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Shome I, Thathapudi NC, Aramati BMR, Kowtharapu BS, Jangamreddy JR. Stages, pathogenesis, clinical management and advancements in therapies of age-related macular degeneration. Int Ophthalmol 2023; 43:3891-3909. [PMID: 37347455 DOI: 10.1007/s10792-023-02767-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/08/2023] [Indexed: 06/23/2023]
Abstract
Age-related macular degeneration (AMD) is a retinal degenerative disorder prevalent in the elderly population, which leads to the loss of central vision. The disease progression can be managed, if not prevented, either by blocking neovascularization ("wet" form of AMD) or by preserving retinal pigment epithelium and photoreceptor cells ("dry" form of AMD). Although current therapeutic modalities are moderately successful in delaying the progression and management of the disease, advances over the past years in regenerative medicine using iPSC, embryonic stem cells, advanced materials (including nanomaterials) and organ bio-printing show great prospects in restoring vision and efficient management of either forms of AMD. This review focuses on the molecular mechanism of the disease, model systems (both cellular and animal) used in studying AMD, the list of various regenerative therapies and the current treatments available. The article also highlights on the recent clinical trials using regenerative therapies and management of the disease.
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Affiliation(s)
- Ishita Shome
- UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India
| | - Neethi C Thathapudi
- Centre de Recherche Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada
- Department of Ophthalmology and Institute of Biomedical Engineering, Université de Montréal, Montréal, QC, Canada
| | - Bindu Madhav Reddy Aramati
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India
| | - Bhavani S Kowtharapu
- UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India
| | - Jaganmohan R Jangamreddy
- UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India.
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2
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Targeting autophagy, oxidative stress, and ER stress for neurodegenerative diseases treatment. J Control Release 2022; 345:147-175. [DOI: 10.1016/j.jconrel.2022.03.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/13/2022]
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Rehni AK, Cho S, Dave KR. Ischemic brain injury in diabetes and endoplasmic reticulum stress. Neurochem Int 2022; 152:105219. [PMID: 34736936 PMCID: PMC8918032 DOI: 10.1016/j.neuint.2021.105219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 10/07/2021] [Accepted: 10/29/2021] [Indexed: 01/03/2023]
Abstract
Diabetes is a widespread disease characterized by high blood glucose levels due to abnormal insulin activity, production, or both. Chronic diabetes causes many secondary complications including cardiovascular disease: a life-threatening complication. Cerebral ischemia-related mortality, morbidity, and the extent of brain injury are high in diabetes. However, the mechanism of increase in ischemic brain injury during diabetes is not well understood. Multiple mechanisms mediate diabetic hyperglycemia and hypoglycemia-induced increase in ischemic brain injury. Endoplasmic reticulum (ER) stress mediates both brain injury as well as brain protection after ischemia-reperfusion injury. The pathways of ER stress are modulated during diabetes. Free radical generation and mitochondrial dysfunction, two of the prominent mechanisms that mediate diabetic increase in ischemic brain injury, are known to stimulate the pathways of ER stress. Increased ischemic brain injury in diabetes is accompanied by a further increase in the activation of ER stress. As there are many metabolic changes associated with diabetes, differential activation of the pathways of ER stress may mediate pronounced ischemic brain injury in subjects suffering from diabetes. We presently discuss the literature on the significance of ER stress in mediating increased ischemia-reperfusion injury in diabetes.
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Affiliation(s)
- Ashish K Rehni
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Sunjoo Cho
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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The Role of Caspase-12 in Retinal Bystander Cell Death and Innate Immune Responses against MCMV Retinitis. Int J Mol Sci 2021; 22:ijms22158135. [PMID: 34360899 PMCID: PMC8348425 DOI: 10.3390/ijms22158135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/29/2021] [Accepted: 07/04/2021] [Indexed: 11/25/2022] Open
Abstract
(1) Background: caspase-12 is activated during cytomegalovirus retinitis, although its role is presently unclear. (2) Methods: caspase-12−/− (KO) or caspase-12+/+ (WT) mice were immunosup eyes were analyzed by plaque assay, TUNEL assay, immunohistochemical staining, western blotting, and real-time PCR. (3) Results: increased retinitis and a more extensive virus spread were detected in the retina of infected eyes of KO mice compared to WT mice at day 14 p.i. Compared to MCMV injected WT eyes, mRNA levels of interferons α, β and γ were significantly reduced in the neural retina of MCMV-infected KO eyes at day 14 p.i. Although similar numbers of MCMV infected cells, similar virus titers and similar numbers of TUNEL-staining cells were detected in injected eyes of both KO and WT mice at days 7 and 10 p.i., significantly lower amounts of cleaved caspase-3 and p53 protein were detected in infected eyes of KO mice at both time points. (4) Conclusions: caspase-12 contributes to caspase-3-dependent and independent retinal bystander cell death during MCMV retinitis and may also play an important role in innate immunity against virus infection of the retina.
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Potic J, Mbefo M, Berger A, Nicolas M, Wanner D, Kostic C, Matet A, Behar-Cohen F, Moulin A, Arsenijevic Y. An in vitro Model of Human Retinal Detachment Reveals Successive Death Pathway Activations. Front Neurosci 2020; 14:571293. [PMID: 33324144 PMCID: PMC7726250 DOI: 10.3389/fnins.2020.571293] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/29/2020] [Indexed: 01/30/2023] Open
Abstract
Purpose was to create an in vitro model of human retinal detachment (RD) to study the mechanisms of photoreceptor death. Methods Human retinas were obtained through eye globe donations for research purposes and cultivated as explants. Cell death was investigated in retinas with (control) and without retinal pigment epithelium (RPE) cells to mimic RD. Tissues were studied at different time points and immunohistological analyses for TUNEL, Cleaved caspase3, AIF, CDK4 and the epigenetic mark H3K27me3 were performed. Human and monkey eye globes with retinal detachment served as controls. Results The number of TUNEL-positive cells, compared between 1 and 7 days, increased with time in both retinas with RPE (from 1.2 ± 0.46 to 8 ± 0.89, n = 4) and without RPE (from 2.6 ± 0.73 to 16.3 ± 1.27, p < 0.014). In the group without RPE, cell death peaked at day 3 (p = 0.014) and was high until day 7. Almost no Cleaved-Caspase3 signal was observed, whereas a transient augmentation at day 3 of AIF-positive cells was observed to be about 10-fold in comparison to the control group (n = 2). Few CDK4-positive cells were found in both groups, but significantly more in the RD group at day 7 (1.8 ± 0.24 vs. 4.7 ± 0.58, p = 0.014). The H3K27me3 mark increased by 7-fold after 5 days in the RD group (p = 0.014) and slightly decreased at day 7 and was also observed to be markedly increased in human and monkey detached retina samples. Conclusion AIF expression coincides with the first peak of cell death, whereas the H3K27me3 mark increases during the cell death plateau, suggesting that photoreceptor death is induced by different successive pathways after RD. This in vitro model should permit the identification of neuroprotective drugs with clinical relevance.
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Affiliation(s)
- Jelena Potic
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.,Clinic for Eye Diseases, Clinical Center of Serbia, Belgrade, Serbia.,Department of Ophthalmology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Martial Mbefo
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Adeline Berger
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Michael Nicolas
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Dana Wanner
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Corinne Kostic
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Alexandre Matet
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.,Department of Ophthalmology, Institut Curie, Université de Paris, Paris, France
| | - Francine Behar-Cohen
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland.,INSERM U 1138, Centre de Recherches des Cordeliers, Université Paris Descartes, Université Pierre et Marie Curie, Paris, France
| | - Alexandre Moulin
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - Yvan Arsenijevic
- Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
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Xie RJ, Hu XX, Zheng L, Cai S, Chen YS, Yang Y, Yang T, Han B, Yang Q. Calpain-2 activity promotes aberrant endoplasmic reticulum stress-related apoptosis in hepatocytes. World J Gastroenterol 2020; 26:1450-1462. [PMID: 32308346 PMCID: PMC7152521 DOI: 10.3748/wjg.v26.i13.1450] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/20/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Calpain-2 is a Ca2+-dependent cysteine protease, and high calpain-2 activity can enhance apoptosis mediated by multiple triggers.
AIM To investigate whether calpain-2 can modulate aberrant endoplasmic reticulum (ER) stress-related apoptosis in rat hepatocyte BRL-3A cells.
METHODS BRL-3A cells were treated with varying doses of dithiothreitol (DTT), and their viability and apoptosis were quantified by 3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2-H-tetrazolium bromide and flow cytometry. The expression of ER stress- and apoptosis-related proteins was detected by Western blot analysis. The protease activity of calpain-2 was determined using a fluorescent substrate, N-succinyl-Leu-Leu-Val-Tyr-AMC. Intracellular Ca2+ content, and ER and calpain-2 co-localization were characterized by fluorescent microscopy. The impact of calpain-2 silencing by specific small interfering RNA on caspase-12 activation and apoptosis of BRL-3A cells was quantified.
RESULTS DTT exhibited dose-dependent cytotoxicity against BRL-3A cells and treatment with 2 mmol/L DTT triggered BRL-3A cell apoptosis. DTT treatment significantly upregulated 78 kDa glucose-regulated protein, activating transcription factor 4, C/EBP-homologous protein expression by >2-fold, and enhanced PRKR-like ER kinase phosphorylation, caspase-12 and caspase-3 cleavage in BRL-3A cells in a trend of time-dependence. DTT treatment also significantly increased intracellular Ca2+ content, calpain-2 expression, and activity by >2-fold in BRL-3A cells. Furthermore, immunofluorescence revealed that DTT treatment promoted the ER accumulation of calpain-2. Moreover, calpain-2 silencing to decrease calpain-2 expression by 85% significantly mitigated DTT-enhanced calpain-2 expression, caspase-12 cleavage, and apoptosis in BRL-3A cells.
CONCLUSION The data indicated that Ca2+-dependent calpain-2 activity promoted the aberrant ER stress-related apoptosis of rat hepatocytes by activating caspase-12 in the ER.
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Affiliation(s)
- Ru-Jia Xie
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Xiao-Xia Hu
- Department of Physiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Lu Zheng
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Shuang Cai
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yu-Si Chen
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yi Yang
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Ting Yang
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Bing Han
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Qin Yang
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
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7
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Comitato A, Schiroli D, Montanari M, Marigo V. Calpain Activation Is the Major Cause of Cell Death in Photoreceptors Expressing a Rhodopsin Misfolding Mutation. Mol Neurobiol 2019; 57:589-599. [PMID: 31401765 DOI: 10.1007/s12035-019-01723-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/26/2019] [Indexed: 10/26/2022]
Abstract
The majority of mutations in rhodopsin (RHO) cause misfolding of the protein and has been linked to degeneration of photoreceptor cells in the retina. A lot of attention has been set on targeting ER stress for the development of new therapies for inherited retinal degeneration caused by mutations in the RHO gene. Nevertheless, the cell death pathway activated by RHO misfolded protein is still debated. In this study, we analyzed the retina of the knock-in mouse expressing the P23H misfolded mutant RHO. We found persistent unfolded protein response (UPR) during degeneration. Interestingly, long-term stimulation of the PERK branch of ER stress had a protective effect by phosphorylating nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, associated with antioxidant responses. Otherwise, we provide evidence that increased intracellular calcium and activation of calpains strongly correlated with rod photoreceptor cell death. By blocking calpain activity, we significantly decreased the activation of caspase-7 and apoptosis-inducing factor (AIF), two cell death effectors, and cell demise, and effectively protected the retina from degeneration caused by the P23H dominant mutation in RHO.
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Affiliation(s)
- Antonella Comitato
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 287, 41125, Modena, Italy
| | - Davide Schiroli
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 287, 41125, Modena, Italy
| | - Monica Montanari
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 287, 41125, Modena, Italy
| | - Valeria Marigo
- Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 287, 41125, Modena, Italy.
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8
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Akgun O, Erkisa M, Ari F. Effective and new potent drug combination: Histone deacetylase and Wnt/β-catenin pathway inhibitors in lung carcinoma cells. J Cell Biochem 2019; 120:15467-15482. [PMID: 31037769 DOI: 10.1002/jcb.28813] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/01/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023]
Abstract
Lung cancer is the most commonly diagnosed cancer worldwide with a high mortality rate. In this study, the therapeutic effect of combination valproic acid and niclosamide was investigated on human lung cancer cell line. The effects of the compounds alone and combination therapy on cell viability were determined by sulforhodamine B and adenosine 5'-triphosphate viability assays. Flow cytometry was used to determine the cell death mechanism and DNA damage levels responsible for the cytotoxic effects of combination therapy. The presence of apoptosis in cells was supported by fluorescence microscopy and also by using inhibitors of the apoptotic signaling pathway. The increase in cellular reactive oxygen species (ROS) level in combination therapy was determined by H2DCFDA staining. The effect of N-acetyl-l-cysteine combination on ROS increase was investigated on cell viability. In addition, the expression levels of the proteins associated with epigenetic regulation and cell death were analyzed by Western blotting and gene expression levels were determined using real-time quantitative polymerase chain reaction.It was observed that the combination therapy showed a cytotoxic effect on the A549 lung cancer cells compared to the individual use of the inhibitors. The absence of this effect on normal lung cells revealed the presence of a selective toxic effect. When the mechanism of cytotoxicity is examined, it has been observed that combination therapy initiates the activation of tumor necrosis receptors and causes apoptosis by activated caspase. It was also observed that this extrinsic apoptotic pathway was activated on the mitochondrial pathway. In addition, ER stress and mitochondrial membrane potential loss associated with increased ROS levels induce cell death. When the data in this study were evaluated, combination therapy caused a dramatic decrease in cell viability by inducing the extrinsic apoptotic pathway in lung cancer cell line. Therefore, it was concluded that it can be used as an effective and new treatment option for lung cancer.
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Affiliation(s)
- Oguzhan Akgun
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey
| | - Merve Erkisa
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey.,Department of Clinical Biochemistry, School of Medicine, Istinye University, Istanbul, Turkey
| | - Ferda Ari
- Department of Biology, Science and Art Faculty, Bursa Uludag University, Bursa, Turkey
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9
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Wiberg R, Novikova LN, Kingham PJ. Evaluation of apoptotic pathways in dorsal root ganglion neurons following peripheral nerve injury. Neuroreport 2019; 29:779-785. [PMID: 29659443 DOI: 10.1097/wnr.0000000000001031] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Peripheral nerve injuries induce significant sensory neuronal cell death in the dorsal root ganglia (DRG); however, the role of specific apoptotic pathways is still unclear. In this study, we performed peripheral nerve transection on adult rats, after which the corresponding DRGs were harvested at 7, 14, and 28 days after injury for subsequent molecular analyses with quantitative reverse transcription-PCR, western blotting, and immunohistochemistry. Nerve injury led to increased levels of caspase-3 mRNA and active caspase-3 protein in the DRG. Increased expression of caspase-8, caspase-12, caspase-7, and calpain suggested that both the extrinsic and the endoplasmic reticulum (ER) stress-mediated apoptotic pathways were activated. Phosphorylation of protein kinase R-like ER kinase further implied the involvement of ER-stress in the DRG. Phosphorylated protein kinase R-like ER kinase was most commonly associated with isolectin B4 (IB4)-positive neurons in the DRG and this may provide an explanation for the increased susceptibility of these neurons to die following nerve injury, likely in part because of an activation of the ER-stress response.
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Affiliation(s)
- Rebecca Wiberg
- Department of Integrative Medical Biology, Section of Anatomy.,Department of Surgical & Perioperative Sciences, Section of Hand and Plastic Surgery, Umeå University, Umeå, Sweden
| | | | - Paul J Kingham
- Department of Integrative Medical Biology, Section of Anatomy
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10
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Zhang Y, Xu X, Li W, Miao H, Huang S, Zhou Y, Sun Y, Li Z, Guo Q, Zhao L. Activation of endoplasmic reticulum stress and the extrinsic apoptotic pathway in human lung cancer cells by the new synthetic flavonoid, LZ-205. Oncotarget 2018; 7:87257-87270. [PMID: 27895312 PMCID: PMC5349986 DOI: 10.18632/oncotarget.13535] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 11/02/2016] [Indexed: 01/08/2023] Open
Abstract
It has been shown that flavonoids have anti-tumor activity. In this study, LZ-205, a newly synthesized flavonoid, was found to be effective in inducing apoptosis in human lung cancer cells in vivo and in vitro. Mechanistically, LZ-205 triggers reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress and unfolded protein response, which could be reversed by silencing CHOP, a mediator of the ER stress-associated apoptosis. In addition, LZ-205-induced apoptosis is accompanied by the activation of both the mitochondrial apoptotic and extrinsic pathways, followed by decreased mitochondrial membrane potential (ΔΨm) and the alteration of the expression of mitochondria-related pro- and anti-apoptotic proteins. LZ-205 exhibits a potential antitumor effect in BALB/c nude mice bearing H460 tumor with low systemic toxicity. In summary, both the ROS-mediated ER stress pathway and the exogenous apoptotic pathway are involved in LZ-205-induced apoptosis in vitro and in vivo. Our data show a therapeutic potential of LZ-205 for the treatment of lung cancer.
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Affiliation(s)
- Yi Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Xuefen Xu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Wei Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Hanchi Miao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Shaoliang Huang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Yuxin Zhou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Yang Sun
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Zhiyu Li
- School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Li Zhao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, People's Republic of China
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11
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Souza LRR, da Silva VS, Franchi LP, de Souza TAJ. Toxic and Beneficial Potential of Silver Nanoparticles: The Two Sides of the Same Coin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1048:251-262. [DOI: 10.1007/978-3-319-72041-8_15] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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12
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Djiadeu P, Farmakovski N, Azzouz D, Kotra LP, Sweezey N, Palaniyar N. Surfactant protein D regulates caspase-8-mediated cascade of the intrinsic pathway of apoptosis while promoting bleb formation. Mol Immunol 2017; 92:190-198. [PMID: 29107869 DOI: 10.1016/j.molimm.2017.10.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 10/17/2017] [Accepted: 10/17/2017] [Indexed: 01/10/2023]
Abstract
Surfactant-associated protein D (SP-D) is a soluble innate immune collectin present on many mucosal surfaces. We recently showed that SP-D suppresses the extrinsic pathway of apoptosis by downregulating caspase-8 activation. However, the effects of SP-D on the intrinsic pathway of apoptosis are not clearly understood. In the intrinsic pathway, cytochrome c is released by mitochondria into the cytoplasm. Oxidation of cytochrome c by cytochrome c oxidase activates the apoptosome and caspase-9 cascade. Both caspase-8- and caspase-9-mediated branches are activated in the intrinsic pathway of apoptosis; however, little is known about the relevance of the caspase-8 pathway in this context. Here we studied the effects of SP-D on different branches of the intrinsic pathway of apoptosis using UV-irradiated Jurkat T-cells. We found that SP-D does not inhibit the caspase-9 branch of apoptosis and the relevance of the caspase-8-related branch became apparent when the caspase-9 pathway was inhibited by blocking cytochrome c oxidase. Under these conditions, SP-D reduces the activation of caspase-8, executioner caspase-3 and exposure of phosphatidylserine (PS) on the membranes of dying cells. By contrast, SP-D increases the formation of nuclear and membrane blebs. Inhibition of caspase-8 confirms the effect of SP-D is unique to the caspase-8 pathway. Overall, SP-D suppresses certain aspects of the intrinsic pathway of apoptosis via reduction of caspase-8 activation and PS flipping while at the same time increasing membrane and nuclear bleb formation. This novel regulatory aspect of SP-D could help to regulate intrinsic pathway of apoptosis to promote effective blebbing and breakdown of dying cells.
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Affiliation(s)
- Pascal Djiadeu
- Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada
| | - Nicole Farmakovski
- Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada
| | - Dhia Azzouz
- Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada
| | - Lakshmi P Kotra
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada; Center for Molecular Design and Preformulations, Toronto General Research Institute, University Health Network, 101 College Street, Toronto, Ontario, M5G 1L7, Canada
| | - Neil Sweezey
- Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada; Departments of Paediatrics, Physiology and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5G 1X8, Canada
| | - Nades Palaniyar
- Lung Innate Immunity Research Laboratory, Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada; Departments of Laboratory Medicine and Pathobiology and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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13
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da Silva DC, Andrade PB, Valentão P, Pereira DM. Neurotoxicity of the steroidal alkaloids tomatine and tomatidine is RIP1 kinase- and caspase-independent and involves the eIF2α branch of the endoplasmic reticulum. J Steroid Biochem Mol Biol 2017; 171:178-186. [PMID: 28300624 DOI: 10.1016/j.jsbmb.2017.03.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 02/18/2017] [Accepted: 03/09/2017] [Indexed: 12/29/2022]
Abstract
Steroidal alkaloids are a class of natural products that occur in several species of the Solanaceae family. In the case of the tomato plant (Lycopersicon esculentum Mill.), tomatine and its aglycone, tomatidine, are the most representative molecules. These steroidal alkaloids have already shown several potentially useful biological activities, from anticancer to anti-inflammatory or antibacterial. In this work, the toxicity of these molecules in neuronal cells, namely in the neuroblastoma cell line SH-SY5Y, was assessed, emphasis being given to the cellular mechanisms underlying the effects observed. The results show that tomatine/tomatidine-induced cell death is caspase- and RIP1 kinase-independent, as cell death is not prevented by the pan-caspase inhibitor Z-VAD.fmk or by RIP1 inhibitor necrostatin-1. Analysis of Ca2+ levels using the fluorescent probe Fura-2/AM indicates that both tomatine and tomatidine have a marked effect upon Ca2+ homeostasis by increasing cytosolic Ca2+, an event that might be associated with their effect upon the endoplasmic reticulum. We show that the toxicity of these molecules require the PERK/eIF2α branch of the unfolded protein response, but not the IRE1α branch. Given the role of the endoplasmic reticulum in proteostasis, the ability of these molecules to inhibit the proteasome was also evaluated. Tomatine was able to inhibit the chymotrypsin-like catalytic core of purified human 20S proteasome, as shown by its ability to prevent degradation of the fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC, thus suggesting that interference with proteostasis can be responsible for the toxicity of these steroidal alkaloids. This study is relevant as it sheds a light regarding the toxicity of molecules present in one of the most consumed plants worldwide.
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Affiliation(s)
- Daniela Correia da Silva
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, N° 228, 4050-213 Porto, Portugal
| | - Paula B Andrade
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, N° 228, 4050-213 Porto, Portugal
| | - Patrícia Valentão
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, N° 228, 4050-213 Porto, Portugal
| | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, N° 228, 4050-213 Porto, Portugal.
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14
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Calpain inhibitor attenuates ER stress-induced apoptosis in injured spinal cord after bone mesenchymal stem cells transplantation. Neurochem Int 2016; 97:15-25. [DOI: 10.1016/j.neuint.2016.04.015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 04/09/2016] [Accepted: 04/28/2016] [Indexed: 12/25/2022]
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15
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Nakka VP, Prakash-Babu P, Vemuganti R. Crosstalk Between Endoplasmic Reticulum Stress, Oxidative Stress, and Autophagy: Potential Therapeutic Targets for Acute CNS Injuries. Mol Neurobiol 2016; 53:532-544. [PMID: 25482050 PMCID: PMC4461562 DOI: 10.1007/s12035-014-9029-6] [Citation(s) in RCA: 190] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 11/30/2014] [Indexed: 01/06/2023]
Abstract
Endoplasmic reticulum (ER) stress induces a variety of neuronal cell death pathways that play a critical role in the pathophysiology of stroke. ER stress occurs when unfolded/misfolded proteins accumulate and the folding capacity of ER chaperones exceeds the capacity of ER lumen to facilitate their disposal. As a consequence, a complex set of signaling pathways will be induced that transmit from ER to cytosol and nucleus to compensate damage and to restore the normal cellular homeostasis, collectively known as unfolded protein response (UPR). However, failure of UPR due to severe or prolonged stress leads to cell death. Following acute CNS injuries, chronic disturbances in protein folding and oxidative stress prolong ER stress leading to sustained ER dysfunction and neuronal cell death. While ER stress responses have been well studied after stroke, there is an emerging need to study the association of ER stress with other cell pathways that exacerbate neuronal death after an injury. In this review, we summarize the current understanding of the role for ER stress in acute brain injuries, highlighting the diverse molecular mechanisms associated with ER stress and its relation to oxidative stress and autophagy. We also discussed the existing and developing therapeutic options aimed to reduce ER stress to protect the CNS after acute injuries.
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Affiliation(s)
- Venkata Prasuja Nakka
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53792, USA
- Department of Biotechnology & Bioinformatics, School of Life sciences, University of Hyderabad, Hyderabad, India
| | - Phanithi Prakash-Babu
- Department of Biotechnology & Bioinformatics, School of Life sciences, University of Hyderabad, Hyderabad, India
| | - Raghu Vemuganti
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53792, USA.
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16
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Fernández-Sánchez L, Lax P, Noailles A, Angulo A, Maneu V, Cuenca N. Natural Compounds from Saffron and Bear Bile Prevent Vision Loss and Retinal Degeneration. Molecules 2015; 20:13875-93. [PMID: 26263962 PMCID: PMC6332441 DOI: 10.3390/molecules200813875] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 07/23/2015] [Accepted: 07/28/2015] [Indexed: 12/13/2022] Open
Abstract
All retinal disorders, regardless of their aetiology, involve the activation of oxidative stress and apoptosis pathways. The administration of neuroprotective factors is crucial in all phases of the pathology, even when vision has been completely lost. The retina is one of the most susceptible tissues to reactive oxygen species damage. On the other hand, proper development and functioning of the retina requires a precise balance between the processes of proliferation, differentiation and programmed cell death. The life-or-death decision seems to be the result of a complex balance between pro- and anti-apoptotic signals. It has been recently shown the efficacy of natural products to slow retinal degenerative process through different pathways. In this review, we assess the neuroprotective effect of two compounds used in the ancient pharmacopoeia. On one hand, it has been demonstrated that administration of the saffron constituent safranal to P23H rats, an animal model of retinitis pigmentosa, preserves photoreceptor morphology and number, the capillary network and the visual response. On the other hand, it has been shown that systemic administration of tauroursodeoxycholic acid (TUDCA), the major component of bear bile, to P23H rats preserves cone and rod structure and function, together with their contact with postsynaptic neurons. The neuroprotective effects of safranal and TUDCA make these compounds potentially useful for therapeutic applications in retinal degenerative diseases.
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Affiliation(s)
- Laura Fernández-Sánchez
- Departament of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain.
| | - Pedro Lax
- Departament of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain.
| | - Agustina Noailles
- Departament of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain.
| | - Antonia Angulo
- Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain.
| | - Victoria Maneu
- Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain.
| | - Nicolás Cuenca
- Departament of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain.
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17
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Hashimoto Y, Inagaki H, Hoshino SI. Calpain mediates processing of the translation termination factor eRF3 into the IAP-binding isoform p-eRF3. FEBS Lett 2015; 589:2241-7. [PMID: 26172506 DOI: 10.1016/j.febslet.2015.06.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 06/26/2015] [Accepted: 06/27/2015] [Indexed: 10/23/2022]
Abstract
The involvement of polypeptide chain-releasing factor eRF3 in translation termination and mRNA decay is well established. Moreover, the finding that the proteolytically processed isoform of eRF3 (p-eRF3) interacts with inhibitors of apoptosis proteins (IAPs) to activate caspase, implies that eRF3 is a cell death regulator. However, the protease(s) responsible for p-eRF3 production and how p-eRF3 regulates apoptosis remain unknown. Here, we show that calpain mediates p-eRF3 production in vitro and in living cells. p-eRF3 is produced in cells treated with ER stressors in a calpain-dependent manner. These findings suggest that p-eRF3 is a novel regulator of calpain-dependent cell death.
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Affiliation(s)
- Yoshifumi Hashimoto
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
| | - Hiroto Inagaki
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
| | - Shin-ichi Hoshino
- Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
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18
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Zhu Y, Wang B, Phillips J, Zhang ZN, Du H, Xu T, Huang LC, Zhang XF, Xu GH, Li WL, Wang Z, Wang L, Liu YX, Deng X. Global Transcriptome Analysis Reveals Acclimation-Primed Processes Involved in the Acquisition of Desiccation Tolerance in Boea hygrometrica. PLANT & CELL PHYSIOLOGY 2015; 56:1429-41. [PMID: 25907569 DOI: 10.1093/pcp/pcv059] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 04/14/2015] [Indexed: 05/18/2023]
Abstract
Boea hygrometrica resurrection plants require a period of acclimation by slow soil-drying in order to survive a subsequent period of rapid desiccation. The molecular basis of this observation was investigated by comparing gene expression profiles under different degrees of water deprivation. Transcripts were clustered according to the expression profiles in plants that were air-dried (rapid desiccation), soil-dried (gradual desiccation), rehydrated (acclimated) and air-dried after acclimation. Although phenotypically indistinguishable, it was shown by principal component analysis that the gene expression profiles in rehydrated, acclimated plants resemble those of desiccated plants more closely than those of hydrated acclimated plants. Enrichment analysis based on gene ontology was performed to deconvolute the processes that accompanied desiccation tolerance. Transcripts associated with autophagy and α-tocopherol accumulation were found to be activated in both air-dried, acclimated plants and soil-dried non-acclimated plants. Furthermore, transcripts associated with biosynthesis of ascorbic acid, cell wall catabolism, chaperone-assisted protein folding, respiration and macromolecule catabolism were activated and maintained during soil-drying and rehydration. Based on these findings, we hypothesize that activation of these processes leads to the establishment of an optimal physiological and cellular state that enables tolerance during rapid air-drying. Our study provides a novel insight into the transcriptional regulation of critical priming responses to enable survival following rapid dehydration in B. hygrometrica.
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Affiliation(s)
- Yan Zhu
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China These authors contributed equally to this work
| | - Bo Wang
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China These authors contributed equally to this work
| | - Jonathan Phillips
- IMBIO (Molekulare Physiologie und Biotechnologie der Pflanzen), University of Bonn, Kirschallee 1, D-53115 Bonn, Germany Present address: Monsanto Company, 800 North Lindbergh Blvd, St. Louis, MO 63167, USA
| | - Zhen-Nan Zhang
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Hong Du
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Tao Xu
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Lian-Cheng Huang
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Xiao-Fei Zhang
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Guang-Hui Xu
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Wen-Long Li
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
| | - Zhi Wang
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China Key Laboratory of Plant Molecular Physiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China
| | - Ling Wang
- Shanghai OE Biomedical Technology Co., Ltd., Shanghai 201210, China
| | - Yong-Xiu Liu
- Key Laboratory of Plant Molecular Physiology, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China
| | - Xin Deng
- Key Laboratory of Plant Resources and Beijing Botanical Garden, Institute of Botany, the Chinese Academy of Sciences, Beijing 100093, China
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Ma H, Butler MR, Thapa A, Belcher J, Yang F, Baehr W, Biel M, Michalakis S, Ding XQ. cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice. J Biol Chem 2015; 290:20880-20892. [PMID: 26124274 DOI: 10.1074/jbc.m115.641159] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Indexed: 11/06/2022] Open
Abstract
Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca(2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3(-/-)/Nrl(-/-) mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Müller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca(2+) channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency.
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Affiliation(s)
- Hongwei Ma
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Michael R Butler
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Arjun Thapa
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Josh Belcher
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Fan Yang
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
| | - Wolfgang Baehr
- John A. Moran Eye Center, University of Utah, Salt Lake City, Utah 84132
| | - Martin Biel
- Center for Integrated Protein Science Munich and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Stylianos Michalakis
- Center for Integrated Protein Science Munich and Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Xi-Qin Ding
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
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20
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Salvianolic acid A attenuates TNF-α- and d-GalN-induced ER stress-mediated and mitochondrial-dependent apoptosis by modulating Bax/Bcl-2 ratio and calcium release in hepatocyte LO2 cells. Naunyn Schmiedebergs Arch Pharmacol 2015; 388:817-30. [DOI: 10.1007/s00210-015-1116-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 03/13/2015] [Indexed: 02/07/2023]
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21
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Mayakrishnan T, Nakkala JR, Jeepipalli SPK, Raja K, Khub Chandra V, Mohan VK, Sadras SR. Fenugreek seed extract and its phytocompounds- trigonelline and diosgenin arbitrate their hepatoprotective effects through attenuation of endoplasmic reticulum stress and oxidative stress in type 2 diabetic rats. Eur Food Res Technol 2014. [DOI: 10.1007/s00217-014-2322-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Tharaheswari M, Jayachandra Reddy N, Kumar R, Varshney KC, Kannan M, Sudha Rani S. Trigonelline and diosgenin attenuate ER stress, oxidative stress-mediated damage in pancreas and enhance adipose tissue PPARγ activity in type 2 diabetic rats. Mol Cell Biochem 2014; 396:161-74. [DOI: 10.1007/s11010-014-2152-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 07/11/2014] [Indexed: 12/11/2022]
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Cuenca N, Fernández-Sánchez L, Campello L, Maneu V, De la Villa P, Lax P, Pinilla I. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 2014; 43:17-75. [PMID: 25038518 DOI: 10.1016/j.preteyeres.2014.07.001] [Citation(s) in RCA: 313] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 07/03/2014] [Accepted: 07/07/2014] [Indexed: 01/17/2023]
Abstract
Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.
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Affiliation(s)
- Nicolás Cuenca
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain; Multidisciplinary Institute for Environmental Studies "Ramon Margalef", University of Alicante, Alicante, Spain.
| | - Laura Fernández-Sánchez
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Laura Campello
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Victoria Maneu
- Department of Optics, Pharmacology and Anatomy, University of Alicante, Alicante, Spain
| | - Pedro De la Villa
- Department of Systems Biology, University of Alcalá, Alcalá de Henares, Spain
| | - Pedro Lax
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Isabel Pinilla
- Department of Ophthalmology, Lozano Blesa University Hospital, Aragon Institute of Health Sciences, Zaragoza, Spain
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Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation. J Gastroenterol 2014; 49:727-36. [PMID: 23771404 DOI: 10.1007/s00535-013-0823-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2013] [Accepted: 04/18/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND ATP-sensitive potassium (K-ATP) channels couple cellular metabolism to electric activity. Although Kir6.2-composed K-ATP channel (Kir6.2/K-ATP channel) has been demonstrated to regulate inflammation, a common cause of most liver diseases, its role in liver injury remains elusive. METHODS Kir6.2 knockout mice were used to prepared LPS-induced liver injury model so as to investigate the role of Kir6.2/K-ATP channels in the injury. Histochemistry was applied to evaluate the extent of liver injury. Proinflammatory cytokines were analyzed by ELISA. Endoplasmic reticulum (ER) stress and autophagy were assessed by western blotting. RESULTS We showed that Kir6.2 knockout markedly promoted the infiltration of lymphocytes and neutrophils in liver and significantly elevated serum levels of alanine transaminase (ALT) in respond to LPS treatment. We further found that Kir6.2 deficiency enhanced the activation of NF-κB and NLRP3 inflammasome following LPS challenge, and thereby increased the levels of pro-inflammatory cytokines IL-1β, IL-18 and TNF-α. Treatment of wild-type mice with the K-ATP channel opener iptakalim (IPT) could protect against LPS-induced liver injury through attenuating NLRP3 inflammasome-mediated inflammatory responses. Furthermore, Kir6.2 knockout-induced activation of NLRP3 inflammasome aggravated endoplasmic reticulum (ER) stress, autophagy and subsequent hepatocyte death. CONCLUSION Kir6.2 deficiency exacerbated LPS-induced liver injury by enhancing NLRP3 inflammasome-mediated inflammatory response. Thus, Kir6.2/K-ATP channel may be a potential candidate target for the treatment and prevention of liver injury.
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Zhang M, Liu C, Zhang Z, Yang S, Zhang B, Yin L, Swarts S, Vidyasagar S, Zhang L, Okunieff P. A new flavonoid regulates angiogenesis and reactive oxygen species production. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 812:149-155. [PMID: 24729227 DOI: 10.1007/978-1-4939-0620-8_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The tumor vascular system, which is critical to the survival and growth of solid tumors, has been an attractive target for anticancer research. Building on studies that show that some flavonoids have anticancer vascular effects, we developed and analyzed the flavonoid derivative R24 [3, 6-bis (2-oxiranylmethoxy)-9H-xanthen-9-one]. A CAM assay revealed that R24 disrupted neovascular formation; fewer dendrites were detected and overall dendritic length was shorter in the R24-treated chicken embryos. The antiproliferative effect of R24 was measured by MTT assay in A549 (lung cancer), AsPC-1 (pancreatic cancer), HCT-116 (colorectal cancer), and PC-3 (prostate cancer) cell lines. R24 reduced proliferation with an IC50 of 3.44, 3.59, 1.22, and 11.83 μM, respectively. Cell-cycle analysis and Annexin-V/propidium iodide staining showed that R24 induced apoptosis. In addition, R24 regulated intracellular ROS production in a dose-dependent manner. CM-H2DCFDA staining indicated that intracellular ROS production increased with the R24 dose. In summary, we found that R24 exhibits potent antiangiogenic and antiproliferative effects, induces apoptosis, and promotes ROS production.
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Affiliation(s)
- Mei Zhang
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Chaomei Liu
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Zhenhuan Zhang
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Shanmin Yang
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Bingrong Zhang
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Liangjie Yin
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Steven Swarts
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Sadasivan Vidyasagar
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Lurong Zhang
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA
| | - Paul Okunieff
- Department of Radiation Oncology, University of Florida, Cancer/Genetics Research Complex, 2033 Mowry Road, Suite 145, 103633, Gainesville, FL, 32610, USA.
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Xia P, Qi Y. Cellular inhibitor of apoptosis protein-1 and survival of beta cells undergoing endoplasmic reticulum stress. VITAMINS AND HORMONES 2014; 95:269-98. [PMID: 24559922 DOI: 10.1016/b978-0-12-800174-5.00011-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Pancreatic beta cells rely heavily on the endoplasmic reticulum (ER) to process folding and posttranslational modification of a large amount of insulin and many other proteins and are therefore vulnerable to ER stress. The role of the ER is thus crucial in the regulation of beta cell function and survival through the unfolded protein response (UPR) pathways. However, the UPR can either allow cells to survive by adapting to stress or kill cells through apoptosis in a context-dependent manner. How cell fate is determined following UPR activation remains enigmatic. In this review, we discuss the molecular mechanisms linking ER stress to beta cell survival or apoptosis. Specifically, we focus on the role of the cellular inhibitor of apoptosis protein-1 and propose a new model for understanding survival of beta cells undergoing ER stress.
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Affiliation(s)
- Pu Xia
- Signal Transduction Program, Centenary Institute, Sydney, Australia; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, PR China.
| | - Yanfei Qi
- Signal Transduction Program, Centenary Institute, Sydney, Australia
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V8, a newly synthetic flavonoid, induces apoptosis through ROS-mediated ER stress pathway in hepatocellular carcinoma. Arch Toxicol 2013; 88:97-107. [PMID: 23835921 DOI: 10.1007/s00204-013-1085-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 06/20/2013] [Indexed: 10/26/2022]
Abstract
Natural flavonoids from plants have been demonstrated to possess promising chemopreventive activities against various diseases. 7-{4-[Bis-(2-hydroxy-ethyl)-amino]-butoxy}-5-hydroxy-8-methoxy-2-phenyl-chromen-4-one (V8), a newly synthesized derivative of wogonin may have antioxidant, antiviral, anti-inflammatory and anti-tumor potentials as wogonin. Based on the recent findings of V8, the anti-tumor activities and fundamental mechanisms by which V8 inhibits growth of hepatocellular carcinoma were further investigated in this study. After the treatment of V8, a significant inhibition of HepG2 cell proliferation was observed in a dose-dependent manner with the IC50 value of 23 μM using MTT assay. The exposure to V8 also resulted in apoptosis induction and an accumulation of ROS and Ca(2+). Meanwhile, a release of cytochrome c (Cyt-c), activation of BH-3 only proteins and Bax, decrease in mitochondrial membrane potential ΔΨ, as well as a suppression of Bcl-2, pro-caspase9 and pro-caspase3 expression were shown. Moreover, knocking down CHOP partly decreased the effect of V8-mediated apoptosis and activation of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP modulated ER stress triggered by V8. In vivo, V8 inhibited the transplanted mice H22 liver carcinomas in a dose-dependent manner. Compared with wogonin, V8 exhibited stronger anti-proliferative effects both in vitro and in vivo. The underlying mechanism of activating PERK-eIF2α-ATF4 pathway by which V8 induces apoptosis was verified once again in vivo. The apoptosis induction via the mitochondrial pathway by modulating the ROS-mediated ER signaling pathway might serve to provide support for further studies of V8 as a possible anticancer drug in the clinical treatment of cancer.
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Yoo JO, Ha KS. New insights into the mechanisms for photodynamic therapy-induced cancer cell death. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2012; 295:139-74. [PMID: 22449489 DOI: 10.1016/b978-0-12-394306-4.00010-1] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Photodynamic therapy (PDT) is a promising therapeutic modality for cancer treatment; however, a more detailed understanding is needed to improve the clinical use of this therapy. PDT induces cancer cell death by apoptosis, necrosis, and autophagy, and these mechanisms can be concurrently occurred. PDT destroys cancer cells by inducing apoptosis through diverse signaling pathways coupled with Bcl-2 family members, caspases, and apopotosis-inducing factor. When the apoptotic pathway is unavailable, PDT can cause cancer cell death through induction of a necrotic or autophagic mechanism. Autophagy is occurred in a Bax-independent manner and can be stimulated in parallel with apoptosis. PDT directly destroys cancer cells by inducing either apoptotic or necrotic death. PDT also can induce autophagy as a death or a survival mechanism. These mechanisms are dependent on a variety of parameters including the nature of the photosensitizer, PDT dose, and cell genotype. Understanding the complex cross talk between these pathways may improve the effectiveness of PDT. Here, we discuss the interplay between these mechanisms based on recent evidence and suggest prospects with regard to advances in PDT.
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Affiliation(s)
- Je-Ok Yoo
- Department of Molecular and Cellular Biochemistry, Kangwon National University School of Medicine, Chuncheon, Kangwon-do, South Korea
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29
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Dou G, Sreekumar PG, Spee C, He S, Ryan SJ, Kannan R, Hinton DR. Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction. Free Radic Biol Med 2012; 53:1111-22. [PMID: 22781655 PMCID: PMC3454510 DOI: 10.1016/j.freeradbiomed.2012.06.042] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Revised: 06/12/2012] [Accepted: 06/28/2012] [Indexed: 01/29/2023]
Abstract
Endoplasmic reticulum (ER) stress is linked to several pathological conditions including age-related macular degeneration. Excessive ER stress initiates cell death cascades which are mediated, in part, through mitochondrial dysfunction. Here, we identify αB crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from αB crystallin (-/-) mice, and human RPE cells transfected with αB crystallin siRNA, are more vulnerable to ER stress induced by tunicamycin. ER stress-mediated cell death is associated with increased levels of reactive oxygen species, depletion of glutathione in mitochondria, decreased superoxide dismutase activity, increased release of cytochrome c, and activation of caspases 3 and 4. The ER stress signaling inhibitors, salubrinal and 4-(2-aminoethyl) benzenesulfonyl fluoride, decrease mitochondrial damage and reduce RPE apoptosis induced by ER stress. Prolonged ER stress decreases levels of αB crystallin, thus exacerbating mitochondrial dysfunction. Overexpression of αB crystallin protects RPE cells from ER stress-induced apoptosis by attenuating increases in Bax, CHOP, mitochondrial permeability transition, and cleaved caspase 3. Thus, these data collectively demonstrate that αB crystallin provides critical protection of mitochondrial function during ER stress-induced RPE apoptosis.
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Affiliation(s)
- Guorui Dou
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Parameswaran G Sreekumar
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
| | - Christine Spee
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Shikun He
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Stephen J Ryan
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Ram Kannan
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - David R Hinton
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Corresponding Author: David R Hinton MD, Department of Pathology, 2011 Zonal Avenue, HMR 209, Los Angeles, CA 90033, USA. Tel.: + 1 323 442 6617; Fax: + 1 323 442 6688.
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Thapa A, Morris L, Xu J, Ma H, Michalakis S, Biel M, Ding XQ. Endoplasmic reticulum stress-associated cone photoreceptor degeneration in cyclic nucleotide-gated channel deficiency. J Biol Chem 2012; 287:18018-29. [PMID: 22493484 DOI: 10.1074/jbc.m112.342220] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 account for >70% of all known cases of achromatopsia. Cones degenerate in achromatopsia patients and in CNGA3(-/-) and CNGB3(-/-) mice. This work investigates the molecular basis of cone degeneration in CNG channel deficiency. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice. The retinal phenotype and potential cell death pathways were examined by functional, biochemical, and immunohistochemical approaches. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice showed impaired cone function, opsin mislocalization, and cone degeneration similar to that in the single knock-out mice. The endoplasmic reticulum stress marker proteins, including Grp78/Bip, phospho-eIF2α, phospho-IP(3)R, and CCAAT/enhancer-binding protein homologous protein, were elevated significantly in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, compared with the age-matched (postnatal 30 days) Nrl(-/-) controls. Along with these, up-regulation of the cysteine protease calpains and cleavage of caspase-12 and caspase-7 were found in the channel-deficient retinas, suggesting an endoplasmic reticulum stress-associated apoptosis. In addition, we observed a nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, implying a mitochondrial insult in the endoplasmic reticulum stress-activated cell death process. Taken together, our findings suggest a crucial role of endoplasmic reticulum stress in cone degeneration associated with CNG channel deficiency.
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Affiliation(s)
- Arjun Thapa
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
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31
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Yoo JO, Lim YC, Kim YM, Ha KS. Transglutaminase 2 promotes both caspase-dependent and caspase-independent apoptotic cell death via the calpain/Bax protein signaling pathway. J Biol Chem 2012; 287:14377-88. [PMID: 22418443 DOI: 10.1074/jbc.m111.326074] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Transglutaminase 2 (TG2) is a versatile protein that is implicated in significant biological processes, including cell death and degenerative diseases. A possible role of TG2 in the apoptotic death of cancer cells induced by photodynamic therapy (PDT) was suggested recently; however, the mechanism by which TG2 regulates apoptotic responses to PDT remains to be elucidated. In this study, we investigated the key signaling pathways stimulated during apoptotic cell death following PDT and whether inhibition of TG2 activation using pharmacological approaches and siRNAs affects the signaling pathways. PDT caused the release of both cytochrome c and apoptosis-inducing factor (AIF) by damaging mitochondria, which resulted in caspase-dependent and caspase-independent apoptotic cell death, respectively. Released AIF translocated to the nucleus and, synergistically with the caspase-dependent pathway, led to apoptotic cell death. Both the caspase cascade and the activation of AIF following PDT were mediated by TG2 activation. In addition, PDT-activated calpain was responsible for the sequential events of Bax translocation, the collapse of ΔΨ(m), caspase-3 activation, and AIF translocation, all of which were provoked by TG2 activation. Together, these results demonstrate that PDT with a chlorin-based photosensitizer targets TG2 by activating calpain-induced Bax translocation, which induces apoptotic cell death through both caspase-dependent and AIF-mediated pathways. Moreover, these results indicate that TG2 may be a possible therapeutic target for PDT treatment of cancer.
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Affiliation(s)
- Je-Ok Yoo
- Department of Molecular and Cellular Biochemistry and Institute of Medical Science, Kangwon National University School of Medicine, Kangwon-do 200-701, Korea
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32
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Eloy L, Jarrousse AS, Teyssot ML, Gautier A, Morel L, Jolivalt C, Cresteil T, Roland S. Anticancer Activity of Silver-N-Heterocyclic Carbene Complexes: Caspase-Independent Induction of Apoptosis via Mitochondrial Apoptosis-Inducing Factor (AIF). ChemMedChem 2012; 7:805-14. [DOI: 10.1002/cmdc.201200055] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Indexed: 01/20/2023]
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Retinal degeneration and cellular suicide. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 723:207-14. [PMID: 22183335 DOI: 10.1007/978-1-4614-0631-0_28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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34
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Zhang R, Piao MJ, Kim KC, Kim AD, Choi JY, Choi J, Hyun JW. Endoplasmic reticulum stress signaling is involved in silver nanoparticles-induced apoptosis. Int J Biochem Cell Biol 2011; 44:224-32. [PMID: 22064246 DOI: 10.1016/j.biocel.2011.10.019] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 10/19/2011] [Accepted: 10/25/2011] [Indexed: 10/15/2022]
Abstract
Although silver nanoparticles (AgNPs) have been reported to exert strong acute toxic effects on various cultured cells by inducing oxidative stress, the molecular mechanisms by which AgNPs-damaged cells are unknown. Because the endoplasmic reticulum (ER) may play an important role in the response to oxidative stress-induced damage and is quite sensitive to oxidative damage, we hypothesized that AgNPs may exert cytotoxic effects on cells by modulating ER stress. In our study, AgNPs resulted in cytotoxicity and apoptotic cell death when analyzing cell viability, DNA fragmentation and the apoptotic sub-G(1) population. Flow cytometry and confocal microscopy indicated that the cells were sensitive to AgNPs with respect to the induction of mitochondrial Ca(2+) overloading and enhancement of ER stress. AgNPs induced a number of signature ER stress markers, including phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and its downstream eukaryotic initiation factor 2α, phosphorylation of inositol-requiring protein 1 (IRE1), splicing of ER stress-specific X-box transcription factor-1, cleavage of activating transcription factor 6 (ATF6) and up-regulation of glucose-regulated protein-78 and CCAAT/enhancer-binding protein-homologous protein (CHOP/GADD153). Down-regulation of PERK, IRE1 and ATF6 expression using siRNA significantly decreased AgNPs-induced the enhancement of ER stress. In addition, down-regulation of CHOP expression with siRNA CHOP attenuated AgNPs-induced apoptosis. Taken together, the present study supports an important role for the ER stress response in mediating AgNPs-induced apoptosis.
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Affiliation(s)
- Rui Zhang
- School of Medicine and Applied Radiological Science Research Institute, Jeju National University, Jeju, Republic of Korea
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35
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Ribeiro N, Thuaud F, Nebigil C, Désaubry L. Recent advances in the biology and chemistry of the flavaglines. Bioorg Med Chem 2011; 20:1857-64. [PMID: 22071525 DOI: 10.1016/j.bmc.2011.10.048] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 10/04/2011] [Accepted: 10/15/2011] [Indexed: 01/03/2023]
Abstract
The flavaglines are a family of plant natural products that induce potent anticancer and neuroprotective activities. This review summarizes recent synthetic approaches to flavaglines and the current status of their pharmacological properties.
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Affiliation(s)
- Nigel Ribeiro
- Therapeutic Innovation Laboratory, UMR 7200, CNRS/Université de Strasbourg, 67401 Illkirch, France
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36
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Kim HR, Kim MS, Kwon DY, Chae SW, Chae HJ. Bosellia serrata-induced apoptosis is related with ER stress and calcium release. GENES AND NUTRITION 2011; 2:371-4. [PMID: 18850233 DOI: 10.1007/s12263-007-0072-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
It has been reported that the gum resin of Boswellia serrata (BS), which has been shown to have antiinflammatory properties, might also have anticancer effects. This study examined the potential of BS as an anticancer agent. The BS extract induces apoptosis in HeLa human cervical carcinoma cells, as confirmed by two apoptosis analyses, Hoechst staining and Annexin V/PI assay. Among the apoptosis pathways, the ER stress-associated mechanism was examined to determine its role in BS-induced apoptosis. The expression of GRP78 and CHOP, which are representatives of the ER stress proteins, and the calcium-binding protein-calpain were determined. The results showed significantly higher levels of both GRP78 and CHOP, and stronger calpain activity in the BS-treated cells than in the control cells. This shows that there is a correlation between ER stress signaling and apoptosis, which suggests the possibility of the BS-ER stress initiator as an anticancer therapeutic agent in human cervical carcinoma.
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Affiliation(s)
- Hyung-Ryong Kim
- Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Republic of Korea
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Choe ES, Ahn SM, Yang JH, Go BS, Wang JQ. Linking cocaine to endoplasmic reticulum in striatal neurons: role of glutamate receptors. ACTA ACUST UNITED AC 2011; 1:59-63. [PMID: 21808746 DOI: 10.1016/j.baga.2011.05.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The endoplasmic reticulum (ER) controls protein folding. Accumulation of unfolded and misfolded proteins in the ER triggers an ER stress response to accelerate normal protein folding or if failed to cause apoptosis. The ER stress response is a conserved cellular response in mammalian cells and is sensitive to various physiological or pathophysiological stimuli. Recent studies unravel that this response in striatal neurons is subject to the tight modulation by psychostimulants. Cocaine and amphetamines markedly increased expression of multiple ER stress reporter proteins in the dorsal striatum (caudate putamen) and other basal ganglia sites. This evoked ER stress response is mediated by activation of group I metabotropic glutamate receptors and N-methyl-D-aspartate receptors. Converging Ca(2+) signals derived from activation of these receptors activate the c-Jun N-terminal kinase pathway to evoke ER stress responses. The discovery of robust ER stress responses to stimulant exposure establishes a previously unrecognized stimulant-ER coupling. This inducible coupling seems to contribute to neurotoxicity of stimulants related to various neuropsychiatric and neurodegenerative illnesses. Elucidating cellular mechanisms linking cocaine and other stimulants to ER is therefore important for the development of therapeutic agents for treating neurological disorders resulted from stimulant toxicity.
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Affiliation(s)
- Eun Sang Choe
- Department of Biological Sciences, Pusan National University, Pusan 609-735, Korea
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38
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Abstract
The efficient functioning of the ER is indispensable for most of the cellular activities and survival. Disturbances in the physiological functions of the ER result in the activation of a complex set of signaling pathways from the ER to the cytosol and nucleus, and these are collectively known as unfolded protein response (UPR), which is aimed to compensate damage and can eventually trigger cell death if ER stress is severe or persists for a longer period. The precise molecular mechanisms that facilitate this switch in brain damage have yet to be understood completely with multiple potential participants involved. The ER stress-associated cell death pathways have been recognized in the numerous pathophysiological conditions, such as diabetes, hypoxia, ischemia/reperfusion injury, and neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and bipolar disorder. Hence, there is an emerging need to study the basic molecular mechanisms of ER stress-mediating multiple cell survival/death signaling pathways. These molecules that regulate the ER stress response would be potential drug targets in brain diseases.
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Affiliation(s)
- Ram Raghubir
- Division of Pharmacology, Central Drug Research Institute, (CSIR), Chatter Manzil Palace, Lucknow, India
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39
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Abstract
The unfolded protein response (UPR) is an evolutionarily conserved cell signaling pathway that is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed from increased client protein load or the accumulation of unfolded or malfolded proteins. Once activated, this signaling pathway can either result in the recovery of homeostasis or can activate a cascade of events that ultimately result in cell death. The UPR/endoplasmic reticulum (ER) stress response spectrum and its interplay with other cellular organelles play an important role in the pathogenesis of disease in secretory cells rich in ER, such as hepatocytes. Over the past 2 decades, the contribution of ER stress to various forms of liver diseases has been examined. Robust support for a contributing, as opposed to a secondary role, for ER stress response is seen in the nonalcoholic steatohepatitis, alcoholic liver disease, ischemia/reperfusion injury, and cholestatic models of liver disease. The exact direction of the cause and effect relationship between modes of cell injury and ER stress remains elusive. It is apparent that a complex interplay exists between ER stress response, conditions that promote it, and those that result from it. A vicious cycle in which ER stress promotes inflammation, cell injury, and steatosis and in which steatogenesis, inflammation, and cell injury aggravate ER stress seems to be at play. It is perhaps the nature of such a vicious cycle that is the key pathophysiologic concept. Therapeutic approaches aimed at interrupting the cycle may dampen the stress response and the ensuing injury.
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Affiliation(s)
- Lily Dara
- University of Southern California Research Center for Liver Diseases, Los Angeles, CA, USA.
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Death of photoreceptors in organotypic retinal explant cultures: Implication of rhodopsin accumulation and endoplasmic reticulum stress. J Neurosci Methods 2011; 197:56-64. [DOI: 10.1016/j.jneumeth.2011.01.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Revised: 01/21/2011] [Accepted: 01/29/2011] [Indexed: 01/17/2023]
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Calpain and caspase processing of caspase-12 contribute to the ER stress-induced cell death pathway in differentiated PC12 cells. Apoptosis 2011; 15:1480-93. [PMID: 20640600 DOI: 10.1007/s10495-010-0526-4] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Neuronal cell death after traumatic brain injury, Alzheimer's disease and ischemic stroke may in part be mediated through endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR results in induction of molecular chaperone GRP78 and the ER-resident caspase-12, whose activation has been proposed to be mediated by calpain and caspase processing, although their relative contribution remains unclear. In this study we induced ER stress with thapsigargin (TG), and determined the activation profile of calpain-2, caspase-3, caspase-7, and caspase-12 by analyses of protein levels, corresponding substrates and breakdown products (BDP). Specific calpain and caspase activity was assessed by analysis of αII-spectrin BDP of 145 kDa (SBDP145), BDP of 150 kDa (SBDP150) and BDP of 120 kDa (SBDP120). Decrease in pro-calpain-2 protein and increased SBDP145 levels by 3 h after TG treatment indicated early calpain activity. Active caspase-7 (p20) increase occurred after 8 h, followed by concomitant up-regulation of active caspase-3 and SBDP120 after 24 h. In vitro digestion experiments supported that SBDP120 was exclusively generated by active caspase-3 and validated that kinectin and co-chaperone p23 were calpain and caspase-7 substrates, respectively. Pro-caspase-12 protein processing by the specific action of calpain and caspase-3/7 was observed in a time-dependent manner. N-terminal pro-domain processing of pro-caspase-12 by calpain generated a 38 kDa fragment, while caspase-3/7 generated a 35 kDa fragment. Antibody developed specifically against the caspase-3/7 C-terminal cleavage site D(341) detected the presence of large subunit (p20) containing 23 kDa fragment that increased after 24 h of TG treatment. Significant caspase-12 enzyme activity was only detected after 24 h of TG treatment and was completely inhibited by caspase 3/7 inhibitor DEVD-fmk and partially by calpain inhibitor SNJ-1945. ER-stress-induced cell death pathway in TG-treated PC12 cells was characterized by up-regulation of GRP-78 and processing and activation of caspase-12 by the orchestrated proteolytic activity of calpain-2 and caspase-3/7.
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Sahaboglu A, Tanimoto N, Kaur J, Sancho-Pelluz J, Huber G, Fahl E, Arango-Gonzalez B, Zrenner E, Ekström P, Löwenheim H, Seeliger M, Paquet-Durand F. PARP1 gene knock-out increases resistance to retinal degeneration without affecting retinal function. PLoS One 2010; 5:e15495. [PMID: 21124852 PMCID: PMC2990765 DOI: 10.1371/journal.pone.0015495] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Accepted: 10/03/2010] [Indexed: 11/25/2022] Open
Abstract
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP.
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Affiliation(s)
- Ayse Sahaboglu
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Naoyuki Tanimoto
- Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Jasvir Kaur
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Javier Sancho-Pelluz
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Gesine Huber
- Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Edda Fahl
- Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Blanca Arango-Gonzalez
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Eberhart Zrenner
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - Per Ekström
- Department of Ophthalmology, Clinical Sciences Lund, University of Lund, Lund, Sweden
| | - Hubert Löwenheim
- Otolaryngology Department, University of Tübingen, Tübingen, Germany
| | - Mathias Seeliger
- Ocular Neurodegeneration Research Group, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
| | - François Paquet-Durand
- Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany
- * E-mail:
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Thuaud F, Bernard Y, Türkeri G, Dirr R, Aubert G, Cresteil T, Baguet A, Tomasetto C, Svitkin Y, Sonenberg N, Nebigil CG, Désaubry L. Synthetic analogue of rocaglaol displays a potent and selective cytotoxicity in cancer cells: involvement of apoptosis inducing factor and caspase-12. J Med Chem 2010; 52:5176-87. [PMID: 19655762 DOI: 10.1021/jm900365v] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Flavaglines constitute a family of natural anticancer compounds. We present here 3 (FL3), the first synthetic flavagline that inhibits cell proliferation and viability (IC(50) approximately 1 nM) at lower doses than did the parent compound, racemic rocaglaol. Compound 3 enhanced doxorubicin cytotoxicity in HepG2 cells and retained its potency against adriamycin-resistant cell lines without inducing cardiomyocyte toxicity. Compound 3 induced apoptosis of HL60 and Hela cells by triggering the translocation of Apoptosis Inducing Factor (AIF) and caspase-12 to the nucleus. A fluorescent conjugate of 3 accumulated in endoplasmic reticulum (ER), suggesting that flavaglines bind to their target in the ER, where it triggers a cascade of events that leads to the translocation of AIF and caspase-12 to the nucleus and probably inhibition of eIF4A. Our studies highlight structural features critical to their antineoplastic potential and suggest that these compounds would retain their activity in cells refractory to caspase activation.
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Affiliation(s)
- Frédéric Thuaud
- Therapeutic Innovation Laboratory, UMR7200, CNRS/Universite de Strasbourg, Illkirch, France
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Zhao CQ, Zhang YH, Jiang SD, Jiang LS, Dai LY. Both endoplasmic reticulum and mitochondria are involved in disc cell apoptosis and intervertebral disc degeneration in rats. AGE (DORDRECHT, NETHERLANDS) 2010; 32:161-77. [PMID: 19960285 PMCID: PMC2861755 DOI: 10.1007/s11357-009-9121-4] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Accepted: 11/10/2009] [Indexed: 05/12/2023]
Abstract
Intervertebral disc cell apoptosis occurs through either death receptor or mitochondrial pathway, but whether disc cell apoptosis is also mediated by the endoplasmic reticulum (ER) pathway remains unclear. The objective of this study was to investigate whether ER and mitochondria are co-involved in disc cell apoptosis and intervertebral disc degeneration (IVDD) in rats. Forty-eight rats were used for in vivo experiments. IVDD was characterized by X-ray and histomorphology examination, disc cell apoptosis was detected by TUNEL staining, and the co-involvement of ER and mitochondria in apoptosis was determined by immunohistochemical staining for GRP78, GADD153, caspase-12, and cytochrome C. Additional eight rats were used for annular cell isolation and culture. After sodium nitroprusside treatment, annular cell apoptosis was observed morphologically and quantified by flow cytometry; the expression of biomarkers of ER stress and mitochondrial dysfunction were analyzed by reverse transcriptase PCR (RT-PCR), fluorescence double labeling, and Western blot; and mitochondrial membrane potential was detected by 5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbo cyanine iodide (JC-1) staining. Finally, NS3694 and Z-ATAD-FMK were employed to inhibit the formation of apoptosome complex and the activation of caspase-12, respectively, and apoptotic incidence and caspase-9 activity were assayed. We found that IVDD, induced by unbalanced dynamic and static forces in the rats, was accompanied by increased disc cell apoptosis and enhanced expression of GRP78, GADD153, caspase-12, and cytochrome C. Annular cell apoptosis induced by sodium nitroprusside was confirmed by morphologic observation and flow cytometry. With increased apoptosis, the expression of GRP78, GADD153, and caspase-12 upregulated, mitochondrial membrane potential decreased, and accumulation of cytochrome C in the cytosol manifested. Furthermore, NS3694 and Z-ATAD-FMK dramatically suppress annular cell apoptosis and caspase-9 activity. In conclusion, disc cell apoptosis mediated simultaneously by ER and mitochondria plays a potent role in IVDD.
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Affiliation(s)
- Chang-Qing Zhao
- Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yue-Hui Zhang
- Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Sheng-Dan Jiang
- Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lei-Sheng Jiang
- Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Li-Yang Dai
- Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Orthopedic Surgery, Xinhua Hospital, 1665 Kongjiang Road, 200092 Shanghai, China
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Suryakumar G, Kasiganesan H, Balasubramanian S, Kuppuswamy D. Lack of beta3 integrin signaling contributes to calpain-mediated myocardial cell loss in pressure-overloaded myocardium. J Cardiovasc Pharmacol 2010; 55:567-73. [PMID: 20224428 PMCID: PMC3319054 DOI: 10.1097/fjc.0b013e3181d9f5d4] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Although cardiac hypertrophy initially ensues as a compensatory mechanism, it often culminates in congestive heart failure. Based on our earlier studies that calpain and beta3 integrin play cell death and survival roles, respectively, during pressure-overload (PO) hypertrophy, we investigated if the loss of beta3 integrin signaling is a potential mechanism for calpain-mediated cardiomyocyte death during PO. beta3 Integrin knockout (beta3) and wild-type mice were used to induce either moderate or severe PO in vivo for short-term (72-hour) and long-term (4-week) transverse aortic constriction. Whereas wild-type mice showed no changes during moderate PO at both time points, beta3 mice exhibited both enrichment of the mu-calpain isoform and programmed cell death of cardiomyocytes after 4-week PO. However, with severe PO that caused increased mortality in both mice groups, cell death was observed in wild-type mice also. To study calpain's role, calpeptin, a specific inhibitor of calpain, was administered through an osmotic mini-pump at 2.5 mg/kg per day beginning 3 days before moderate transverse aortic constriction or sham surgery. Calpeptin administration blocked both calpain enrichment and myocardial cell death in the 4-week PO beta3 mice. Because beta3 integrin contributes to cardioprotective signaling, these studies indicate that the loss of specific integrin function could be a key mechanism for calpain-mediated programmed cell death of cardiomyocytes in PO myocardium.
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Affiliation(s)
- Geetha Suryakumar
- Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina
| | - Harinath Kasiganesan
- Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina
| | - Sundaravadivel Balasubramanian
- Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina
| | - Dhandapani Kuppuswamy
- Cardiology Division of the Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina
- Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29425
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Calpains are activated by light but their inhibition has no neuroprotective effect against light-damage. Exp Eye Res 2009; 89:989-94. [DOI: 10.1016/j.exer.2009.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2009] [Accepted: 08/20/2009] [Indexed: 11/21/2022]
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Mani SK, Balasubramanian S, Zavadzkas JA, Jeffords LB, Rivers WT, Zile MR, Mukherjee R, Spinale FG, Kuppuswamy D. Calpain inhibition preserves myocardial structure and function following myocardial infarction. Am J Physiol Heart Circ Physiol 2009; 297:H1744-51. [PMID: 19734364 PMCID: PMC2781387 DOI: 10.1152/ajpheart.00338.2009] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Accepted: 09/01/2009] [Indexed: 12/13/2022]
Abstract
Cardiac pathology, such as myocardial infarction (MI), activates intracellular proteases that often trigger programmed cell death and contribute to maladaptive changes in myocardial structure and function. To test whether inhibition of calpain, a Ca(2+)-dependent cysteine protease, would prevent these changes, we used a mouse MI model. Calpeptin, an aldehydic inhibitor of calpain, was intravenously administered at 0.5 mg/kg body wt before MI induction and then at the same dose subcutaneously once per day. Both calpeptin-treated (n = 6) and untreated (n = 6) MI mice were used to study changes in myocardial structure and function after 4 days of MI, where end-diastolic volume (EDV) and left ventricular ejection fraction (EF) were measured by echocardiography. Calpain activation and programmed cell death were measured by immunohistochemistry, Western blotting, and TdT-mediated dUTP nick-end labeling (TUNEL). In MI mice, calpeptin treatment resulted in a significant improvement in EF [EF decreased from 67 + or - 2% pre-MI to 30 + or - 4% with MI only vs. 41 + or - 2% with MI + calpeptin] and attenuated the increase in EDV [EDV increased from 42 + or - 2 microl pre-MI to 73 + or - 4 microl with MI only vs. 55 + or - 4 microl with MI + calpeptin]. Furthermore, calpeptin treatment resulted in marked reduction in calpain- and caspase-3-associated changes and TUNEL staining. These studies indicate that calpain contributes to MI-induced alterations in myocardial structure and function and that it could be a potential therapeutic target in treating MI patients.
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Affiliation(s)
- Santhosh K Mani
- Division of Cardiology, Department of Medicine, Charleston, South Carolina, USA
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Zuppini A, Gerotto C, Moscatiello R, Bergantino E, Baldan B. Chlorella saccharophila cytochrome f and its involvement in the heat shock response. JOURNAL OF EXPERIMENTAL BOTANY 2009; 60:4189-200. [PMID: 19773387 PMCID: PMC2755035 DOI: 10.1093/jxb/erp264] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 07/15/2009] [Accepted: 07/30/2009] [Indexed: 05/08/2023]
Abstract
Cytochrome f is an essential component of the major redox complex of the thylakoid membrane. Cloning and characterization are presented here of a novel partial cDNA (ChspetA) encoding cytochrome f in the psychrophile unicellular green alga Chlorella saccharophila and its involvement in the heat shock (HS) response pathway has been analysed. Semi-quantitative reverse transcriptase PCR analysis showed that ChspetA expression is up-regulated in heat-shocked cells and the protein profile of cytochrome f highlighted a release of cytochrome f into the cytosol depending on the time lapse from the HS. Evans Blue assay, analysis of chromatin condensation, and chloroplast alterations showed the induction of cell death in cell suspensions treated with cytosolic extracts from heat-shocked cells. This study identifies cytochrome f in C. saccharophila that seems to be involved in the HS-induced programmed cell death process. The data suggest that cytochrome f fulfils its role through a modulation of its transcription and translation levels, together with its intracellular localization. This work focuses on a possible role of cytochrome f into the programmed cell death-like process in a unicellular chlorophyte and suggests the existence of chloroplast-mediated programmed cell death machinery in an organism belonging to one of the primary lineages of photosynthetic eukaryotes.
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Affiliation(s)
- Anna Zuppini
- Dipartimento di Biologia, Università di Padova, via U. Bassi 58/B, 35131 Padova, Italy.
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Gill MB, Perez-Polo JR. Bax shuttling after rotenone treatment of neuronal primary cultures: Effects on cell death phenotypes. J Neurosci Res 2009; 87:2047-65. [DOI: 10.1002/jnr.22019] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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50
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Hiss DC, Gabriels GA. Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part II: targeting cell cycle events, caspases, NF-κB and the proteasome. Expert Opin Drug Discov 2009; 4:907-21. [PMID: 23480539 DOI: 10.1517/17460440903055032] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Endoplasmic reticulum stress (ERS), the unfolded protein response (UPR) and apoptosis signal transduction pathways are fundamental to normal cellular homeostasis and survival, but are exploited by cancer cells to promote the cancer phenotype. OBJECTIVE Collateral activation of ERS and UPR role players impact on cell growth, cell cycle arrest or apoptosis, genomic stability, tumour initiation and progression, tumour aggressiveness and drug resistance. An understanding of these processes affords promising prospects for specific cancer drug targeting of the ERS, UPR and apoptotic pathways. METHOD This review (Part II of II) brings forward the latest developments relevant to the molecular connections among cell cycle regulators, caspases, NF-κB, and the proteasome with ERS and UPR signalling cascades, their functions in apoptosis induction, apoptosis resistance and oncogenesis, and how these relationships can be exploited for targeted cancer therapy. CONCLUSION Overall, ERS, the UPR and apoptosis signalling cascades (the molecular therapeutic targets) and the development of drugs that attack these targets signify a success story in cancer drug discovery, but a more reductionist approach is necessary to determine the precise molecular switches that turn on antiapoptotic and pro-apoptotic programmes.
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Affiliation(s)
- Donavon C Hiss
- Head, Molecular Oncology Research Programme, University of the Western Cape, Department of Medical BioSciences, Bellville, 7535, South Africa +27 21 959 2334 ; +27 959 1563 ;
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