Role of sorbitol-mediated cellular stress response in obesity-associated retinal degeneration

Godisela, Kishore Kumar; Reddy, S. Sreenivasa; Reddy, P. Yadagiri; Kumar, Ch. Uday; Reddy, Vinodini; Ayyagari, Radha; Reddy, G. Bhanuprakash

doi:10.1016/j.abb.2019.108207

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…Levels of BiP are increased under conditions of ER stress to counterbalance the deleterious effects of the latter, through restoration of protein folding and assembly [ 33 ]. Our findings are in agreement with studies underlining ER stress stimulation by hyperosmotic conditions in rat hypothalamus [ 34 ], SK-N-SH human neuroblastoma cells and in obese rats’ retina [ 35 ], as well as in adult rat cardiac myocytes [ 6 ].…”

Section: Discussionsupporting

confidence: 92%

Severe Hyperosmotic Stress Issues an ER Stress-Mediated “Death Sentence” in H9c2 Cells, with p38-MAPK and Autophagy “Coming to the Rescue”

et al. 2022

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With several cardiovascular pathologies associated with osmotic perturbations, researchers are in pursuit of identifying the signaling sensors, mediators and effectors involved, aiming at formulating novel diagnostic and therapeutic strategies. In the present study, H9c2 cells were treated with 0.5 M sorbitol to elicit hyperosmotic stress. Immunoblotting as well as cell viability analyses revealed the simultaneous but independent triggering of multiple signaling pathways. In particular, our findings demonstrated the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) and upregulation of the immunoglobulin heavy-chain-binding protein (BiP) expression, indicating the onset of the Integrated Stress Response (IRS) and endoplasmic reticulum stress (ERS), respectively. In addition, autophagy was also induced, evidenced by the enhancement of Beclin-1 protein expression and of AMP-dependent kinase (AMPK) and Raptor phosphorylation levels. The involvement of a Na+/H+ exchanger-1 (NHE-1) as well as NADPH oxidase (Nox) in 0.5 M sorbitol-induced eIF2α phosphorylation was also indicated. Of note, while inhibition of ERS partially alleviated the detrimental effect of 0.5 M sorbitol on H9c2 cellular viability, attenuation of p38-MAPK activity and late phase autophagy further mitigated it. Deciphering the mode of these pathways’ potential interactions and of their complications may contribute to the quest for effective clinical interventions against associated cardiovascular diseases.

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Section: Discussionsupporting

confidence: 92%

Severe Hyperosmotic Stress Issues an ER Stress-Mediated “Death Sentence” in H9c2 Cells, with p38-MAPK and Autophagy “Coming to the Rescue”

et al. 2022

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“…These results indicate that R49/R149 have a role in modulating the activation of p38α. To further assess whether R49 and R149 modulate the activation of p38α in conditions other than AraC-induced differentiation, we stimulated K562 cells with sorbitol, which is a well-known strong stimulator of p38α in hyperosmotic stress [23]. The activation of p38α wild type was stimulated by around 4.0 folds at 0.5 h; however, it was reduced to around 2 folds in R49/149K mutant (Figure 4C).…”

Section: The R49 and R149 Residues Play A Crucial Role In The Activation Of P38αmentioning

confidence: 99%

The MKK-Dependent Phosphorylation of p38α Is Augmented by Arginine Methylation on Arg49/Arg149 during Erythroid Differentiation

Liu¹,

Hua²,

Chen³

et al. 2020

IJMS

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The activation of p38 mitogen-activated protein kinases (MAPKs) through a phosphorylation cascade is the canonical mode of regulation. Here, we report a novel activation mechanism for p38α. We show that Arg49 and Arg149 of p38α are methylated by protein arginine methyltransferase 1 (PRMT1). The non-methylation mutations of Lys49/Lys149 abolish the promotive effect of p38α on erythroid differentiation. MAPK kinase 3 (MKK3) is identified as the major p38α upstream kinase and MKK3-mediated activation of the R49/149K mutant p38α is greatly reduced. This is due to a profound reduction in the interaction of p38α and MKK3. PRMT1 can enhance both the methylation level of p38α and its interaction with MKK3. However, the phosphorylation of p38α by MKK3 is not a prerequisite for methylation. MAPK-activated protein kinase 2 (MAPKAPK2) is identified as a p38α downstream effector in the PRMT1-mediated promotion of erythroid differentiation. The interaction of MAPKAPK2 with p38α is also significantly reduced in the R49/149K mutant. Together, this study unveils a novel regulatory mechanism of p38α activation via protein arginine methylation on R49/R149 by PRMT1, which impacts partner interaction and thus promotes erythroid differentiation. This study provides a new insight into the complexity of the regulation of the versatile p38α signaling and suggests new directions in intervening p38α signaling.

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“…The National Institute of Nutrition has developed a unique spontaneous mutant obese rat model with impaired glucose tolerance (WNIN/GR-Ob) that can be transformed into frank diabetes by dietary manipulations [28]. WNIN/GR-Ob rat displays a set of characteristics and features associated with the other obese animal models and in addition, exhibits impaired glucose tolerance (IGT), all of which make WNIN/GR-Ob rat a suitable model of metabolic syndrome (MetS) [29]. The present study was undertaken to investigate the combined effect of obesity and IGT on the development of chemically induced mammary tumors in the WNIN/GR-Ob rat model.…”

Section: Introductionmentioning

confidence: 99%

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance

Kallamadi,

Esari,

Addi

et al. 2023

IJMS

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Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.

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Role of sorbitol-mediated cellular stress response in obesity-associated retinal degeneration

Cited by 7 publications

References 46 publications

Severe Hyperosmotic Stress Issues an ER Stress-Mediated “Death Sentence” in H9c2 Cells, with p38-MAPK and Autophagy “Coming to the Rescue”

Severe Hyperosmotic Stress Issues an ER Stress-Mediated “Death Sentence” in H9c2 Cells, with p38-MAPK and Autophagy “Coming to the Rescue”

The MKK-Dependent Phosphorylation of p38α Is Augmented by Arginine Methylation on Arg49/Arg149 during Erythroid Differentiation

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression—A Study on an Obese Rat Model with Impaired Glucose Tolerance

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