased the amount of cleaved caspase-3, cleaved caspase-9, and cleaved poly ADP-ribose polymerase (PARP) in aHSCs. Furthermore, SME treatment induced a dose-dependent reduction in Bcl-2 expression and increased the expression of Bax in aHSCs.Conclusions. SME did not cause cytotoxicity in HCs, but it induced apoptosis in aHSCs through the mitochondria-dependent caspase-3 pathway. Therefore, SME may possess therapeutic potential for liver fibrosis.
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Xiao, Ting, Zhonghua Luo, Zhenghong Guo, Xude Wang, Meng Ding, Wei Wang, Xiangchun Shen, and Yuqing Zhao. "Multiple Roles of Black Raspberry Anthocyanins Protecting against Alcoholic Liver Disease." Molecules 26, no. 8 (April 16, 2021): 2313. http://dx.doi.org/10.3390/molecules26082313.
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This study aimed to investigate the protective effect of black raspberry anthocyanins (BRAs) against acute and subacute alcoholic liver disease (ALD). Network analysis and docking study were carried out to understand the potential mechanism. Thereafter, the serum biochemical parameters and liver indexes were measured, the histopathological changes of the liver were analyzed in vivo. The results showed that all tested parameters were ameliorated after the administration of BRAs with alcohol. Meanwhile, there was increased protein expression of NF-κB and TGF-β in extracted livers, which was associated with hepatitis and hepatic fibrosis. Furthermore, BRAs and cyanidin-3-O-rutinoside exhibited cytotoxic effects on t-HSC/Cl-6, HepG2, and Hep3B and induced the apoptosis of HepG2 cells; downregulated the protein expression level of Bcl-2; upregulated the level of Bax; and promoted the release of cytochrome C, cleaved caspase-9, cleaved caspase-3, and cleaved PARP in HepG2 cells. In addition, the antioxidant activity of BRAs was tested, and the chemical components were analyzed by FT-ICR MS. The results proved that BRAs exert preventive effect on ALD through the antioxidant and apoptosis pathways.
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Hassan, Iftekhar, Hossam Ebaid, Ibrahim M. Alhazza, Jameel Al-Tamimi, Shazia Aman, and Ahmad M. Abdel-Mageed. "Copper Mediates Anti-Inflammatory and Antifibrotic Activity of Gleevec in Hepatocellular Carcinoma-Induced Male Rats." Canadian Journal of Gastroenterology and Hepatology 2019 (March 3, 2019): 1–11. http://dx.doi.org/10.1155/2019/9897315.
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The elevated level of copper is one of the hallmark features of cancer cells in most of the types of cancer. In the present study, this feature has been targeted to investigate if coadministration of exogenous copper (Cu+) and its chelating agent like disulfiram (DSF+) influence the antineoplastic activity of the anticancer drug, Gleevec (GLV+), in hepatocellular carcinoma (HCC)-induced rats via immunomodulation. After the treatment, the level of proinflammatory interleukins (IL-1, 2, 6, and 7), anti-inflammatory interleukin (IL-10) concomitant with transcription factors (NF-kB and TNF-a), and the apoptotic marker (cleaved PARP) was estimated. The cancer-induced group without treatment (CN+) demonstrated abnormally elevated level of all proinflammatory cytokines and transcription factors concomitant with a compromised level of cleaved PARP as compared to the control normal (CN-). The detailed histological analysis also supported the results exhibiting extensive inflammation and tissue fibrosis confirming the second stage of HCC. Cu+, DSF+, and GLV+ displayed mild improvement in most of the parameters, but the combination group GLV + Cu+ demonstrated remarkable recovery in histology and most of the parameters tended towards the CN- followed by GLV + DSF+. Therefore, the management of copper level is critical in realizing the antineoplastic activity of GLV up to its full potential in cancer treatment. These findings will help in improving chemoimmunotherapy and personalized cancer treatment.
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Kim, Min Sung, Yong Tae Ahn, Chul Won Lee, Hyungwoo Kim, and Won Gun An. "Astaxanthin Modulates Apoptotic Molecules to Induce Death of SKBR3 Breast Cancer Cells." Marine Drugs 18, no. 5 (May 19, 2020): 266. http://dx.doi.org/10.3390/md18050266.
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Astaxanthin (AST) is related to apoptosis but the details of the mechanism of how AST makes apoptosis is not clear. The present study investigated apoptotic effects of AST to SKBR3, a breast cancer cell line in detail. Cell viability assay showed cellular proliferation and morphological changes of the cells were observed under AST treatment. FACS analysis indicated that AST blocked cell cycle progression at G0/G1, suppressed proliferation dose-dependently, and induced apoptosis of the cells. The apoptosis of the cells by AST was further demonstrated through the decreased expression level of mutp53 and cleaved a PARP-1 fragment, respectively. In addition, AST induced the intrinsic apoptosis of the cells by activation of Bax/Bcl2, cleaved caspase-3, and cleaved caspase-9 as well as the phosphorylation of ERK1/2, JNK, and p38. Furthermore, AST decreased production of intracellular reactive oxygen species as well as modulated expressions of superoxide dismutases and Pontin, an anti-apoptotic factor. Co-immunoprecipitation assay revealed AST reduced interaction between Pontin and mutant p53. Taken together, these studies proved that AST regulates the expression of apoptotic molecules to induce intrinsic apoptosis of the cells, suggesting AST therapy might provide an alternative for improving the efficacies of other anti-cancer therapies for breast cancer.
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Kim, Juyoung, Kyung Hee Jung, Hyung Won Ryu, Doo-Young Kim, Sei-Ryang Oh, and Soon-Sun Hong. "Apoptotic Effects of Xanthium strumarium via PI3K/AKT/mTOR Pathway in Hepatocellular Carcinoma." Evidence-Based Complementary and Alternative Medicine 2019 (November 7, 2019): 1–13. http://dx.doi.org/10.1155/2019/2176701.
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Xanthium strumarium (XS) has been traditionally used as a medicinal herb for treating inflammatory diseases, such as appendicitis, chronic bronchitis, rheumatism, and rhinitis. In this study, we yielded ethanol extracts from XS and investigated whether they could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. The XS-5 and XS-6 extracts dose-dependently inhibited the growth and proliferation in HCC cell lines. The apoptotic effects of them were observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling- (TUNEL-) positive apoptotic cells. They also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, they inhibited the invasion and migration of HCC cells. In an ex vivo model, the extracts significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of the cleaved caspase-3. A mechanistic study revealed that they effectively suppressed PI3K/AKT/mTOR signaling pathways in HCC cells. Taken together, our findings demonstrate that they could efficiently not only induce apoptosis but also inhibit cell growth, migration, and invasion of human HCC cells by blocking the PI3K/AKT/mTOR pathway. We suggest XS-5 and XS-6 as novel natural anti-HCC agents.
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Kim, Donghee, Hyo-Jin Kim, Seon-Heui Cha, and Hee-Sook Jun. "Protective Effects of Broussonetia kazinoki Siebold Fruit Extract against Palmitate-Induced Lipotoxicity in Mesangial Cells." Evidence-Based Complementary and Alternative Medicine 2019 (January 8, 2019): 1–12. http://dx.doi.org/10.1155/2019/4509403.
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Diabetic nephropathy is one of the most serious complications of diabetes. Lipotoxicity in glomerular mesangial cells is associated with the progression of diabetic nephropathy. Paper mulberry, Broussonetia kazinoki Siebold (BK), has been used in oriental medicine for human health problems. However, to date, the beneficial effect of BK fruit has not been studied. In this study, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against palmitate- (PA-) induced toxicity in mesangial cells. BKFE significantly increased the viability of PA-treated SV40 MES13 cells. BKFE significantly inhibited PA-induced apoptosis and decreased the expression of apoptotic genes, cleaved caspase-3, and cleaved PARP. Moreover, BKFE inhibited the expression of endoplasmic reticulum (ER) stress-related genes, such as BiP, phosphorylated eIF2α, cleaved ATF6, and spliced XBP-1, in PA-treated SV40 MES13 cells. BKFE decreased PA-induced ROS production. In addition, BKFE activated the transcription factor Nrf2 and increased the expression of antioxidant enzymes. However, knockdown of Nrf2 using siRNA suppressed this BKFE-induced increase in antioxidant enzyme expression. Furthermore, the protective effect of BKFE on PA-induced apoptosis was significantly reduced by Nrf2 knockdown. In conclusion, BKFE induced the expression of antioxidant enzymes via activation of Nrf2 and protected against PA-induced lipotoxicity in mesangial cells.
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Jiang, Li, Jinghui Zhang, Naifeng Hu, Aichun Liu, Hailong Zhu, Lianqiao Li, Yuyang Tian, Xue Chen, and Lina Quan. "Lentivirus-mediated down-regulation of CK2α inhibits proliferation and induces apoptosis of malignant lymphoma and leukemia cells." Biochemistry and Cell Biology 96, no. 6 (December 2018): 786–96. http://dx.doi.org/10.1139/bcb-2017-0345.
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Casein kinase II subunit alpha (CK2α) is highly expressed in many malignant tumor tissues, including lymphomas and leukemia. To investigate the role of CK2α in cell proliferation and apoptosis of malignant lymphomas and leukemia, 2 lymphoma cell lines and one leukemia cell line were infected with CK2α shRNA lentivirus or negative control shRNA lentivirus, and stably infected cell lines were established. Real-time PCR and Western blot results showed that the mRNA and protein levels of CK2α were significantly reduced in CK2α knockdown cells. The tetrazolium-based colorimetric (MTT) assay found that down-regulation of CK2α inhibited the proliferation of these cells. Flow cytometry analysis showed that inhibition of CK2α induced cell cycle arrest and apoptosis of lymphoma and leukemia cells. In accordance with these, down-regulation of CK2α also reduced the protein levels of proliferating cell nuclear antigen (PCNA), cyclinD1, and bcl-2, and increased the protein expression of bax, cleaved caspase-3, cleaved caspase-9, and cleaved poly(ADP ribose) polymerase (PARP). Moreover, knockdown of CK2α impeded the growth of xenograft tumors in vivo. In summary, our study revealed that CK2α may contribute to the development of malignant lymphoma and leukemia, and serve as the therapeutic target of these malignant tumors.
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Noh, Ji-In, Seul-Ki Mun, Eui Hyeon Lim, Hangun Kim, Dong-Jo Chang, Jae-Seoun Hur, and Sung-Tae Yee. "Induction of Apoptosis in MDA-MB-231 Cells Treated with the Methanol Extract of Lichen Physconia hokkaidensis." Journal of Fungi 7, no. 3 (March 5, 2021): 188. http://dx.doi.org/10.3390/jof7030188.
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Physconia hokkaidensis methanol extract (PHE) was studied to identify anticancer effects and reveal its mechanism of action by an analysis of cytotoxicity, cell cycles, and apoptosis biomarkers. PHE showed strong cytotoxicity in various cancer cells, including HL-60, HeLa, A549, Hep G2, AGS, MDA-MB-231, and MCF-7. Of these cell lines, the growth of MDA-MB-231 was concentration-dependently suppressed by PHE, but MCF-7 was not affected. MDA-MB-231 cells, triple-negative breast cancer (TNBC) cells, do not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), whereas MCF-7 cells are ER-positive, PR-positive, and HER-2-negative breast cancer cells. The number of cells in sub-G1 phase was increased after 24 h of treatment, and annexin V/PI staining showed that the population size of apoptotic cells was increased by prolonged exposure to PHE. Moreover, PHE treatment downregulated the transcriptional levels of Bcl-2, AMPK, and p-Akt, whereas it significantly upregulated the levels of cleaved caspase-3, cleaved caspase-9, and cleaved-PARP. In conclusion, it was confirmed that the PHE exhibited selective cytotoxicity toward MDA-MB-231, not toward MCF-7, and its cytotoxic activity is based on induction of apoptosis.
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Butler, Madison, Yu-Ting Su, Lee Hwang, Laetitia Marzi, Mark Gilbert, Yves Pommier, and Jing Wu. "EXTH-58. INHIBITION OF DNA TOPOISOMERASE 1 AND POLY(ADP-RIBOSE) POLYMERASE SYNERGISTICALLY INDUCES CELL DEATH IN GLIOBLASTOMA WITH PTEN LOSS." Neuro-Oncology 21, Supplement_6 (November 2019): vi94—vi95. http://dx.doi.org/10.1093/neuonc/noz175.389.
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Abstract BACKGROUND Glioblastoma is known for its aggressive behavior and resistance to most available treatments. Topoisomerase 1 (Top1) functions by relaxing DNA supercoiling to facilitate replication. The novel Top1 inhibitor, LMP400, traps the enzyme and prevents its normal function, particularly in highly proliferative cells, resulting in DNA damage. Poly(ADP-ribose) polymerase (PARP) is involved in DNA repair responses triggered by Top1 inhibition. Phosphatase and tensin homolog (PTEN) loss, a frequent occurrence in glioblastoma, promotes DNA damage repair deficiency. We hypothesize that PTEN loss presents a vulnerability to combined induction of DNA damage and inhibition of repair mechanisms. METHODS Human glioblastoma cells were treated with LMP400 and/or Olaparib, a PARP inhibitor. Effects on cell proliferation and cell death were determined using a Beckman Coulter cell viability analyzer and colony formation assays. Synergism was calculated using COMPUSYN software. Cell cycle analysis was performed by FACS with EdU/DAPI staining, and Western blotting of lysate from drug-treated cells was performed to explore mechanisms of cytotoxicity. RESULTS LMP400 inhibited cell proliferation with an EC50 of 8.0 nM in U251 cells, and combination of LMP400 and Olaparib had a synergistic cytotoxic effect. Combination treatment enhanced activation of ATM-Chk2 and ATR-Chk1 pathways involved in DNA damage response signaling and increased S phase arrest. Increased protein expression of gamma-H2AX, cleaved caspase 3, and cleaved PARP was observed in combination-treated cells compared to single agents. Cell viability assays using isogenic glioblastoma cell lines with and without PTEN indicate that PTEN loss increases sensitivity to combination treatment. CONCLUSION Our results suggest that LMP400 and Olaparib combined treatment synergistically induces glioblastoma cell death, partially through inducing DNA damage, cell cycle arrest, and apoptosis. Mechanistic studies to investigate this vulnerability in glioblastoma with PTEN loss are ongoing. These results may lead to an effective personalized therapy for a molecularly defined subset of glioblastoma patients.
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Wei, Xiaolei, Jialin Song, Yongqiang Wei, Hong Zeng, Weimin Huang, Jingxia Zheng, and Ru Feng. "Curcumin Enhances the Sensitivity of Bortezomib By Inhibiting NF-Κb in ABC Diffuse Large B-Cell Lymphoma Cells." Blood 134, Supplement_1 (November 13, 2019): 5237. http://dx.doi.org/10.1182/blood-2019-127705.
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Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-hodgkin lymphoma with great heterogeneity in clinical behavior and response to treatment. According to gene expression profile, DLBCL can be divided into at least two subtypes: germinal center B cell type (GCB) and activated B cell type (ABC). ABC-type DLBCL is commonly activated by the NF-κB pathway, but the proteasome inhibitor bortezomib does not significantly improve the prognosis of ABC-DLBCL. Curcumin inhibit the proliferation of various tumor cells by inhibiting the activation of NF-κB. Our purpose was to evaluate whether curcumin could enhance the ensitivity of Bortezomib in ABC-DLBCL. Methods MTT assay was used to evaluate the proliferation of 2 ABC-DLBCL cell lines by treated with curcumin and bortezomib. Apoptosis were detected by FCM after staining with Annexin V/SYTOX Green.Western Blot was used to evaluated the expression of PARP, NF-κB, I κBα/p-IκBα and caspase-3 in ABC-DLBCL cells treated with curcumin and bortezomib. Results Both curcumin and bortezomib could inhibit the proliferation and induce apoptosis in ABC-DLBCL cell lines. Curcumin decreased the expression of p-IκBα, NF-κB/p65 and increased the expression of Cleaved PARP in ABC-DLBCL cell lines. Caspase Inhibitor Z-VAD could reverse the curcumin induced proliferation inhibition and apoptosis by decreasing the cleaved PARP expression. The combination of curcumin and bortezomib could further enhance the proliferation inhibition and apoptosis in ABC-DLBCL cell lines by inhibiting NF-κB. Conclusions Curcumin induced proliferation inhibition and apoptosis by inhibiting NF-κB in ABC-DLBCL. It may sensitize ABC-DLBCL cell lines to the cytotoxic effects of bortezomib by inhibiting NF-κB. Disclosures No relevant conflicts of interest to declare.
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Lei, Xuemeng, Xukun Li, Hongyan Chen, and Zhihua Liu. "USP48 Sustains Chemoresistance and Metastasis in Ovarian Cancer." Current Cancer Drug Targets 20, no. 9 (September 28, 2020): 689–99. http://dx.doi.org/10.2174/1568009620666200503045400.
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Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.
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Lee, HansongI, Miji Yeom, Seoungwoo Shin, Kyungeun Jeon, Deokhoon Park, and Eunsun Jung. "Protective Effects of Aqueous Extract of Mentha suaveolens against Oxidative Stress-Induced Damages in Human Keratinocyte HaCaT Cells." Evidence-Based Complementary and Alternative Medicine 2019 (September 22, 2019): 1–8. http://dx.doi.org/10.1155/2019/5045491.
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Mentha suaveolens is an aromatic herb that has a wide range of biological activities, including antimicrobial, antifungal, anti-inflammatory, and hepatoprotective properties. Although there are a few reports on the antioxidant property of M. suaveolens, its cytoprotective activity against oxidative stress has not been reported yet. The objective of this study was to determine the protective activity of M. suaveolens aqueous extract (MSAE) against hydrogen peroxide- (H2O2-) induced oxidative stress and apoptosis in human keratinocyte HaCaT cells. MSAE pretreatment decreased H2O2-induced cytotoxicity and suppressed H2O2-induced intracellular ROS generation. Furthermore, MSAE suppressed expression levels of H2O2-induced apoptotic genes such as cleaved caspase-3, caspase-9, and cleaved poly (ADP-ribose) polymerase (PARP). Pretreatment with MSAE induced expression of phase II enzyme such as HO-1 through translocation of NF-E2-related factor (Nrf2) upon H2O2 exposure. These results revealed that the cytoprotective effect of MSAE against oxidative stress-induced cell death was associated with activation of Nrf2-mediated phase II enzyme expression.
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Krupinski, J., I. Ferrer, M. Barrachina, J. J. Secades, J. Mercadal, and R. Lozano. "CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat." Neuropharmacology 42, no. 6 (May 2002): 846–54. http://dx.doi.org/10.1016/s0028-3908(02)00032-1.
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