Endoplasmic reticulum stress induces degradation of glucose transporter proteins during hyperglycemic hepatotoxicity: Role of PERK-eIF2α-ATF4 axis

Pandey, Vivek Kumar; Mathur, Alpana; Khan, Mohammad Fareed; Kakkar, Poonam

doi:10.1016/j.ejphar.2022.175012

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…These ER stress pathways are also activated by necroptosis [22]. The difference of these multiple axes depends on the type of cells and is important for the targeting of therapeutics [23].…”

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confidence: 99%

Endoplasmic reticulum stress associated with lead (Pb)‐induced olfactory epithelium toxicity in an olfactory dark basal cell line

Han,

Kamogashira,

Kikuta

et al. 2023

FEBS Open Bio

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Lead (Pb) can damage organs and also have undesirable effects on neural development. To explore the effects of Pb on olfactory cells, we investigated Pb‐induced cell toxicity in the DBC1.2 olfactory cell line, which a focus on endoplasmic reticulum (ER) stress, apoptosis and necroptosis. Representative markers of ER stress, apoptosis and necroptosis were analyzed by quantitative PCR. The mRNA expression levels of GRP94, GRP78, spliced XBP1, PERK and ATF6 increased significantly after Pb exposure in a dose‐dependent manner. The expression of Caspase 3 and Caspase 12 did not increase after Pb exposure, which suggested that apoptosis‐induced cell death was not activated after Pb exposure. However, the mRNA of RIPK3 and MLKL showed increases in expression, which indicated that necroptosis‐induced cell death was activated after Pb exposure. These results indicate that Pb exposure induced dose‐dependent cytotoxicity through ER stress and necroptosis pathways in DBC1.2 cells, whereas the apoptosis pathway was not significantly stimulated. HEPES buffer showed a partial protective effect in terms of ER stress, apoptosis and necroptosis. In summary, the necroptosis pathway plays a crucial rule in Pb exposure‐induced cytotoxicity in olfactory cells.

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confidence: 99%

Endoplasmic reticulum stress associated with lead (Pb)‐induced olfactory epithelium toxicity in an olfactory dark basal cell line

Han,

Kamogashira,

Kikuta

et al. 2023

FEBS Open Bio

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“…ER stress activates apoptosis of cells [65,66], and ER stress pathways are also activated by necroptosis [67]. The difference between these pathways, apoptosis or necroptosis, depends on the cell type and is an important therapeutic target [68]. Lead acetate induces the overexpression of interleukin 6 (IL-6) in the brain and excessive activation of nerve cells, leading to necrosis [69,70].…”

Section: Heavy Metal Exposure Induces Apoptosis Necrosis and Necroptosismentioning

confidence: 99%

Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies

Koyama,

Kamogashira,

Yamasoba

2024

Antioxidants

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Heavy metals are often found in soil and can contaminate drinking water, posing a serious threat to human health. Molecular pathways and curation therapies for mitigating heavy metal toxicity have been studied for a long time. Recent studies on oxidative stress and aging have shown that the molecular foundation of cellular damage caused by heavy metals, namely, apoptosis, endoplasmic reticulum stress, and mitochondrial stress, share the same pathways as those involved in cellular senescence and aging. In recent aging studies, many types of heavy metal exposures have been used in both cellular and animal aging models. Chelation therapy is a traditional treatment for heavy metal toxicity. However, recently, various antioxidants have been found to be effective in treating heavy metal-induced damage, shifting the research focus to investigating the interplay between antioxidants and heavy metals. In this review, we introduce the molecular basis of heavy metal-induced cellular damage and its relationship with aging, summarize its clinical implications, and discuss antioxidants and other agents with protective effects against heavy metal damage.

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“…), whereas activation of GCN2/eIF2α/ATF4 signaling pathway is a transcriptional factor that main task is to replenish the cellular amino acid pool (Figure 9). Activation of this module is also characteristic for amino acid demand tumor cells excited by in addition microenvironmental stress (hypoxia or decreased glucose level) (Mazor and Stipanuk, 2016;Kumar Pandey et al, 2022).…”

Section: Slc6a19; Transporter Associated With Absorption and Reabsorp...mentioning

confidence: 99%

The SLC6A15–SLC6A20 Neutral Amino Acid Transporter Subfamily: Functions, Diseases, and Their Therapeutic Relevance

Kukułowicz,

Pietrzak-Lichwa,

Klimończyk

et al. 2023

Pharmacol Rev

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The neutral amino acid transporter subfamily that consists of six members; consecutively SLC6A15-SLC620, also called orphan transporters, represents membrane, sodium-dependent symporter proteins that belong to the family of solute carrier 6 (SLC6). Primarily, they mediate the transport of neutral amino acids from the extracellular milieu toward cell or storage vesicles utilizing an electric membrane potential as the driving force. Orphan transporters are widely distributed throughout the body, covering many systems; for instance, the central nervous, renal, or intestinal system, supplying cells into molecules utilized in biochemical, signaling, and building pathways afterward. They are responsible for intestinal absorption and renal reabsorption of amino acids. In the CNS, orphan transporters constitute a significant medium for the provision of neurotransmitter precursors. Diseases related with aforementioned transporters highlight their significance; SLC6A19 mutations are associated with metabolic Hartnup disorder, whereas altered expression of SLC6A15 has been associated with a depression/stress-related disorders.Mutations of SLC6A18-SLCA20 cause iminoglycinuria and/or hyperglycinuria. SLC6A18-SLC6A20 to reach the cellular membrane require an ancillary unit ACE2 that is a molecular target for the spike protein of the SARS-CoV-2 virus. SLC6A19 has been proposed as a molecular target for the treatment of metabolic disorders resembling gastric surgery bypass. Inhibition of SLC6A15 appears to have a promising outcome in the treatment of psychiatric disorders. SLC6A19 and SLC6A20 have been suggested as potential targets in the treatment of COVID-19. In this review, we gathered recent advances on orphan transporters, their structure, functions, related disorders, and diseases, and in particular their relevance as therapeutic targets.

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Endoplasmic reticulum stress induces degradation of glucose transporter proteins during hyperglycemic hepatotoxicity: Role of PERK-eIF2α-ATF4 axis

Cited by 6 publications

References 44 publications

Endoplasmic reticulum stress associated with lead (Pb)‐induced olfactory epithelium toxicity in an olfactory dark basal cell line

Endoplasmic reticulum stress associated with lead (Pb)‐induced olfactory epithelium toxicity in an olfactory dark basal cell line

Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies

The SLC6A15–SLC6A20 Neutral Amino Acid Transporter Subfamily: Functions, Diseases, and Their Therapeutic Relevance

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