Trigonelline, a naturally occurring alkaloidal agent protects ultraviolet-B (UV-B) irradiation induced apoptotic cell death in human skin fibroblasts via attenuation of oxidative stress, restoration of cellular calcium homeostasis and prevention of endoplasmic reticulum (ER) stress

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss and is characterized by progressive degeneration of the retina resulting in loss of central vision. The retinal pigment epithelium (RPE) is a critical site of pathology of AMD. Mitochondria and the endoplasmic reticulum which lie in close anatomic proximity to each other are targets of oxidative stress and endoplasmic reticulum (ER) stress, respectively, and contribute to the progression of AMD. The two organelles exhibit close interactive function via various signaling mechanisms. Evidence for ER-mitochondrial crosstalk in RPE under ER stress and signaling pathways of apoptotic cell death is presented. The role of humanin (HN), a prominent member of a newly discovered family of mitochondrial-derived peptides (MDPs) expressed from an open reading frame of mitochondrial 16S rRNA, in modulation of ER and oxidative stress in RPE is discussed. HN protected RPE cells from oxidative and ER stress-induced cell death by upregulation of mitochondrial GSH, inhibition of ROS generation, and caspase 3 and 4 activation. The underlying mechanisms of ER-mitochondrial crosstalk and modulation by exogenous HN are discussed. The therapeutic use of HN and related MDPs could potentially prove to be a valuable approach for treatment of AMD.

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Alginate oligosaccharide protects against endoplasmic reticulum- and mitochondrial-mediated apoptotic cell death and oxidative stress

Biomaterials ◽

10.1016/j.biomaterials.2011.04.024 ◽

2011 ◽

Vol 32 (23) ◽

pp. 5438-5458 ◽

Cited By ~ 104

Author(s):

Solaleh Khoramian Tusi ◽

Leila Khalaj ◽

Ghorbangol Ashabi ◽

Mahmoud Kiaei ◽

Fariba Khodagholi

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Alginate Oligosaccharide ◽

And Oxidative Stress

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Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Cancers ◽

10.3390/cancers13164173 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4173

Author(s):

Faustino Mollinedo ◽

Consuelo Gajate

Keyword(s):

Pancreatic Cancer ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Cancer Cells ◽

Tumor Cells ◽

Apoptotic Cell ◽

Ether Lipid ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

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Pyridoxine Preferentially Induces Auditory Neuropathy Through Mitochondrial Dysfunction and Endoplasmic Reticulum Stress-Mediated Apoptosis

Annals of Otology Rhinology & Laryngology ◽

10.1177/0003489419836116 ◽

2019 ◽

Vol 128 (6_suppl) ◽

pp. 117S-124S ◽

Cited By ~ 2

Author(s):

Channy Park ◽

Hyewon Lim ◽

Sung K. Moon ◽

Raekil Park

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Protein Expression ◽

Er Stress ◽

Nerve Fiber ◽

Apoptotic Cell ◽

Auditory Neuropathy ◽

Parp Cleavage ◽

Ros Generation ◽

Ganglion Neurons

Objectives: Auditory neuropathy due to toxicity mechanism of pyridoxine has not yet been fully documented. Therefore, the present study explored a direct mechanism underlying the effects of pyridoxine on auditory neuropathy in organ of Corti (OC) explants ex vivo and cochlear neuroblast cell line, VOT-33 in vitro. Methods: Primary OC explants containing spiral ganglion neurons and cultured VOT-33 cells were treated with pyridoxine. Results: In nerve fiber of primary OC explants, pyridoxine decreased staining for NF200, a neuro-cytoskeletal protein. We also found that pyridoxine-induced VOT-33 apoptosis, as indicated by accumulation of the sub-G0/G1 fraction, caspase-3 activation, and PARP cleavage. In addition, pyridoxine induced reactive oxygen species (ROS) generation and alteration of mitochondrial membrane potential transition (MPT), including Bcl-2 family protein expression and consequently Ca2+ accumulation and changes of endoplasmic reticulum (ER) stress-related protein expression such as phospho-PERK, caspase-12, Grp78, and CHOP. Conclusion: Pyridoxine preferentially induced severe cell death on nerve fiber in primary OC explants and markedly increased apoptotic cell death via mitochondria-mediated ER stress in VOT-33 cells.

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Epigallocatechin-3-Gallate (EGCG) Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/6721530 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Marianna Holczer ◽

Boglárka Besze ◽

Veronika Zámbó ◽

Miklós Csala ◽

Gábor Bánhegyi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Egcg Treatment ◽

Life And Death ◽

Er Stress Response ◽

Negative Effect ◽

External Stimuli

The maintenance of cellular homeostasis is largely dependent on the ability of cells to give an adequate response to various internal and external stimuli. We have recently proposed that the life-and-death decision in endoplasmic reticulum (ER) stress response is defined by a crosstalk between autophagy, apoptosis, and mTOR-AMPK pathways, where the transient switch from autophagy-dependent survival to apoptotic cell death is controlled by GADD34. The aim of the present study was to investigate the role of epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, in promoting autophagy-dependent survival and to verify the key role in connecting GADD34 with mTOR-AMPK pathways upon prolonged ER stress. Our findings, obtained by using HEK293T cells, revealed that EGCG treatment is able to extend cell viability by inducing autophagy. We confirmed that EGCG-induced autophagy is mTOR-dependent and PKA-independent; furthermore, it also required ULK1. We show that pretreatment of cells with EGCG diminishes the negative effect of GADD34 inhibition (by guanabenz or siGADD34 treatment) on autophagy. EGCG was able to delay apoptotic cell death by upregulating autophagy-dependent survival even in the absence of GADD34. Our data suggest a novel role for EGCG in promoting cell survival via shifting the balance of mTOR-AMPK pathways in ER stress.

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Calcium and cell death signaling in neurodegeneration and aging

Anais da Academia Brasileira de Ciências ◽

10.1590/s0001-37652009000300011 ◽

2009 ◽

Vol 81 (3) ◽

pp. 467-475 ◽

Cited By ~ 45

Author(s):

Soraya Smaili ◽

Hanako Hirata ◽

Rodrigo Ureshino ◽

Priscila T. Monteforte ◽

Ana P. Morales ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Apoptotic Cell ◽

Essential Elements ◽

Apoptotic Cell Death ◽

Nuclear Fragmentation ◽

Physiological Processes ◽

Cell Death Signaling ◽

Lines Of Evidence

Transient increase in cytosolic (Cac2+) and mitochondrial Ca2+ (Ca m2+) are essential elements in the control of many physiological processes. However, sustained increases in Ca c2+ and Ca m2+ may contribute to oxidative stress and cell death. Several events are related to the increase in Ca m2+, including regulation and activation of a number of Ca2+ dependent enzymes, such as phospholipases, proteases and nucleases. Mitochondria and endoplasmic reticulum (ER) play pivotal roles in the maintenance of intracellular Ca2+ homeostasis and regulation of cell death. Several lines of evidence have shown that, in the presence of some apoptotic stimuli, the activation of mitochondrial processes maylead to the release of cytochrome c followed by the activation of caspases, nuclear fragmentation and apoptotic cell death. The aim of this review was to show how changes in calcium signaling can be related to the apoptotic cell death induction. Calcium homeostasis was also shown to be an important mechanism involved in neurodegenerative and aging processes.

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