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Topical Collection "Programmed Cell Death and Apoptosis"

Editor

Collection Editor
Prof. Dr. Anthony Lemarié

Research Team: Tumor radioresistance, from signalling pathways to therapy Department of Experimental Therapeutics Inserm U1037 Toulouse Cancer Research Center (CRCT) & IUCT 2 av. Hubert Curien, 31100 Toulouse, France
Website | E-Mail
Interests: cell death; apoptosis; cellular differentiation; cellular and mitochondrial metabolism; cellular and mitochondrial homoeostasis; oxidative stress; cancer; cancer stem cells; glioma; radiotherapy & radioresistance

Topical Collection Information

Dear Colleagues,

Apoptosis is considered as an essential physiological process in eukaryotes for development, tissue homeostasis, wound healing or immune response. Moreover, apoptosis appears as a key player in physiopathological deregulations, since sustained apoptotic cell death characterizes ischemic and degenerative diseases as well as toxicological responses and since impaired cell death confers to cells and tissues a hyperproliferative phenotype as observed in cancer cells or autoimmune diseases. This collection is dedicated to bring to light some recent developments in the cell death area and to further present some comprehensive reviews on specific “hot” spots in the apoptotic field. In particular, it is of major interest to present the different types of programmed cell death, such as apoptosis, autophagic cell death, necroptosis and secondary necrosis, mitotic catastrophe or senescence and to depict their specific mechanisms and crossovers. The physiopathological context of each process is of particular importance. In addition, the different upstream early events leading to cell death signalling remain to be fully deciphered, notably the role of oxidative stress, ionic homeostasis, metabolic stress signals (e.g. hypoxia), DNA damages and microRNAs.
Concerning apoptosis, several aspects have to be addressed as the dependency on the caspase proteases, the involvement of extrinsic (death receptors) and intrinsic (mitochondrial) pathways and the role of the endoplasmic reticulum pathway. Finally, it would be of great interest to focus on the pro-survival vs pro-apoptotic regulation in tumour cells and during anticancer treatments (either chemo or radiotherapy), particularly towards several emerging targets such as cancer stem cells or circulating cancer cells.
Research articles, review articles as well as communications are invited.

Prof. Dr. Anthony Lemarié
Collection Editor

Manuscript Submission Information

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Keywords

  • cell death
  • apoptosis
  • cellular differentiation
  • cellular and mitochondrial metabolism
  • cellular and mitochondrial homoeostasis
  • oxidative stress
  • cancer
  • cancer stem cells
  • glioma
  • radiotherapy & radioresistance

Related Special Issues

Published Papers (107 papers)

2018

Jump to: 2017, 2016, 2015, 2014, 2013, 2012

Open AccessArticle Anti-Proliferative Properties and Proapoptotic Function of New CB2 Selective Cannabinoid Receptor Agonist in Jurkat Leukemia Cells
Int. J. Mol. Sci. 2018, 19(7), 1958; https://doi.org/10.3390/ijms19071958
Received: 29 May 2018 / Revised: 28 June 2018 / Accepted: 29 June 2018 / Published: 4 July 2018
PDF Full-text (2853 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe
[...] Read more.
Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist. Full article
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Open AccessReview Immunogenic Apoptosis as a Novel Tool for Anticancer Vaccine Development
Int. J. Mol. Sci. 2018, 19(2), 594; https://doi.org/10.3390/ijms19020594
Received: 19 January 2018 / Revised: 5 February 2018 / Accepted: 13 February 2018 / Published: 16 February 2018
Cited by 1 | PDF Full-text (710 KB) | HTML Full-text | XML Full-text
Abstract
Immunogenic apoptosis, or more appropriately called immunogenic cell death (ICD), is a recently described form of apoptosis induced by a specific set of chemotherapeutic drugs or by physical therapeutic modalities, such as ionizing irradiation and photodynamic therapy. The peculiar characteristic of ICD is
[...] Read more.
Immunogenic apoptosis, or more appropriately called immunogenic cell death (ICD), is a recently described form of apoptosis induced by a specific set of chemotherapeutic drugs or by physical therapeutic modalities, such as ionizing irradiation and photodynamic therapy. The peculiar characteristic of ICD is the ability to favor recognition and elimination of dying tumor cells by phagocytes in association with the release of pro-inflammatory molecules (such as cytokines and high-mobility group box-1). While in vitro and animal models pointed to ICD as one of the molecular mechanisms mediating the clinical efficacy of some anticancer agents, it is hard to clearly demonstrate its contribution in cancer patients. Clinical evidence suggests that the induction of ICD alone is possibly not sufficient to fully subvert the immunosuppressive tumor microenvironment. However, interesting results from recent studies contemplate the exploitation of ICD for improving the immunogenicity of cancer cells to use them as an antigen cargo in the development of dendritic cell (DC) vaccines. Herein, we discuss the effects of danger signals expressed or released by cancer cells undergoing ICD on the maturation and activation of immature and mature DC, highlighting the potential added value of ICD in adoptive immunotherapy protocols. Full article
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Open AccessReview Apoptosis: A Target for Anticancer Therapy
Int. J. Mol. Sci. 2018, 19(2), 448; https://doi.org/10.3390/ijms19020448
Received: 21 November 2017 / Accepted: 14 December 2017 / Published: 2 February 2018
Cited by 4 | PDF Full-text (1462 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis, the cell’s natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a
[...] Read more.
Apoptosis, the cell’s natural mechanism for death, is a promising target for anticancer therapy. Both the intrinsic and extrinsic pathways use caspases to carry out apoptosis through the cleavage of hundreds of proteins. In cancer, the apoptotic pathway is typically inhibited through a wide variety of means including overexpression of antiapoptotic proteins and under-expression of proapoptotic proteins. Many of these changes cause intrinsic resistance to the most common anticancer therapy, chemotherapy. Promising new anticancer therapies are plant-derived compounds that exhibit anticancer activity through activating the apoptotic pathway. Full article
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Open AccessArticle In Vitro Antitumor Activity of Aloperine on Human Thyroid Cancer Cells through Caspase-Dependent Apoptosis
Int. J. Mol. Sci. 2018, 19(1), 312; https://doi.org/10.3390/ijms19010312
Received: 30 November 2017 / Revised: 4 January 2018 / Accepted: 17 January 2018 / Published: 21 January 2018
PDF Full-text (5291 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or
[...] Read more.
The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with aloperine treatment. This study suggests the potential therapeutic use of aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Full article
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Open AccessReview Post-Transcriptional Regulation of Anti-Apoptotic BCL2 Family Members
Int. J. Mol. Sci. 2018, 19(1), 308; https://doi.org/10.3390/ijms19010308
Received: 13 December 2017 / Revised: 5 January 2018 / Accepted: 16 January 2018 / Published: 20 January 2018
Cited by 1 | PDF Full-text (1238 KB) | HTML Full-text | XML Full-text
Abstract
Anti-apoptotic B cell lymphoma 2 (BCL2) family members (BCL2, MCL1, BCLxL, BCLW, and BFL1) are key players in the regulation of intrinsic apoptosis. Dysregulation of these proteins not only impairs normal development, but also contributes to tumor progression and resistance to various anti-cancer
[...] Read more.
Anti-apoptotic B cell lymphoma 2 (BCL2) family members (BCL2, MCL1, BCLxL, BCLW, and BFL1) are key players in the regulation of intrinsic apoptosis. Dysregulation of these proteins not only impairs normal development, but also contributes to tumor progression and resistance to various anti-cancer therapies. Therefore, cells maintain strict control over the expression of anti-apoptotic BCL2 family members using multiple mechanisms. Over the past two decades, the importance of post-transcriptional regulation of mRNA in controlling gene expression and its impact on normal homeostasis and disease have begun to be appreciated. In this review, we discuss the RNA binding proteins (RBPs) and microRNAs (miRNAs) that mediate post-transcriptional regulation of the anti-apoptotic BCL2 family members. We describe their roles and impact on alternative splicing, mRNA turnover, and mRNA subcellular localization. We also point out the importance of future studies in characterizing the crosstalk between RBPs and miRNAs in regulating anti-apoptotic BCL2 family member expression and ultimately apoptosis. Full article
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Open AccessReview Apoptotic and Nonapoptotic Activities of Pterostilbene against Cancer
Int. J. Mol. Sci. 2018, 19(1), 287; https://doi.org/10.3390/ijms19010287
Received: 12 December 2017 / Revised: 9 January 2018 / Accepted: 16 January 2018 / Published: 18 January 2018
Cited by 1 | PDF Full-text (1552 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is a major cause of death. The outcomes of current therapeutic strategies against cancer often ironically lead to even increased mortality due to the subsequent drug resistance and to metastatic recurrence. Alternative medicines are thus urgently needed. Cumulative evidence has pointed out
[...] Read more.
Cancer is a major cause of death. The outcomes of current therapeutic strategies against cancer often ironically lead to even increased mortality due to the subsequent drug resistance and to metastatic recurrence. Alternative medicines are thus urgently needed. Cumulative evidence has pointed out that pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene, PS) has excellent pharmacological benefits for the prevention and treatment for various types of cancer in their different stages of progression by evoking apoptotic or nonapoptotic anti-cancer activities. In this review article, we first update current knowledge regarding tumor progression toward accomplishment of metastasis. Subsequently, we review current literature regarding the anti-cancer activities of PS. Finally, we provide future perspectives to clinically utilize PS as novel cancer therapeutic remedies. We, therefore, conclude and propose that PS is one ideal alternative medicine to be administered in the diet as a nutritional supplement. Full article
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2017

Jump to: 2018, 2016, 2015, 2014, 2013, 2012

Open AccessReview Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases?
Int. J. Mol. Sci. 2018, 19(1), 7; https://doi.org/10.3390/ijms19010007
Received: 22 November 2017 / Revised: 11 December 2017 / Accepted: 19 December 2017 / Published: 21 December 2017
Cited by 1 | PDF Full-text (4292 KB) | HTML Full-text | XML Full-text
Abstract
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells,
[...] Read more.
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed. Full article
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Open AccessArticle Preparation of A Spaceflight: Apoptosis Search in Sutured Wound Healing Models
Int. J. Mol. Sci. 2017, 18(12), 2604; https://doi.org/10.3390/ijms18122604
Received: 20 October 2017 / Revised: 23 November 2017 / Accepted: 1 December 2017 / Published: 3 December 2017
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Abstract
To prepare the ESA (European Space Agency) spaceflight project “Wound healing and Sutures in Unloading Conditions”, we studied mechanisms of apoptosis in wound healing models based on ex vivo skin tissue cultures, kept for 10 days alive in serum-free DMEM/F12 medium supplemented with
[...] Read more.
To prepare the ESA (European Space Agency) spaceflight project “Wound healing and Sutures in Unloading Conditions”, we studied mechanisms of apoptosis in wound healing models based on ex vivo skin tissue cultures, kept for 10 days alive in serum-free DMEM/F12 medium supplemented with bovine serum albumin, hydrocortisone, insulin, ascorbic acid and antibiotics at 32 °C. The overall goal is to test: (i) the viability of tissue specimens; (ii) the gene expression of activators and inhibitors of apoptosis and extracellular matrix components in wound and suture models; and (iii) to design analytical protocols for future tissue specimens after post-spaceflight download. Hematoxylin-Eosin and Elastica-van-Gieson staining showed a normal skin histology with no signs of necrosis in controls and showed a normal wound suture. TdT-mediated dUTP-biotin nick end labeling for detecting DNA fragmentation revealed no significant apoptosis. No activation of caspase-3 protein was detectable. FASL, FADD, CASP3, CASP8, CASP10, BAX, BCL2, CYC1, APAF1, LAMA3 and SPP1 mRNAs were not altered in epidermis and dermis samples with and without a wound compared to 0 day samples (specimens investigated directly post-surgery). BIRC5, CASP9, and FN1 mRNAs were downregulated in epidermis/dermis samples with and/or without a wound compared to 0 day samples. BIRC2, BIRC3 were upregulated in 10 day wound samples compared to 0 day samples in epidermis/dermis. RELA/FAS mRNAs were elevated in 10 day wound and no wound samples compared to 0 day samples in dermis. In conclusion, we demonstrate that it is possible to maintain live skin tissue cultures for 10 days. The viability analysis showed no significant signs of cell death in wound and suture models. The gene expression analysis demonstrated the interplay of activators and inhibitors of apoptosis and extracellular matrix components, thereby describing important features in ex vivo sutured wound healing models. Collectively, the performed methods defining analytical protocols proved to be applicable for post-flight analyzes of tissue specimens after sample return. Full article
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Open AccessArticle Reg Gene Expression in Periosteum after Fracture and Its In Vitro Induction Triggered by IL-6
Int. J. Mol. Sci. 2017, 18(11), 2257; https://doi.org/10.3390/ijms18112257
Received: 12 September 2017 / Revised: 24 October 2017 / Accepted: 24 October 2017 / Published: 27 October 2017
Cited by 1 | PDF Full-text (1910 KB) | HTML Full-text | XML Full-text
Abstract
The periosteum is a thin membrane that surrounds the outer surface of bones and participates in fracture healing. However, the molecular signals that trigger/initiate the periosteal reaction are not well established. We fractured the rat femoral bone at the diaphysis and fixed it
[...] Read more.
The periosteum is a thin membrane that surrounds the outer surface of bones and participates in fracture healing. However, the molecular signals that trigger/initiate the periosteal reaction are not well established. We fractured the rat femoral bone at the diaphysis and fixed it with an intramedullary inserted wire, and the expression of regenerating gene (Reg) I, which encodes a tissue regeneration/growth factor, was analyzed. Neither bone/marrow nor muscle showed Reg I gene expression before or after the fracture. By contrast, the periosteum showed an elevated expression after the fracture, thereby confirming the localization of Reg I expression exclusively in the periosteum around the fractured areas. Expression of the Reg family increased after the fracture, followed by a decrease to basal levels by six weeks, when the fracture had almost healed. In vitro cultures of periosteal cells showed no Reg I expression, but the addition of IL-6 significantly induced Reg I gene expression. The addition of IL-6 also increased the cell number and reduced pro-apoptotic gene expression of Bim. The increased cell proliferation and reduction in Bim gene expression were abolished by transfection with Reg I siRNA, indicating that these IL-6-dependent effects require the Reg I gene expression. These results indicate the involvement of the IL-6/Reg pathway in the osteogenic response of the periosteum, which leads to fracture repair. Full article
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Open AccessArticle Upregulated Autophagy in Sertoli Cells of Ethanol-Treated Rats Is Associated with Induction of Inducible Nitric Oxide Synthase (iNOS), Androgen Receptor Suppression and Germ Cell Apoptosis
Int. J. Mol. Sci. 2017, 18(5), 1061; https://doi.org/10.3390/ijms18051061
Received: 23 February 2017 / Revised: 22 April 2017 / Accepted: 10 May 2017 / Published: 15 May 2017
Cited by 3 | PDF Full-text (3430 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
This study was conducted to investigate the autophagic response of Sertoli cells (SCs) to acute ethanol toxicity using in vivo and in vitro models. Adult Wistar rats were intraperitoneally injected with either 5 g/kg ethanol or phosphate-buffered saline (for the control group) and
[...] Read more.
This study was conducted to investigate the autophagic response of Sertoli cells (SCs) to acute ethanol toxicity using in vivo and in vitro models. Adult Wistar rats were intraperitoneally injected with either 5 g/kg ethanol or phosphate-buffered saline (for the control group) and sacrificed 0, 3, 6 and 24 h after injection. Compared to the control group, enhanced germ cell apoptosis was observed in the ethanol-treated rats (ETRs) in association with upregulation of iNOS and reduced expression of androgen receptor protein levels in SCs, which were resistant to apoptosis. Meanwhile, autophagy was upregulated in ETR SCs (peaking at 24 h) compared to the control group, as evidenced by transcription factor EB (TFEB) nuclear translocation, enhanced expression of microtubule-associated protein 1 light chain3-II (LC3-II), lysosome-associated membrane protein-2 (LAMP-2), pan cathepsin protein levels and reduced expression of p62. This upregulation of SC autophagy was confirmed ultrastructurally by enhanced formation of autophagic vacuoles and by immunofluorescent double labelling of autophagosomal and lysosomal markers. Study of cultured SCs confirmed enhanced autophagic response to ethanol toxicity, which was cytoprotective based on decreased viability of SCs upon blocking autophagy with 3-methyladenine (3-MA). The results highlighted the molecular mechanisms of prosurvival autophagy in ETR SCs for the first time, and may have significant implications for male fertility. Full article
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Open AccessArticle E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis
Int. J. Mol. Sci. 2017, 18(4), 892; https://doi.org/10.3390/ijms18040892
Received: 6 January 2017 / Revised: 28 March 2017 / Accepted: 11 April 2017 / Published: 24 April 2017
Cited by 3 | PDF Full-text (2394 KB) | HTML Full-text | XML Full-text
Abstract
Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen
[...] Read more.
Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs). In addition, protein phosphatase such as protein phosphatase 1 (PP1) and calcineurin (PP2B) are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO)-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage. Full article
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Open AccessArticle Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy
Int. J. Mol. Sci. 2017, 18(4), 723; https://doi.org/10.3390/ijms18040723
Received: 9 January 2017 / Revised: 2 March 2017 / Accepted: 24 March 2017 / Published: 29 March 2017
Cited by 1 | PDF Full-text (2398 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure
[...] Read more.
Apoptosis (type I programmed cell death) of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM). Transferase dUTP nick end labeling (TUNEL) and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure. Full article
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Open AccessArticle Inhibition of CCAR1, a Coactivator of β-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells
Int. J. Mol. Sci. 2017, 18(2), 460; https://doi.org/10.3390/ijms18020460
Received: 27 October 2016 / Revised: 30 January 2017 / Accepted: 15 February 2017 / Published: 21 February 2017
Cited by 4 | PDF Full-text (4006 KB) | HTML Full-text | XML Full-text
Abstract
The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a
[...] Read more.
The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/β-catenin signaling, and which plays an important role in transcriptional regulation by β-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target. Full article
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Open AccessArticle Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3β Signaling Pathway
Int. J. Mol. Sci. 2017, 18(2), 315; https://doi.org/10.3390/ijms18020315
Received: 27 September 2016 / Revised: 12 January 2017 / Accepted: 27 January 2017 / Published: 8 February 2017
Cited by 3 | PDF Full-text (2765 KB) | HTML Full-text | XML Full-text
Abstract
Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently,
[...] Read more.
Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose‑regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3β, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of β-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3β, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection. Full article
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Open AccessReview Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma
Int. J. Mol. Sci. 2017, 18(1), 149; https://doi.org/10.3390/ijms18010149
Received: 14 November 2016 / Revised: 19 December 2016 / Accepted: 6 January 2017 / Published: 13 January 2017
Cited by 4 | PDF Full-text (714 KB) | HTML Full-text | XML Full-text
Abstract
Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in
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Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment. Full article
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Open AccessArticle The Impact of Growth Hormone Therapy on the Apoptosis Assessment in CD34+ Hematopoietic Cells from Children with Growth Hormone Deficiency
Int. J. Mol. Sci. 2017, 18(1), 111; https://doi.org/10.3390/ijms18010111
Received: 18 August 2016 / Revised: 10 December 2016 / Accepted: 21 December 2016 / Published: 7 January 2017
PDF Full-text (4889 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Growth hormone (GH) modulates hematopoietic cell homeostasis and is associated with apoptosis control, but with limited mechanistic insights. Aim of the study was to determine whether GH therapeutic supplementation (GH-TS) could affect apoptosis of CD34+ cells enriched in hematopoietic progenitor cells of GH
[...] Read more.
Growth hormone (GH) modulates hematopoietic cell homeostasis and is associated with apoptosis control, but with limited mechanistic insights. Aim of the study was to determine whether GH therapeutic supplementation (GH-TS) could affect apoptosis of CD34+ cells enriched in hematopoietic progenitor cells of GH deficient (GHD) children. CD34+ cells from peripheral blood of 40 GHD children were collected before and in 3rd and 6th month of GH-TS and compared to 60 controls adjusted for bone age, sex, and pubertal development. Next, apoptosis assessment via different molecular techniques was performed. Finally, to comprehensively characterize apoptosis process, global gene expression profile was determined using genome-wide RNA microarray technology. Results showed that GH-TS significantly reduced spontaneous apoptosis in CD34+ cells (p < 0.01) and results obtained using different methods to detect early and late apoptosis in analyzed cells population were consistent. GH-TS was also associated with significant downregulation of several members of TNF-alpha superfamily and other genes associated with apoptosis and stress response. Moreover, the significant overexpression of cyto-protective and cell cycle-associated genes was detected. These findings suggest that recombinant human GH has a direct anti-apoptotic activity in hematopoietic CD34+ cells derived from GHD subjects in course of GH-TS. Full article
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Open AccessArticle A Systems Biological View of Life-and-Death Decision with Respect to Endoplasmic Reticulum Stress—The Role of PERK Pathway
Int. J. Mol. Sci. 2017, 18(1), 58; https://doi.org/10.3390/ijms18010058
Received: 30 September 2016 / Revised: 6 December 2016 / Accepted: 19 December 2016 / Published: 5 January 2017
Cited by 1 | PDF Full-text (3618 KB) | HTML Full-text | XML Full-text
Abstract
Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role
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Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try to drive back the system to the former or a new homeostatic state by self-eating dependent autophagy, while excessive level of ER stress results in apoptotic cell death. Our study focuses on the role of PERK- and IRE-1-induced arms of UPR in life-or-death decision. Here we confirm that silencing of PERK extends autophagy-dependent survival, whereas the IRE-1-controlled apoptosis inducer is downregulated during ER stress. We also claim that the proper order of surviving and self-killing mechanisms is controlled by a positive feedback loop between PERK and IRE-1 branches. This regulatory network makes possible a smooth, continuous activation of autophagy with respect to ER stress, while the induction of apoptosis is irreversible and switch-like. Using our knowledge of molecular biological techniques and systems biological tools we give a qualitative description about the dynamical behavior of PERK- and IRE-1-controlled life-or-death decision. Our model claims that the two arms of UPR accomplish an altered upregulation of autophagy and apoptosis inducers during ER stress. Since ER stress is tightly connected to aging and age-related degenerative disorders, studying the signaling pathways of UPR and their role in maintaining ER proteostasis have medical importance. Full article
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Open AccessReview Cancer Therapy Due to Apoptosis: Galectin-9
Int. J. Mol. Sci. 2017, 18(1), 74; https://doi.org/10.3390/ijms18010074
Received: 22 September 2016 / Revised: 25 November 2016 / Accepted: 27 December 2016 / Published: 1 January 2017
Cited by 9 | PDF Full-text (1855 KB) | HTML Full-text | XML Full-text
Abstract
Dysregulation of apoptosis is a major hallmark in cancer biology that might equip tumors with a higher malignant potential and chemoresistance. The anti-cancer activities of lectin, defined as a carbohydrate-binding protein that is not an enzyme or antibody, have been investigated for over
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Dysregulation of apoptosis is a major hallmark in cancer biology that might equip tumors with a higher malignant potential and chemoresistance. The anti-cancer activities of lectin, defined as a carbohydrate-binding protein that is not an enzyme or antibody, have been investigated for over a century. Recently, galectin-9, which has two distinct carbohydrate recognition domains connected by a linker peptide, was noted to induce apoptosis in thymocytes and immune cells. The apoptosis of these cells contributes to the development and regulation of acquired immunity. Furthermore, human recombinant galectin-9, hG9NC (null), which lacks an entire region of the linker peptide, was designed to resist proteolysis. The hG9NC (null) has demonstrated anti-cancer activities, including inducing apoptosis in hematological, dermatological and gastrointestinal malignancies. In this review, the molecular characteristics, history and apoptosis-inducing potential of galectin-9 are described. Full article
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Open AccessReview Cancer’s Achilles’ Heel: Apoptosis and Necroptosis to the Rescue
Int. J. Mol. Sci. 2017, 18(1), 23; https://doi.org/10.3390/ijms18010023
Received: 7 November 2016 / Revised: 5 December 2016 / Accepted: 19 December 2016 / Published: 23 December 2016
Cited by 9 | PDF Full-text (1640 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis, and the more recently discovered necroptosis, are two avenues of programmed cell death. Cancer cells survive by evading these two programs, driven by oncogenes and tumor suppressor genes. While traditional therapy using small molecular inhibitors and chemotherapy are continuously being utilized, a
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Apoptosis, and the more recently discovered necroptosis, are two avenues of programmed cell death. Cancer cells survive by evading these two programs, driven by oncogenes and tumor suppressor genes. While traditional therapy using small molecular inhibitors and chemotherapy are continuously being utilized, a new and exciting approach is actively underway by identifying and using synergistic relationship between driver and rescue genes in a cancer cell. Through these synthetic lethal relationships, we are gaining tremendous insights into tumor vulnerabilities and specific molecular avenues for induction of programmed cell death. In this review, we briefly discuss the two cell death processes and cite examples of such synergistic manipulations for therapeutic purposes. Full article
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Open AccessCommunication Patterns of Apoptosis and Proliferation throughout the Biennial Reproductive Cycle of Viviparous Female Typhlonectes compressicauda (Amphibia, Gymnophiona)
Int. J. Mol. Sci. 2017, 18(1), 16; https://doi.org/10.3390/ijms18010016
Received: 20 September 2016 / Revised: 8 December 2016 / Accepted: 15 December 2016 / Published: 22 December 2016
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Abstract
Typhlonectes compressicauda is an aquatic gymnophionan amphibian living in South America. Its breeding cycle is linked to seasons, characterized by a regular alternation of rainy and dry seasons. During a complex biennial cycle, the female genital tract undergoes a series of alternations of
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Typhlonectes compressicauda is an aquatic gymnophionan amphibian living in South America. Its breeding cycle is linked to seasons, characterized by a regular alternation of rainy and dry seasons. During a complex biennial cycle, the female genital tract undergoes a series of alternations of increasing and decreasing, governed by equilibrium of proliferation and apoptotic phenomena. Immunohistochemical methods were used to visualize cell proliferation with the detection of Ki67 antibody, a protein present in proliferative cells; terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Apostain were performed to detect apoptotic cells on sections of ovaries and oviducts. In ovaries, both phenomena affect the germinal nests and follicles according to the cycle period. In the oviduct, the balance was in favor of proliferation during preparation for reproduction, and in favor of apoptosis when genital ducts regress. Apoptosis and proliferation are narrowly implicated in the remodeling of the genital tract and they are accompanied by the differentiation of tissues according to the phase of the breeding cycle. These variations permit the capture of oocytes at ovulation, always at the same period, and the parturition after 6–7 months of gestation, at a period in which the newborns live with their mother, protected in burrows in the mud. During the intervening year of sexual inactivity, the female reconstitutes body reserves. Full article
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Open AccessArticle CD11c+ CD8+ T Cells Reduce Renal Fibrosis Following Ureteric Obstruction by Inducing Fibroblast Apoptosis
Int. J. Mol. Sci. 2017, 18(1), 1; https://doi.org/10.3390/ijms18010001
Received: 10 October 2016 / Revised: 5 December 2016 / Accepted: 11 December 2016 / Published: 22 December 2016
Cited by 14 | PDF Full-text (4750 KB) | HTML Full-text | XML Full-text
Abstract
Tubulointerstitial fibrosis is a common consequence of various kidney diseases that lead to end-stage renal failure, and lymphocyte infiltration plays an important role in renal fibrosis. We previously found that depletion of cluster of differentiation 8+ (CD8+) T cells increases
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Tubulointerstitial fibrosis is a common consequence of various kidney diseases that lead to end-stage renal failure, and lymphocyte infiltration plays an important role in renal fibrosis. We previously found that depletion of cluster of differentiation 8+ (CD8+) T cells increases renal fibrosis following ureteric obstruction, and interferon-γ (IFN-γ)-expressing CD8+ T cells contribute to this process. CD8+ T cells are cytotoxic T cells; however, whether their cytotoxic effect reduces fibrosis remains unknown. This study showed that CD8+ T cells isolated from obstructed kidney showed mRNA expression of the cytotoxicity-related genes perforin 1, granzyme A, granzyme B, and FAS ligand; additionally, CD8 knockout significantly reduced the expression levels of these genes in obstructed kidney. Infiltrated CD8+ T cells were distributed around fibroblasts, and they are associated with fibroblast apoptosis in obstructed kidney. Moreover, CD11c+ CD8+ T cells expressed higher levels of the cytotoxicity-related genes than CD11c CD8+ T cells, and infiltrated CD11c+ CD8+ T cells in obstructed kidney could induce fibroblast death in vitro. Results indicated that induction of fibroblast apoptosis partly contributed to the effect of CD8+ T cells on reduction of renal fibrosis. Given that inflammatory cells are involved in fibrosis, our results suggest that kidney fibrosis is a multifactorial process involving different arms of the immune system. Full article
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Open AccessReview Apoptosis in Cellular Society: Communication between Apoptotic Cells and Their Neighbors
Int. J. Mol. Sci. 2016, 17(12), 2144; https://doi.org/10.3390/ijms17122144
Received: 2 November 2016 / Revised: 7 December 2016 / Accepted: 15 December 2016 / Published: 20 December 2016
Cited by 7 | PDF Full-text (1370 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors
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Apoptosis is one of the cell-intrinsic suicide programs and is an essential cellular behavior for animal development and homeostasis. Traditionally, apoptosis has been regarded as a cell-autonomous phenomenon. However, recent in vivo genetic studies have revealed that apoptotic cells actively influence the behaviors of surrounding cells, including engulfment, proliferation, and production of mechanical forces. Such interactions can be bidirectional, and apoptosis is non-autonomously induced in a cellular community. Of note, it is becoming evident that active communication between apoptotic cells and living cells contributes to physiological processes during tissue remodeling, regeneration, and morphogenesis. In this review, we focus on the mutual interactions between apoptotic cells and their neighbors in cellular society and discuss issues relevant to future studies of apoptosis. Full article
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Open AccessReview Differential Impacts of Alternative Splicing Networks on Apoptosis
Int. J. Mol. Sci. 2016, 17(12), 2097; https://doi.org/10.3390/ijms17122097
Received: 14 October 2016 / Revised: 26 November 2016 / Accepted: 2 December 2016 / Published: 14 December 2016
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Abstract
Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The
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Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases. Full article
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Open AccessReview Cell Death in Chondrocytes, Osteoblasts, and Osteocytes
Int. J. Mol. Sci. 2016, 17(12), 2045; https://doi.org/10.3390/ijms17122045
Received: 14 July 2016 / Revised: 13 November 2016 / Accepted: 23 November 2016 / Published: 6 December 2016
Cited by 12 | PDF Full-text (2721 KB) | HTML Full-text | XML Full-text
Abstract
Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation
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Cell death in skeletal component cells, including chondrocytes, osteoblasts, and osteocytes, plays roles in skeletal development, maintenance, and repair as well as in the pathogenesis of osteoarthritis and osteoporosis. Chondrocyte proliferation, differentiation, and apoptosis are important steps for endochondral ossification. Although the inactivation of P53 and RB is involved in the pathogenesis of osteosarcomas, the deletion of p53 and inactivation of Rb are insufficient to enhance chondrocyte proliferation, indicating the presence of multiple inhibitory mechanisms against sarcomagenesis in chondrocytes. The inflammatory processes induced by mechanical injury and chondrocyte death through the release of danger-associated molecular patterns (DAMPs) are involved in the pathogenesis of posttraumatic osteoarthritis. The overexpression of BCLXL increases bone volume with a normal structure and maintains bone during aging by inhibiting osteoblast apoptosis. p53 inhibits osteoblast proliferation and enhances osteoblast apoptosis, thereby reducing bone formation, but also exerts positive effects on osteoblast differentiation through the Akt–FoxOs pathway. Apoptotic osteocytes release ATP, which induces the receptor activator of nuclear factor κ-B ligand (Rankl) expression and osteoclastogenesis, from pannexin 1 channels. Osteocyte death ultimately results in necrosis; DAMPs are released to the bone surface and promote the production of proinflammatory cytokines, which induce Rankl expression, and osteoclastogenesis is further enhanced. Full article
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Open AccessArticle The Coexistence of Hypertension and Ovariectomy Additively Increases Cardiac Apoptosis
Int. J. Mol. Sci. 2016, 17(12), 2036; https://doi.org/10.3390/ijms17122036
Received: 26 October 2016 / Revised: 23 November 2016 / Accepted: 30 November 2016 / Published: 6 December 2016
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Abstract
To investigate whether the coexistence of hypertension and ovariectomy will increase cardiac Fas receptor and mitochondrial-dependent apoptotic pathways, histopathological analysis, the TUNEL assay and Western blotting were performed on the excised hearts from three groups of female spontaneously hypertensive rats (SHR), which were
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To investigate whether the coexistence of hypertension and ovariectomy will increase cardiac Fas receptor and mitochondrial-dependent apoptotic pathways, histopathological analysis, the TUNEL assay and Western blotting were performed on the excised hearts from three groups of female spontaneously hypertensive rats (SHR), which were divided into a sham-operated group (SHR-Sham), bilaterally ovariectomized group (SHR-OVX) and normotensive Wistar Kyoto rats (WKY). Compared with the WKY group, the SHR-Sham group exhibited decreased protein levels of ERα, ERβ, p-Akt/Akt, Bcl-2, Bcl-xL and p-Bad and decreased further in the SHR-OVX group, as well as protein levels of t-Bid, Bak, Bad, Bax, cytochrome c, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptosis) increased in the SHR-Sham group and increased further in the SHR-OVX group. Compared with the WKY group, protein levels of Fas ligand, TNF-α, Fas death receptors, TNFR1, FADD and activated caspase-8 (Fas receptor-dependent apoptosis) increased in the SHR-Sham group, but did not increase in the SHR-OVX group, except Fas ligand and TNF-α. The coexistence of hypertension and ovariectomy attenuated the estrogen receptor survival pathway and appeared to additively increase the cardiac mitochondria-dependent, but not the Fas receptor-dependent apoptosis pathway, which might provide one possible mechanism for the development of cardiac abnormalities in hypertensive postmenopausal women. Full article
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Open AccessArticle Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines
Int. J. Mol. Sci. 2016, 17(12), 1995; https://doi.org/10.3390/ijms17121995
Received: 7 July 2016 / Revised: 11 October 2016 / Accepted: 23 November 2016 / Published: 29 November 2016
Cited by 6 | PDF Full-text (5471 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their
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Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO) nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs) and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2) and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS), mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM) for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells. Full article
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Open AccessArticle The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death
Int. J. Mol. Sci. 2016, 17(11), 1939; https://doi.org/10.3390/ijms17111939
Received: 22 August 2016 / Revised: 12 October 2016 / Accepted: 14 November 2016 / Published: 21 November 2016
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Abstract
Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in
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Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK. We found that dCK could decrease IR-induced total cell death and apoptosis. Moreover, dCK increased IR-induced autophagy and dCK-S74 is required for it. Western blotting showed that the ratio of phospho-Akt/Akt, phospho-mTOR/mTOR, phospho-P70S6K/P70S6K significantly decreased in dCK-WT and dCK-S74E cells than that in dCK-S74A cells following IR treatment. Reciprocal experiment by co-immunoprecipitation showed that mTOR can interact with wild-type dCK. IR increased polyploidy and decreased G2/M arrest in dCK knock-down cells as compared with control cells. Taken together, phosphorylated and activated dCK can inhibit IR-induced cell death including apoptosis and mitotic catastrophe, and promote IR-induced autophagy through PI3K/Akt/mTOR pathway. Full article
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Open AccessArticle Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway
Int. J. Mol. Sci. 2016, 17(11), 1832; https://doi.org/10.3390/ijms17111832
Received: 29 July 2016 / Revised: 14 October 2016 / Accepted: 27 October 2016 / Published: 2 November 2016
Cited by 7 | PDF Full-text (3633 KB) | HTML Full-text | XML Full-text
Abstract
The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical
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The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical cancer remains unknown. In this study, HeLa cells were used as a testing model for the treatment of IFN-α on cervical cancer. The results indicate that IFN-α markedly inhibits the proliferation and induces the apoptosis of HeLa cells. The activation of caspase 3, the up-regulation of both Bim and cleaved poly (ADP-ribose) polymerase (PARP) 1, the down-regulation of Bcl-xL, as well as the release of cytochrome c from mitochondria were significantly induced upon IFN-α treatment, indicating that the intrinsic apoptotic pathway could be activated by IFN-α treatment. In addition, caspase 4—which is involved in the endoplasmic reticulum (ER) stress-induced apoptosis—was activated in response to IFN-α treatment. Knocking down caspase 4 by small interfering RNA (siRNA) markedly reduced the IFN-α-mediated cell apoptosis. However, no significant changes in the expressions of caspases 8 and 10 were observed upon IFN-α treatment, indicating that the apoptosis caused by IFN-α might be independent of the extrinsic apoptotic pathway. These findings suggest that IFN-α may possess anti-cervical cancer capacity by activating cell apoptosis via the intrinsic mitochondrial pathway and caspase-4-related ER stress-induced pathway. Full article
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Open AccessArticle Cx43 Mediates Resistance against MPP+-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells via Modulating the Mitochondrial Apoptosis Pathway
Int. J. Mol. Sci. 2016, 17(11), 1819; https://doi.org/10.3390/ijms17111819
Received: 8 September 2016 / Revised: 13 October 2016 / Accepted: 25 October 2016 / Published: 1 November 2016
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Abstract
Neuronal apoptosis in the substantia nigra par compacta (SNpc) appears to play an essential role in the pathogenesis of Parkinson’s disease. However, the mechanisms responsible for the death of dopaminergic neurons are not fully understood yet. To explore the apoptotic mechanisms, we used
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Neuronal apoptosis in the substantia nigra par compacta (SNpc) appears to play an essential role in the pathogenesis of Parkinson’s disease. However, the mechanisms responsible for the death of dopaminergic neurons are not fully understood yet. To explore the apoptotic mechanisms, we used a well-known parkinsonian toxin, 1-methyl-4-phenylpyridine (MPP+), to induce neuronal apoptosis in the human dopaminergic SH-SY5Y cell line. The most common method of interaction between cells is gap junctional intercellular communication (GJIC) mediated by gap junctions (GJs) formed by transmembrane proteins called connexins (Cx). Modulation of GJIC affects cell viability or growth, implying that GJIC may have an important role in maintaining homeostasis in various organs. Here, we hypothesized that increasing the level of the gap junction protein Cx43 in SH-SY5Y neuroblastoma cells could provide neuroprotection. First, our experiments demonstrated that knocking down Cx43 protein by using Cx43-specific shRNA in SH-SY5Y neuroblastoma cells potentiated MPP+-induced neuronal apoptosis evident from decreased cell viability. In another experiment, we demonstrated that over-expression of Cx43 in the SH-SY5Y cell system decreased MPP+-induced apoptosis based on the MTT assay and reduced the Bax/Bcl-2 ratio and the release of cytochrome C based on Western blot analysis. Taken together, our results suggest that Cx43 could mediate resistance against MPP+-induced apoptosis in SH-SY5Y neuroblastoma cells via modulating the mitochondrial apoptosis pathway. Full article
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Open AccessReview Neuroglobin, a Factor Playing for Nerve Cell Survival
Int. J. Mol. Sci. 2016, 17(11), 1817; https://doi.org/10.3390/ijms17111817
Received: 29 August 2016 / Revised: 14 October 2016 / Accepted: 26 October 2016 / Published: 31 October 2016
Cited by 4 | PDF Full-text (1353 KB) | HTML Full-text | XML Full-text
Abstract
Cell death represents the final outcome of several pathological conditions of the central nervous system and available evidence suggests that in both acute injuries and neurodegenerative diseases it is often associated with mitochondrial dysfunction. Thus, the possibility to prevent mitochondrial events involved in
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Cell death represents the final outcome of several pathological conditions of the central nervous system and available evidence suggests that in both acute injuries and neurodegenerative diseases it is often associated with mitochondrial dysfunction. Thus, the possibility to prevent mitochondrial events involved in cell death might represent efficient tools to limit neuronal damage. In recent years, increased attention has been paid to the endogenous protein neuroglobin, since accumulating evidence showed that its high expression was associated with preserved mitochondrial function and to an increased survival of nerve cells in vitro and in vivo in a variety of experimental models of cell insult. The biological and structural features of neuroglobin and the mitochondria-related mechanisms of neuroglobin-induced neuroprotection will be here briefly discussed. In this respect, the inhibition of the intrinsic pathway of apoptosis emerges as a key neuroprotective effect induced by the protein. These findings could open the possibility to develop efficient neuroglobin-mediated therapeutic strategies aimed at minimizing the neuronal cell death occurring in impacting neurological pathologies like stroke and neurodegenerative diseases. Full article
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Open AccessArticle Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)
Int. J. Mol. Sci. 2016, 17(10), 1653; https://doi.org/10.3390/ijms17101653
Received: 5 July 2016 / Revised: 31 August 2016 / Accepted: 9 September 2016 / Published: 18 October 2016
Cited by 6 | PDF Full-text (4729 KB) | HTML Full-text | XML Full-text
Abstract
Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line
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Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPβCD complex leads to cell growth inhibition as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPβCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA)-based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPβCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPβCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future. Full article
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Open AccessReview UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer
Int. J. Mol. Sci. 2016, 17(10), 1724; https://doi.org/10.3390/ijms17101724
Received: 24 August 2016 / Revised: 24 September 2016 / Accepted: 8 October 2016 / Published: 14 October 2016
PDF Full-text (2342 KB) | HTML Full-text | XML Full-text
Abstract
The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of
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The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of UBXD family, the amino-terminal domains are diverse and appear to carry out different roles in a subcellular localization-dependent manner. UBXD proteins are principally associated with the endoplasmic reticulum (ER), where they positively or negatively regulate the ER-associated degradation machinery (ERAD). The distinct protein interaction networks of UBXD proteins allow them to have specific functions independent of the ERAD pathway in a cell type- and tissue context-dependent manner. Recent reports have illustrated that a number of mammalian members of the UBXD family play critical roles in several proliferation and apoptosis pathways dysregulated in selected types of cancer. This review covers recent advances that elucidate the therapeutic potential of selected members of the UBXD family that can contribute to tumor growth. Full article
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Open AccessArticle Induction of Apoptosis in TNF-Treated L929 Cells in the Presence of Necrostatin-1
Int. J. Mol. Sci. 2016, 17(10), 1678; https://doi.org/10.3390/ijms17101678
Received: 3 August 2016 / Revised: 9 September 2016 / Accepted: 27 September 2016 / Published: 7 October 2016
Cited by 4 | PDF Full-text (5721 KB) | HTML Full-text | XML Full-text
Abstract
It has been shown that necroptosis—caspase-independent programmed necrotic cell death—can be induced by treatment with tumor necrosis factor (TNF) in the L929 murine fibrosarcoma cell line, even in the absence of a caspase inhibitor. Although it was reported that necrostatin-1—a specific inhibitor of
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It has been shown that necroptosis—caspase-independent programmed necrotic cell death—can be induced by treatment with tumor necrosis factor (TNF) in the L929 murine fibrosarcoma cell line, even in the absence of a caspase inhibitor. Although it was reported that necrostatin-1—a specific inhibitor of necroptosis—inhibited TNF-induced necroptosis in L929 cells, it has not been elucidated whether the cells eventually die by apoptosis in the presence of necrostatin-1. In this paper, induction of apoptosis was demonstrated in TNF-treated L929 cells in the presence of necrostatin-1. Co-treatment with cycloheximide expedited apoptosis induction in necrostatin-1/TNF-treated L929 cells: typical apoptotic morphological changes, including membrane blebbing and nuclear fragmentation, induction of caspase-3 activity, proteolytic activation of caspases-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) (a well-known substrate of caspase-3) were observed. Moreover, co-treatment with Z-VAD-fmk (a pan-caspase inhibitor) inhibited apoptosis by completely inhibiting caspases, resulting in a shift from apoptosis to necroptosis. In contrast, co-treatment with Z-Asp-CH2-DCB (a caspase inhibitor preferential to caspase-3) inhibited apoptosis without expediting necroptosis. These results indicate that apoptosis can be induced in TNF-treated L929 cells when the cells are protected from necroptosis, and support the notion that partial activation of caspase-8 in the presence of a caspase inhibitor preferential to caspase-3 suppresses both apoptosis and necroptosis. Full article
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Open AccessArticle Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification
Int. J. Mol. Sci. 2016, 17(9), 1567; https://doi.org/10.3390/ijms17091567
Received: 17 May 2016 / Revised: 27 July 2016 / Accepted: 8 September 2016 / Published: 16 September 2016
Cited by 6 | PDF Full-text (3221 KB) | HTML Full-text | XML Full-text
Abstract
Vascular calcification, especially medial artery calcification, is associated with cardiovascular death in patients with diabetes mellitus and chronic kidney disease (CKD). To determine the underlying mechanism of vascular calcification, we have demonstrated in our previous report that advanced glycation end-products (AGEs) stimulated calcium
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Vascular calcification, especially medial artery calcification, is associated with cardiovascular death in patients with diabetes mellitus and chronic kidney disease (CKD). To determine the underlying mechanism of vascular calcification, we have demonstrated in our previous report that advanced glycation end-products (AGEs) stimulated calcium deposition in vascular smooth muscle cells (VSMCs) through excessive oxidative stress and phenotypic transition into osteoblastic cells. Since AGEs can induce apoptosis, in this study we investigated its role on VSMC apoptosis, focusing mainly on the underlying mechanisms. A rat VSMC line (A7r5) was cultured, and treated with glycolaldehyde-derived AGE-bovine serum albumin (AGE3-BSA). Apoptotic cells were identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. To quantify apoptosis, an enzyme-linked immunosorbent assay (ELISA) for histone-complexed DNA fragments was employed. Real-time PCR was performed to determine the mRNA levels. Treatment of A7r5 cells with AGE3-BSA from 100 µg/mL concentration markedly increased apoptosis, which was suppressed by Nox inhibitors. AGE3-BSA significantly increased the mRNA expression of NAD(P)H oxidase components including Nox4 and p22phox, and these findings were confirmed by protein levels using immunofluorescence. Dihydroethidisum assay showed that compared with cBSA, AGE3-BSA increased reactive oxygen species level in A7r5 cells. Furthermore, AGE3-induced apoptosis was significantly inhibited by siRNA-mediated knockdown of Nox4 or p22phox. Double knockdown of Nox4 and p22phox showed a similar inhibitory effect on apoptosis as single gene silencing. Thus, our results demonstrated that NAD(P)H oxidase-derived oxidative stress are involved in AGEs-induced apoptosis of VSMCs. These findings might be important to understand the pathogenesis of vascular calcification in diabetes and CKD. Full article
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Open AccessReview ER Stress-Mediated Signaling: Action Potential and Ca2+ as Key Players
Int. J. Mol. Sci. 2016, 17(9), 1558; https://doi.org/10.3390/ijms17091558
Received: 7 July 2016 / Revised: 6 September 2016 / Accepted: 9 September 2016 / Published: 15 September 2016
Cited by 29 | PDF Full-text (1338 KB) | HTML Full-text | XML Full-text
Abstract
The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order
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The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca2+) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca2+ regulates cell death both at the early and late stages of apoptosis. Severe Ca2+ dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca2+ (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca2+ and action potential in ER stress-mediated apoptosis. Full article
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Open AccessReview Apoptosis in Porcine Pluripotent Cells: From ICM to iPSCs
Int. J. Mol. Sci. 2016, 17(9), 1533; https://doi.org/10.3390/ijms17091533
Received: 4 August 2016 / Revised: 4 August 2016 / Accepted: 8 September 2016 / Published: 12 September 2016
Cited by 1 | PDF Full-text (1068 KB) | HTML Full-text | XML Full-text
Abstract
Pigs have great potential to provide preclinical models for human disease in translational research because of their similarities with humans. In this regard, porcine pluripotent cells, which are able to differentiate into cells of all three primary germ layers, might be a suitable
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Pigs have great potential to provide preclinical models for human disease in translational research because of their similarities with humans. In this regard, porcine pluripotent cells, which are able to differentiate into cells of all three primary germ layers, might be a suitable animal model for further development of regenerative medicine. Here, we describe the current state of knowledge on apoptosis in pluripotent cells including inner cell mass (ICM), epiblast, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Information is focused on the apoptotic phenomenon in pluripotency, maintenance, and differentiation of pluripotent stem cells and reprogramming of somatic cells in pigs. Additionally, this review examines the multiple roles of apoptosis and summarizes recent progress in porcine pluripotent cells. Full article
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Open AccessArticle Melatonin Alleviates Liver Apoptosis in Bile Duct Ligation Young Rats
Int. J. Mol. Sci. 2016, 17(8), 1365; https://doi.org/10.3390/ijms17081365
Received: 6 June 2016 / Revised: 1 August 2016 / Accepted: 15 August 2016 / Published: 20 August 2016
Cited by 2 | PDF Full-text (6107 KB) | HTML Full-text | XML Full-text
Abstract
Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats
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Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats were used: one group received laparotomy (Sham), a second group received BDL for two weeks (BDL), and a third group received BDL and intraperitoneal melatonin (100 mg/day) for two weeks (BDL + M). BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress. In addition, in vitro study showed melatonin exerted its effect mainly through the melatonin 2 receptor (MT2) in HepG2 cells. In conclusion, BDL in young rats caused liver apoptosis. Melatonin rescued the apoptotic changes via the intrinsic pathway, and possibly through the MT2 receptor. Melatonin also reversed ER stress induced by BDL. Full article
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Open AccessReview Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia
Int. J. Mol. Sci. 2016, 17(8), 1311; https://doi.org/10.3390/ijms17081311
Received: 8 July 2016 / Revised: 26 July 2016 / Accepted: 4 August 2016 / Published: 11 August 2016
Cited by 4 | PDF Full-text (747 KB) | HTML Full-text | XML Full-text
Abstract
Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH
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Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targets either the static component of BPH, including finasteride and dutasteride, or the dynamic component of BPH, including α-adrenoceptor antagonists such as tamsulosin and alfuzosin. Both these classes of drugs significantly interfere with the apoptosis machinery. Furthermore, phytotherapic supplements and new drugs may also modulate several molecular steps of apoptosis. Full article
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Open AccessArticle Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells
Int. J. Mol. Sci. 2016, 17(8), 1283; https://doi.org/10.3390/ijms17081283
Received: 17 April 2016 / Revised: 21 July 2016 / Accepted: 27 July 2016 / Published: 6 August 2016
Cited by 7 | PDF Full-text (8270 KB) | HTML Full-text | XML Full-text
Abstract
Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which
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Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2. Full article
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Open AccessArticle Cellular Stress and p53-Associated Apoptosis by Juniperus communis L. Berry Extract Treatment in the Human SH-SY5Y Neuroblastoma Cells
Int. J. Mol. Sci. 2016, 17(7), 1113; https://doi.org/10.3390/ijms17071113
Received: 28 April 2016 / Revised: 27 June 2016 / Accepted: 28 June 2016 / Published: 13 July 2016
Cited by 2 | PDF Full-text (1870 KB) | HTML Full-text | XML Full-text
Abstract
Plant phenolics have shown to activate apoptotic cell death in different tumourigenic cell lines. In this study, we evaluated the effects of juniper berry extract (Juniperus communis L.) on p53 protein, gene expression and DNA fragmentation in human neuroblastoma SH-SY5Y cells. In
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Plant phenolics have shown to activate apoptotic cell death in different tumourigenic cell lines. In this study, we evaluated the effects of juniper berry extract (Juniperus communis L.) on p53 protein, gene expression and DNA fragmentation in human neuroblastoma SH-SY5Y cells. In addition, we analyzed the phenolic composition of the extract. We found that juniper berry extract activated cellular relocalization of p53 and DNA fragmentation-dependent cell death. Differentially expressed genes between treated and non-treated cells were evaluated with the cDNA-RDA (representational difference analysis) method at the early time point of apoptotic process when p53 started to be activated and no caspase activity was detected. Twenty one overexpressed genes related to cellular stress, protein synthesis, cell survival and death were detected. Interestingly, they included endoplasmic reticulum (ER) stress inducer and sensor HSPA5 and other ER stress-related genes CALM2 and YKT6 indicating that ER stress response was involved in juniper berry extract mediated cell death. In composition analysis, we identified and quantified low concentrations of fifteen phenolic compounds. The main groups of them were flavones, flavonols, phenolic acids, flavanol and biflavonoid including glycosides of quercetin, apigenin, isoscutellarein and hypolaetin. It is suggested that juniper berry extract induced the p53-associated apoptosis through the potentiation and synergism by several phenolic compounds. Full article
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Open AccessArticle Differential Apoptosis Radiosensitivity of Neural Progenitors in Adult Mouse Hippocampus
Int. J. Mol. Sci. 2016, 17(6), 970; https://doi.org/10.3390/ijms17060970
Received: 13 May 2016 / Revised: 1 June 2016 / Accepted: 13 June 2016 / Published: 20 June 2016
Cited by 4 | PDF Full-text (5241 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural
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Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation. Full article
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Open AccessReview Mechanism of Action and Applications of Interleukin 24 in Immunotherapy
Int. J. Mol. Sci. 2016, 17(6), 869; https://doi.org/10.3390/ijms17060869
Received: 5 April 2016 / Revised: 23 May 2016 / Accepted: 30 May 2016 / Published: 2 June 2016
Cited by 11 | PDF Full-text (616 KB) | HTML Full-text | XML Full-text
Abstract
Interleukin 24 (IL-24) is an important pleiotropic immunoregulatory cytokine, whose gene is located in human chromosome 1q32-33. IL-24’s signaling pathways have diverse biological functions related to cell differentiation, proliferation, development, apoptosis, and inflammation, placing it at the center of an active area of
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Interleukin 24 (IL-24) is an important pleiotropic immunoregulatory cytokine, whose gene is located in human chromosome 1q32-33. IL-24’s signaling pathways have diverse biological functions related to cell differentiation, proliferation, development, apoptosis, and inflammation, placing it at the center of an active area of research. IL-24 is well known for its apoptotic effect in cancer cells while having no such effect on normal cells. IL-24 can also be secreted by both immune and non-immune cells. Downstream effects of IL-24, after binding to the IL-20 receptor, can occur dependently or independently of the JAK/STAT signal transduction pathway, which is classically involved in cytokine-mediated activities. After exogenous addition of IL-24, apoptosis is induced in tumor cells independently of the JAK/STAT pathway. We have shown that IL-24 binds to Sigma 1 Receptor and this event induces endoplasmic reticulum stress, calcium mobilization, reactive oxygen species generation, p38MAPK activity, and ceramide production. Here we review IL-24’s role in autoimmunity, infectious disease response, wound repair, and vascular disease. Detailed understanding of the pleiotropic roles of IL-24 signaling can assist in the selection of more accurate therapeutic approaches, as well as targeting of appropriate cell types in treatment strategy development, and ultimately achieve desired therapeutic effects. Full article
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Open AccessCommunication Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells
Int. J. Mol. Sci. 2016, 17(4), 558; https://doi.org/10.3390/ijms17040558
Received: 23 February 2016 / Revised: 17 March 2016 / Accepted: 8 April 2016 / Published: 14 April 2016
Cited by 10 | PDF Full-text (1922 KB) | HTML Full-text | XML Full-text
Abstract
Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells
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Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway. Full article
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Open AccessReview Research Advances on Pathways of Nickel-Induced Apoptosis
Int. J. Mol. Sci. 2016, 17(1), 10; https://doi.org/10.3390/ijms17010010
Received: 22 September 2015 / Revised: 15 December 2015 / Accepted: 16 December 2015 / Published: 23 December 2015
Cited by 8 | PDF Full-text (1704 KB) | HTML Full-text | XML Full-text
Abstract
High concentrations of nickel (Ni) are harmful to humans and animals. Ni targets a number of organs and produces multiple toxic effects. Apoptosis is important in Ni-induced toxicity of the kidneys, liver, nerves, and immune system. Apoptotic pathways mediated by reactive oxygen species
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High concentrations of nickel (Ni) are harmful to humans and animals. Ni targets a number of organs and produces multiple toxic effects. Apoptosis is important in Ni-induced toxicity of the kidneys, liver, nerves, and immune system. Apoptotic pathways mediated by reactive oxygen species (ROS), mitochondria, endoplasmic reticulum (ER), Fas, and c-Myc participate in Ni-induced cell apoptosis. However, the exact mechanism of apoptosis caused by Ni is still unclear. Understanding the mechanism of Ni-induced apoptosis may help in designing measures to prevent Ni toxicity. Full article
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Open AccessReview FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP
Int. J. Mol. Sci. 2015, 16(12), 30321-30341; https://doi.org/10.3390/ijms161226232
Received: 10 November 2015 / Revised: 9 December 2015 / Accepted: 11 December 2015 / Published: 18 December 2015
Cited by 23 | PDF Full-text (1713 KB) | HTML Full-text | XML Full-text
Abstract
cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS
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cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR). cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis. Full article
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Open AccessReview Transducer of ERBB2.1 (TOB1) as a Tumor Suppressor: A Mechanistic Perspective
Int. J. Mol. Sci. 2015, 16(12), 29815-29828; https://doi.org/10.3390/ijms161226203
Received: 10 September 2015 / Revised: 22 November 2015 / Accepted: 8 December 2015 / Published: 15 December 2015
Cited by 5 | PDF Full-text (2689 KB) | HTML Full-text | XML Full-text
Abstract
Transducer of ERBB2.1 (TOB1) is a tumor-suppressor protein, which functions as a negative regulator of the receptor tyrosine-kinase ERBB2. As most of the other tumor suppressor proteins, TOB1 is inactivated in many human cancers. Homozygous deletion of TOB1 in mice is reported to
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Transducer of ERBB2.1 (TOB1) is a tumor-suppressor protein, which functions as a negative regulator of the receptor tyrosine-kinase ERBB2. As most of the other tumor suppressor proteins, TOB1 is inactivated in many human cancers. Homozygous deletion of TOB1 in mice is reported to be responsible for cancer development in the lung, liver, and lymph node, whereas the ectopic overexpression of TOB1 shows anti-proliferation, and a decrease in the migration and invasion abilities on cancer cells. Biochemical studies revealed that the anti-proliferative activity of TOB1 involves mRNA deadenylation and is associated with the reduction of both cyclin D1 and cyclin-dependent kinase (CDK) expressions and the induction of CDK inhibitors. Moreover, TOB1 interacts with an oncogenic signaling mediator, β-catenin, and inhibits β-catenin-regulated gene transcription. TOB1 antagonizes the v-akt murine thymoma viral oncogene (AKT) signaling and induces cancer cell apoptosis by activating BCL2-associated X (BAX) protein and inhibiting the BCL-2 and BCL-XL expressions. The tumor-specific overexpression of TOB1 results in the activation of other tumor suppressor proteins, such as mothers against decapentaplegic homolog 4 (SMAD4) and phosphatase and tensin homolog-10 (PTEN), and blocks tumor progression. TOB1-overexpressing cancer cells have limited potential of growing as xenograft tumors in nude mice upon subcutaneous implantation. This review addresses the molecular basis of TOB1 tumor suppressor function with special emphasis on its regulation of intracellular signaling pathways. Full article
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Open AccessReview Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis
Int. J. Mol. Sci. 2015, 16(11), 26035-26054; https://doi.org/10.3390/ijms161125943
Received: 9 August 2015 / Revised: 3 October 2015 / Accepted: 21 October 2015 / Published: 30 October 2015
Cited by 69 | PDF Full-text (698 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states, such as cancer, developmental anomalies and degenerative diseases. Osteoarthritis (OA), the most common chronic joint disease in the elderly population, is
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Apoptosis is a highly-regulated, active process of cell death involved in development, homeostasis and aging. Dysregulation of apoptosis leads to pathological states, such as cancer, developmental anomalies and degenerative diseases. Osteoarthritis (OA), the most common chronic joint disease in the elderly population, is characterized by progressive destruction of articular cartilage, resulting in significant disability. Because articular cartilage depends solely on its resident cells, the chondrocytes, for the maintenance of extracellular matrix, the compromising of chondrocyte function and survival would lead to the failure of the articular cartilage. The role of subchondral bone in the maintenance of proper cartilage matrix has been suggested as well, and it has been proposed that both articular cartilage and subchondral bone interact with each other in the maintenance of articular integrity and physiology. Some investigators include both articular cartilage and subchondral bone as targets for repairing joint degeneration. In late-stage OA, the cartilage becomes hypocellular, often accompanied by lacunar emptying, which has been considered as evidence that chondrocyte death is a central feature in OA progression. Apoptosis clearly occurs in osteoarthritic cartilage; however, the relative contribution of chondrocyte apoptosis in the pathogenesis of OA is difficult to evaluate, and contradictory reports exist on the rate of apoptotic chondrocytes in osteoarthritic cartilage. It is not clear whether chondrocyte apoptosis is the inducer of cartilage degeneration or a byproduct of cartilage destruction. Chondrocyte death and matrix loss may form a vicious cycle, with the progression of one aggravating the other, and the literature reveals that there is a definite correlation between the degree of cartilage damage and chondrocyte apoptosis. Because current treatments for OA act only on symptoms and do not prevent or cure OA, chondrocyte apoptosis would be a valid target to modulate cartilage degeneration. Full article
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Open AccessReview Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approach
Int. J. Mol. Sci. 2015, 16(9), 22830-22855; https://doi.org/10.3390/ijms160922830
Received: 23 August 2015 / Revised: 11 September 2015 / Accepted: 15 September 2015 / Published: 22 September 2015
Cited by 24 | PDF Full-text (1046 KB) | HTML Full-text | XML Full-text
Abstract
Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to
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Glutamine metabolism has been proved to be dysregulated in many cancer cells, and is essential for proliferation of most cancer cells, which makes glutamine an appealing target for cancer therapy. In order to be well used by cells, glutamine must be transported to cells by specific transporters and converted to glutamate by glutaminase. There are currently several drugs that target glutaminase under development or clinical trials. Also, glutamine metabolism restriction has been proved to be effective in inhibiting tumor growth both in vivo and vitro through inducing apoptosis, growth arrest and/or autophagy. Here, we review recent researches about glutamine metabolism in cancer, and cell death induced by targeting glutamine, and their potential roles in cancer therapy. Full article
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Open AccessArticle Curcumol Inhibits Growth and Induces Apoptosis of Colorectal Cancer LoVo Cell Line via IGF-1R and p38 MAPK Pathway
Int. J. Mol. Sci. 2015, 16(8), 19851-19867; https://doi.org/10.3390/ijms160819851
Received: 9 June 2015 / Revised: 27 July 2015 / Accepted: 30 July 2015 / Published: 20 August 2015
Cited by 15 | PDF Full-text (2257 KB) | HTML Full-text | XML Full-text
Abstract
Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its
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Curcumol, isolated from the traditional medical plant Rhizoma Curcumae, is the bioactive component of Zedoary oil, whose potential anti-tumor effect has attracted considerable attention in recent years. Though many researchers have reported curcumol and its bioactivity, the potential molecular mechanism for its anti-cancer effect in colorectal cancer LoVo cells still remains unclear. In the present study, we found that curcumol showed growth inhibition and induced apoptosis of LoVo cells in a dose- and time-dependent manner. The occurrence of its proliferation inhibition and apoptosis came with suppression of IGF-1R expression, and then increased the phosphorylation of p38 mitogen activated protein kinase (MAPK), which might result in a cascade response by inhibiting the CREB survival pathway and finally triggered Bax/Bcl-2 and poly(ADP-ribose) polymerase 1 (PARP-1) apoptosis signals. Moreover, curcumol inhibited colorectal cancer in xenograft models of nude mice. Immunohistochemical and Western blot analysis revealed that curcumol could decrease the expression of ki-67, Bcl-2 as well as CREB1, and increase the expression of Bax and the phosphorylation of p38, which were consistent with our in vitro study. Overall, our in vitro and in vivo data confirmed the anti-cancer activity of curcumol, which was related to a significant inhibition of IGF-1R and activation of p38 MAPKs, indicating that curcumol may be a potential anti-tumor agent for colorectal carcinoma therapy. Full article
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Open AccessArticle MiR-30b Is Involved in the Homocysteine-Induced Apoptosis in Human Coronary Artery Endothelial Cells by Regulating the Expression of Caspase 3
Int. J. Mol. Sci. 2015, 16(8), 17682-17695; https://doi.org/10.3390/ijms160817682
Received: 3 April 2015 / Revised: 20 July 2015 / Accepted: 24 July 2015 / Published: 31 July 2015
Cited by 11 | PDF Full-text (1462 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Homocysteine (Hcy) is an independent risk factor for a variety of cardiovascular diseases, such as coronary heart disease, hypertension, stroke, etc. There is a close relationship between the vascular endothelial cell apoptosis and these diseases. Recent studies have shown homocysteine can induce
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Homocysteine (Hcy) is an independent risk factor for a variety of cardiovascular diseases, such as coronary heart disease, hypertension, stroke, etc. There is a close relationship between the vascular endothelial cell apoptosis and these diseases. Recent studies have shown homocysteine can induce apoptosis in endothelial cells, which may be an important mechanism for the development of theses cardiovascular diseases. Although there are several reports about how the Hcy induces apoptosis in endothelial cells, the exact mechanism is not fully understood. MicroRNAs are small, non-coding RNA. Previous studies have shown that there is a close relationship between several microRNAs and cell apoptosis. However, there are no studies about the role of microRNAs in Hcy-induced apoptosis in endothelial cells so far. In this study, we constructed the model of homocysteine-induced apoptosis in human coronary artery endothelial cells (HCAECs) and found miR-30b was significantly down-regulated by 1 mmol/L Hcy. In addition, overexpression of miR-30b can improve the Hcy-induced apoptosis in HCAECs by downregulating caspase-3 expression. Therefore, miR-30b may play an important role in Hcy-induced apoptosis in endothelial cells. Full article
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Open AccessArticle The Effect of Growth Hormone Administration on the Regulation of Mitochondrial Apoptosis in-Vivo
Int. J. Mol. Sci. 2015, 16(6), 12753-12772; https://doi.org/10.3390/ijms160612753
Received: 24 March 2015 / Revised: 21 May 2015 / Accepted: 29 May 2015 / Published: 5 June 2015
Cited by 6 | PDF Full-text (897 KB) | HTML Full-text | XML Full-text | Supplementary Files
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The purpose of this study was to determine whether recombinant human growth hormone (rhGH) would show any significant effects on the expression of apoptosis regulating proteins in peripheral blood mononuclear cells (PBMCs). Additionally, the potential for post-transcriptional regulation of gene expression by miRNA
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The purpose of this study was to determine whether recombinant human growth hormone (rhGH) would show any significant effects on the expression of apoptosis regulating proteins in peripheral blood mononuclear cells (PBMCs). Additionally, the potential for post-transcriptional regulation of gene expression by miRNA was assessed in two cellular compartments, the cytosol and the mitochondria. Ten male subjects were subcutaneously injected with either rhGH (1 mg) or saline (0.9%) for seven consecutive days in a double-blinded fashion. Blood sampling was undertaken prior to treatment administration and over a period of three weeks following treatment cessation. Bcl-2 and Bak gene and protein expression levels were measured in PBMCs, while attention was also directed to the expression of miR-181a and miR-125b, known translational inhibitors of Bcl-2 and Bak respectively. Results showed that rhGH significantly decreased Bak protein concentrations compared to placebo samples for up to 8 days post treatment. While cytosolic miRNA expression was not found to be significantly affected by rhGH, measurement of the expression of miR-125b in mitochondrial fractions showed a significant down-regulation eight days post-rhGH administration. These findings suggest that rhGH induces short-term anti-apoptotic effects which may be partially mediated through a novel pathway that alters the concentration of mitochondrially-associated miRNAs. Full article
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Open AccessArticle TCF4 Is a Molecular Target of Resveratrol in the Prevention of Colorectal Cancer
Int. J. Mol. Sci. 2015, 16(5), 10411-10425; https://doi.org/10.3390/ijms160510411
Received: 11 December 2014 / Revised: 30 April 2015 / Accepted: 4 May 2015 / Published: 7 May 2015
Cited by 5 | PDF Full-text (1190 KB) | HTML Full-text | XML Full-text
Abstract
The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer.
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The Wnt/β-catenin pathway plays an essential role in the tumorigenesis of colorectal cancer. T-cell factor-4 (TCF4) is a member of the TCF/LEF (lymphoid enhancer factor) family of transcription factors, and dysregulation of β-catenin is decisive for the initiation and progression of colorectal cancer. However, the role of TCF4 in the transcriptional regulation of its target gene remained poorly understood. Resveratrol is a dietary phytoalexin and present in many plants, including grape skin, nuts and fruits. Although resveratrol has been widely implicated in anti-tumorigenic and pro-apoptotic properties in several cancer models, the underlying cellular mechanisms are only partially understood. The current study was performed to elucidate the molecular mechanism of the anti-cancer activity of resveratrol in human colorectal cancer cells. The treatment of resveratrol and other phytochemicals decreased the expression of TCF4. Resveratrol decreases cellular accumulation of exogenously-introduced TCF4 protein, but did not change the TCF4 transcription. The inhibition of proteasomal degradation using MG132 (carbobenzoxy-Leu-Leu-leucinal) and lactacystin ameliorates resveratrol-stimulated down-regulation of TCF4. The half-life of TCF4 was decreased in the cells exposed to resveratrol. Resveratrol increased phosphorylation of TCF4 at serine/threonine residues through ERK (extracellular signal-regulated kinases) and p38-dependent pathways. The TCF4 knockdown decreased TCF/β-catenin-mediated transcriptional activity and sensitized resveratrol-induced apoptosis. The current study provides a new mechanistic link between resveratrol and TCF4 down-regulation and significant benefits for further preclinical and clinical practice. Full article
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Open AccessReview Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate
Int. J. Mol. Sci. 2015, 16(3), 5076-5124; https://doi.org/10.3390/ijms16035076
Received: 20 November 2014 / Revised: 9 February 2015 / Accepted: 12 February 2015 / Published: 5 March 2015
Cited by 18 | PDF Full-text (3152 KB) | HTML Full-text | XML Full-text
Abstract
Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability
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Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed. Full article
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Open AccessReview A Time to Kill: Targeting Apoptosis in Cancer
Int. J. Mol. Sci. 2015, 16(2), 2942-2955; https://doi.org/10.3390/ijms16022942
Received: 12 December 2014 / Revised: 8 January 2015 / Accepted: 23 January 2015 / Published: 28 January 2015
Cited by 73 | PDF Full-text (1001 KB) | HTML Full-text | XML Full-text
Abstract
The process of apoptosis is essential for maintaining the physiologic balance between cell death and cell growth. This complex process is executed by two major pathways that participate in activating an executioner mechanism leading to chromatin disintegration and nuclear fragmentation. Dysregulation of these
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The process of apoptosis is essential for maintaining the physiologic balance between cell death and cell growth. This complex process is executed by two major pathways that participate in activating an executioner mechanism leading to chromatin disintegration and nuclear fragmentation. Dysregulation of these pathways often contributes to cancer development and resistance to cancer therapy. Here, we review the most recent discoveries in apoptosis regulation and possible mechanisms for resensitizing tumor cells to therapy. Full article
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Open AccessReview Lipid Metabolism, Apoptosis and Cancer Therapy
Int. J. Mol. Sci. 2015, 16(1), 924-949; https://doi.org/10.3390/ijms16010924
Received: 8 July 2014 / Accepted: 17 December 2014 / Published: 2 January 2015
Cited by 66 | PDF Full-text (1065 KB) | HTML Full-text | XML Full-text
Abstract
Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved
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Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved in the activation or regulation of different signaling pathways. Lipid metabolism participates in the regulation of many cellular processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, chemotherapy response, and drug resistance. Bioactive lipid molecules promote apoptosis via the intrinsic pathway by modulating mitochondrial membrane permeability and activating different enzymes including caspases. In this review, we discuss recent data in the fields of lipid metabolism, lipid-mediated apoptosis, and cancer therapy. In conclusion, understanding the underlying molecular mechanism of lipid metabolism and the function of different lipid molecules could provide the basis for cancer cell death rationale, discover novel and potential targets, and develop new anticancer drugs for cancer therapy. Full article
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Open AccessArticle Lidocaine Sensitizes the Cytotoxicity of Cisplatin in Breast Cancer Cells via Up-Regulation of RARβ2 and RASSF1A Demethylation
Int. J. Mol. Sci. 2014, 15(12), 23519-23536; https://doi.org/10.3390/ijms151223519
Received: 19 July 2014 / Revised: 26 November 2014 / Accepted: 3 December 2014 / Published: 17 December 2014
Cited by 13 | PDF Full-text (1449 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
It has been reported that lidocaine is toxic to various types of cells. And a recent study has confirmed that lidocaine exerts a demethylation effect and regulates the proliferation of human breast cancer cell lines. To recognize a potential anti-tumor effect of lidocaine,
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It has been reported that lidocaine is toxic to various types of cells. And a recent study has confirmed that lidocaine exerts a demethylation effect and regulates the proliferation of human breast cancer cell lines. To recognize a potential anti-tumor effect of lidocaine, we evaluated the DNA demethylation by lidocaine in human breast cancer lines, MCF-7 and MDA-MB-231 cells, and determined the influence of demethylation on the toxicity to these cells of cisplatin, which is a commonly utilized anti-tumor agent for breast cancer. Results demonstrated that lidocaine promoted a significant global genomic demethylation, and particularly in the promoters of tumor suppressive genes (TSGs), RARβ2 and RASSF1A. Further, the lidocaine treatment increased cisplatin-induced apoptosis and enhanced cisplatin-induced cytotoxicity. The combined treatment with both lidocaine and cisplatin promoted a significantly higher level of MCF-7 cell apoptosis than singular lidocaine or cisplatin treatment. Moreover, the abrogation of RARβ2 or RASSF1A expression inhibited such apoptosis. In conclusion, the present study confirms the demethylation effect of lidocaine in breast cancer cells, and found that the demethylation of RARβ2 and RASSF1A sensitized the cytotoxicity of cisplatin in breast cancer cells. Full article
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Open AccessArticle Inhibition of p53 deSUMOylation Exacerbates Puromycin Aminonucleoside-Induced Apoptosis in Podocytes
Int. J. Mol. Sci. 2014, 15(11), 21314-21330; https://doi.org/10.3390/ijms151121314
Received: 8 September 2014 / Revised: 4 November 2014 / Accepted: 5 November 2014 / Published: 18 November 2014
Cited by 7 | PDF Full-text (4642 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis is a major cause of reduced podocyte numbers, which leads to proteinuria and/or glomerulosclerosis. Emerging evidence has indicated that deSUMOylation, a dynamic post-translational modification that reverses SUMOylation, is involved in the apoptosis of Burkitt’s lymphoma cells and cardiomyocytes; however, the impact of
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Apoptosis is a major cause of reduced podocyte numbers, which leads to proteinuria and/or glomerulosclerosis. Emerging evidence has indicated that deSUMOylation, a dynamic post-translational modification that reverses SUMOylation, is involved in the apoptosis of Burkitt’s lymphoma cells and cardiomyocytes; however, the impact of deSUMOylation on podocyte apoptosis remains unexplored. The p53 protein plays a major role in the pathogenesis of podocyte apoptosis, and p53 can be SUMOylated. Therefore, in the present study, we evaluated the effect of p53 deSUMOylation, which is regulated by sentrin/SUMO-specific protease 1 (SENP1), on podocyte apoptosis. Our results showed that SENP1 deficiency significantly increases puromycin aminonucleoside (PAN)-induced podocyte apoptosis. Moreover, SENP1 knockdown results in the accumulation of SUMOylated p53 protein and the increased expression of the p53 target pro-apoptotic genes, BAX, Noxa and PUMA, in podocytes during PAN stimulation. Thus, SENP1 may be essential for preventing podocyte apoptosis, at least partly through regulating the functions of p53 protein via deSUMOylation. The regulation of deSUMOylation may provide a novel strategy for the treatment of glomerular disorders that involve podocyte apoptosis. Full article
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Open AccessArticle Squamosamide Derivative FLZ Protects Retinal Pigment Epithelium Cells from Oxidative Stress through Activation of Epidermal Growth Factor Receptor (EGFR)-AKT Signaling
Int. J. Mol. Sci. 2014, 15(10), 18762-18775; https://doi.org/10.3390/ijms151018762
Received: 3 June 2014 / Revised: 2 September 2014 / Accepted: 11 September 2014 / Published: 17 October 2014
Cited by 7 | PDF Full-text (1323 KB) | HTML Full-text | XML Full-text
Abstract
Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the
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Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is attributed to age-related macular degeneration (AMD) pathogenesis. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, Annona glabra, has displayed significant cyto-protective activity. In the current study, we explored the pro-survival effect of FLZ in oxidative stressed-RPE cells and studied the underlying signaling mechanisms. Our results showed that FLZ attenuated hydrogen peroxide (H2O2)-induced viability decrease and apoptosis in the RPE cell line (ARPE-19 cells) and in primary mouse RPE cells. Western blotting results showed that FLZ activated AKT signaling in RPE cells. The AKT-specific inhibitor, MK-2206, the phosphoinositide 3-kinase (PI3K)/AKT pan inhibitor, wortmannin, and AKT1-shRNA (short hairpin RNA) depletion almost abolished FLZ-mediated pro-survival/anti-apoptosis activity. We discovered that epidermal growth factor receptor (EGFR) trans-activation mediated FLZ-induced AKT activation and the pro-survival effect in RPE cells, and the anti-apoptosis effect of FLZ against H2O2 was inhibited by the EGFR inhibitor, PD153035, or by EGFR shRNA-knockdown. In conclusion, FLZ protects RPE cells from oxidative stress through activation of EGFR-AKT signaling, and our results suggest that FLZ might have therapeutic values for AMD. Full article
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Open AccessReview Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System
Int. J. Mol. Sci. 2014, 15(10), 18557-18573; https://doi.org/10.3390/ijms151018557
Received: 27 August 2014 / Revised: 30 September 2014 / Accepted: 2 October 2014 / Published: 14 October 2014
Cited by 11 | PDF Full-text (970 KB) | HTML Full-text | XML Full-text
Abstract
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of
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The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients. Full article
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Open AccessArticle Curcumin-Induced Heme Oxygenase-1 Expression Prevents H2O2-Induced Cell Death in Wild Type and Heme Oxygenase-2 Knockout Adipose-Derived Mesenchymal Stem Cells
Int. J. Mol. Sci. 2014, 15(10), 17974-17999; https://doi.org/10.3390/ijms151017974
Received: 11 June 2014 / Revised: 11 September 2014 / Accepted: 23 September 2014 / Published: 8 October 2014
Cited by 14 | PDF Full-text (2086 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and
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Mesenchymal stem cell (MSC) administration is a promising adjuvant therapy to treat tissue injury. However, MSC survival after administration is often hampered by oxidative stress at the site of injury. Heme oxygenase (HO) generates the cytoprotective effector molecules biliverdin/bilirubin, carbon monoxide (CO) and iron/ferritin by breaking down heme. Since HO-activity mediates anti-apoptotic, anti-inflammatory, and anti-oxidative effects, we hypothesized that modulation of the HO-system affects MSC survival. Adipose-derived MSCs (ASCs) from wild type (WT) and HO-2 knockout (KO) mice were isolated and characterized with respect to ASC marker expression. In order to analyze potential modulatory effects of the HO-system on ASC survival, WT and HO-2 KO ASCs were pre-treated with HO-activity modulators, or downstream effector molecules biliverdin, bilirubin, and CO before co-exposure of ASCs to a toxic dose of H2O2. Surprisingly, sensitivity to H2O2-mediated cell death was similar in WT and HO-2 KO ASCs. However, pre-induction of HO-1 expression using curcumin increased ASC survival after H2O2 exposure in both WT and HO-2 KO ASCs. Simultaneous inhibition of HO-activity resulted in loss of curcumin-mediated protection. Co-treatment with glutathione precursor N-Acetylcysteine promoted ASC survival. However, co-incubation with HO-effector molecules bilirubin and biliverdin did not rescue from H2O2-mediated cell death, whereas co-exposure to CO-releasing molecules-2 (CORM-2) significantly increased cell survival, independently from HO-2 expression. Summarizing, our results show that curcumin protects via an HO-1 dependent mechanism against H2O2-mediated apoptosis, and likely through the generation of CO. HO-1 pre-induction or administration of CORMs may thus form an attractive strategy to improve MSC therapy. Full article
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Open AccessArticle Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression
Int. J. Mol. Sci. 2014, 15(8), 14298-14312; https://doi.org/10.3390/ijms150814298
Received: 31 May 2014 / Revised: 14 July 2014 / Accepted: 23 July 2014 / Published: 15 August 2014
Cited by 13 | PDF Full-text (2518 KB) | HTML Full-text | XML Full-text
Abstract
Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART), a traditional Chinese medicine, on inducing apoptosis of
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Bladder cancer is the most common malignant tumor of the urinary tract and remains one of the major causes of cancer death worldwide. In this study, we investigated the effect and mechanism of Artesunate (ART), a traditional Chinese medicine, on inducing apoptosis of human bladder cancer cells. In vivo antitumor activity was investigated in bladder cancer in rat by subcutaneous injection of different concentration of ART. The effect of ART on growth inhibition and apoptosis of bladder cancer cells was evaluated using dimethylthiazoly-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. Cyclooxygenase-2 (COX-2) and miR-16 expression levels were determined with real-time PCR. The concentrations of prostaglandin E2 (PGE2) in the supernatants of bladder cancer cells were measured with an ELISA kit. The miR-16 inhibitor or mimic were transfected into cells to up- or down-regulate miR-16 expression. ART efficiently inhibited orthotopic tumor growth in the bladder cancer rat, which is accompanied with an increase of miR-16 expression and a decrease of COX-2 expression. In vitro, ART could induce cytotoxicity and apoptosis in bladder cancer cells, but presented a much lighter toxicity effect against normal human urothelial cells. ART significantly increased miR-16 expression and decreased the expression of COX-2 and the production of PGE2. More importantly, down-regulation of miR-16 expression could reverse the effect of ART on apoptosis and COX-2 expression in bladder cells. Moreover, exogenous PGE2 could inhibit apoptosis of bladder cancer cells treated with ART. In conclusion, ART can elicit an anti-tumor effect against bladder cancer by up-regulation of miR-16 expression, which resulted in the decrease of COX-2 expression and PGE2 production. Hence, ART might be an effective drug for the treatment of bladder cancer. Full article
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Open AccessArticle Rapamycin-Induced Apoptosis in HGF-Stimulated Lens Epithelial Cells by AKT/mTOR, ERK and JAK2/STAT3 Pathways
Int. J. Mol. Sci. 2014, 15(8), 13833-13848; https://doi.org/10.3390/ijms150813833
Received: 12 May 2014 / Revised: 25 July 2014 / Accepted: 26 July 2014 / Published: 11 August 2014
Cited by 13 | PDF Full-text (2475 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocyte growth factor (HGF) induced the proliferation of lens epithelial cells (LECs) and may be a major cause of posterior capsule opacification (PCO), which is the most frequent postoperative complication of cataract surgery. To date, several agents that can block LECs proliferation have
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Hepatocyte growth factor (HGF) induced the proliferation of lens epithelial cells (LECs) and may be a major cause of posterior capsule opacification (PCO), which is the most frequent postoperative complication of cataract surgery. To date, several agents that can block LECs proliferation have been studied, but none have been used in clinic. Recently, accumulating evidence has suggested rapamycin, the inhibitor of mTOR (mammalian target of Rapamycin), was associated with the induction of apoptosis in LECs. The purpose of our study was to investigate the potential effects of rapamycin on HGF-induced LECs and the underlying mechanisms by which rapamycin exerted its actions. Using cell proliferation, cell viability and flow cytometric apoptosis assays, we found that rapamycin potently not only suppressed proliferation but also induced the apoptosis of LECs in a dose-dependent manner under HGF administration. Further investigation of the underlying mechanism using siRNA transfection revealed that rapamycin could promote apoptosis of LECs via inhibiting HGF-induced phosphorylation of AKT/mTOR, ERK and JAK2/STAT3 signaling molecules. Moreover, the forced expression of AKT, ERK and STAT3 could induce a significant suppression of apoptosis in these cells after treatment of rapamycin. Together, these findings suggested that rapamycin-induced apoptosis in HGF-stimulated LECs is accompanied by inhibition of AKT/mTOR, ERK and JAK2/STAT3 pathways, which supports its use to inhibit PCO in preclinical studies and provides theoretical foundation for future possible practice. Full article
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Open AccessReview Cytotoxic Autophagy in Cancer Therapy
Int. J. Mol. Sci. 2014, 15(6), 10034-10051; https://doi.org/10.3390/ijms150610034
Received: 3 April 2014 / Revised: 17 April 2014 / Accepted: 19 May 2014 / Published: 5 June 2014
Cited by 53 | PDF Full-text (553 KB) | HTML Full-text | XML Full-text
Abstract
Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles,
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Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function. Full article
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Open AccessReview Apoptotic Death of Cancer Stem Cells for Cancer Therapy
Int. J. Mol. Sci. 2014, 15(5), 8335-8351; https://doi.org/10.3390/ijms15058335
Received: 24 February 2014 / Revised: 18 April 2014 / Accepted: 18 April 2014 / Published: 12 May 2014
Cited by 29 | PDF Full-text (352 KB) | HTML Full-text | XML Full-text
Abstract
Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with
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Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides. Full article
Open AccessArticle The Role of Survivin in Podocyte Injury Induced by Puromycin Aminonucleoside
Int. J. Mol. Sci. 2014, 15(4), 6657-6673; https://doi.org/10.3390/ijms15046657
Received: 24 January 2014 / Revised: 4 April 2014 / Accepted: 8 April 2014 / Published: 17 April 2014
Cited by 8 | PDF Full-text (2568 KB) | HTML Full-text | XML Full-text
Abstract
Objective: Survivin is a member of the inhibitor of apoptosis protein family, which uniquely promotes mitosis and regulates apoptosis in cancer cells. Recent studies have demonstrated that survivin also expresses in several normal adult cells. In the present study, we aimed to investigate
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Objective: Survivin is a member of the inhibitor of apoptosis protein family, which uniquely promotes mitosis and regulates apoptosis in cancer cells. Recent studies have demonstrated that survivin also expresses in several normal adult cells. In the present study, we aimed to investigate the function of survivin in the terminally differentiated epithelial cells