TSPA as a novel ATF6α translocation inducer efficiently ameliorates insulin sensitivity restoration and glucose homeostasis in db/db mice

Zhou, Tingting; Cheng, Yanhua; Yan, Wanfeng; Shi, Xiaofan; Xu, Xin; Zhou, Jinpei; Li, Jian; Chen, Jing; Shen, Xu

doi:10.1016/j.bbrc.2018.04.025

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…ATF6 selective modulators are the most recent drugs developed against ER stress. A small molecular compound, which is a structural analogue of other molecules with antipyretic and analgesic effects, induces ATF6α nuclear translocation without the activation of CHOP and restores insulin sensitivity in type 2 diabetes [ 223 ]. This molecule is identified as a novel lead compound and deserves further studies to evaluate its potential in other metabolic diseases.…”

Section: Therapeutic Intervention On Er Stress In Metabolic Diseasmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Metabolic Disorders

Ghemrawi

Battaglia-Hsu

Arnold

2018

Cells

153

113

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Metabolic disorders have become among the most serious threats to human health, leading to severe chronic diseases such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, as well as cardiovascular diseases. Interestingly, despite the fact that each of these diseases has different physiological and clinical symptoms, they appear to share certain pathological traits such as intracellular stress and inflammation induced by metabolic disturbance stemmed from over nutrition frequently aggravated by a modern, sedentary life style. These modern ways of living inundate cells and organs with saturating levels of sugar and fat, leading to glycotoxicity and lipotoxicity that induce intracellular stress signaling ranging from oxidative to ER stress response to cope with the metabolic insults (Mukherjee, et al., 2015). In this review, we discuss the roles played by cellular stress and its responses in shaping metabolic disorders. We have summarized here current mechanistic insights explaining the pathogenesis of these disorders. These are followed by a discussion of the latest therapies targeting the stress response pathways.

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Section: Therapeutic Intervention On Er Stress In Metabolic Diseasmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Metabolic Disorders

Ghemrawi

Battaglia-Hsu

Arnold

2018

Cells

153

113

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“…While ATF6 is beneficial for muscle adaptation to exercise [27,28], its participation in muscle glucose homeostasis remains elusive. Consistently, in liver, Atf6 deletion promotes glucose intolerance in HFD-fed mice [29] and chronic induction of Atf6 translocation and activation improves glucose homeostasis in db/db male mice [30].…”

Section: Discussionmentioning

confidence: 75%

Differential unfolded protein response in skeletal muscle from non-diabetic glucose tolerant or intolerant patients with obesity before and after bariatric surgery

et al. 2020

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Aims: Not all people with obesity become glucose intolerant, suggesting differential activation of cellular pathways. The Unfolded Protein Response (UPR) may contribute to the development of insulin resistance in several organs but its role in skeletal muscle remains debated. Therefore, we explored the UPR activation in muscle from non-diabetic glucose tolerant or intolerant patients with obesity, and the impact of bariatric procedures. Methods: Muscle biopsies from 22 normoglycemic (NG, blood glucose measured 120min after an oral glucose tolerance test, G120 < 7.8mM) and 22 glucose intolerant (GI, G120 between 7.8 and 11.1mM) were used to measure UPR activation by RTqPCR and western-blot. Then, UPR was studied in biopsies from 7 NG and 7 GI patients before and one year after bariatric surgery. Results: Binding Immunoglobulin Protein (BIP) protein was ~40% higher in the GI compared to NG subjects. Contrastingly, expression of the UPR-related genes BIP, Activating Transcription Factor 6 (ATF6) and unspliced X-box Binding Protein 1 (XBP1u) were significantly lower and C/EBP HomolOgous Protein (CHOP) tended to decrease (p=0.08) in GI individuals. While BIP protein positively correlated with fasting blood glucose (r=0.38, p=0.01), ATF6 and CHOP were associated with G120 (r=-0.38 and r=-0.41, p<0.05) and the Matsuda index (r=0.37 and r=0.38, p<0.05). Bariatric surgery improved metabolic parameters, associated with higher CHOP expression in GI patients, while ATF6 tended to increase (p=0.08). Conclusions: CHOP and ATF6 expression decreased in non-diabetic GI patients with obesity and was modified by bariatric surgery. These genes may contribute to glucose homeostasis in human skeletal muscle.

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“…Additionally, the work established TSPA as a solid foundation for future efforts in drug development and discovery. [61] For their research, Ali 4] triazole] emerged as the most successful substance in this situation. [62] The best pharmacophore model was developed in 2017 by Patel and colleagues, which allowed for the creation of 50 triazolo[5,1-c][1,2,4] triazine derivatives (55).…”

Section: As An Anticancer Agent: 124-triazole Derivativesmentioning

confidence: 99%

“…These results demonstrated the potential benefit of focusing on ATF6α while looking for new treatments for type 2 diabetes. Additionally, the work established TSPA as a solid foundation for future efforts in drug development and discovery [61] . For their research, Ali et al.…”

Section: Novel Advancements In 124‐triazole Derivatives For Biologica...mentioning

confidence: 99%

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity

Ajmal,

Mahato,

Khan

et al. 2024

Chemistry & Biodiversity

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One of the triazole tautomers, 1,2,4‐triazole derivatives, has a wide range of biological activities that suggest its potential therapeutic utility in medicinal chemistry. These actions include anti‐inflammatory, anti‐cancer, anti‐bacterial, anti‐tuberculosis, and anti‐diabetic effects. The review highlights anti‐inflammatory effect of 1,2,4‐triazoles in relation to their ability to disrupt significant inflammatory mediators and pathways. We present in‐silico data that illuminate the triazoles capacity to inhibit cell division, encourage apoptosis, and stop metastasis in a range of cancer models. This review looks at the bactericidal and bacteriostatic properties of 1,2,4‐triazole derivatives, with a focus on their potential efficacy against multi‐drug resistant bacterial infections and their usage in tuberculosis therapy. In order to better understand these substances' potential anti‐diabetic benefits, this review also looks at how they affect glucose metabolism regulation and insulin responsiveness. Based on information provided, it can be concluded that 1,2,4‐triazole derivatives are a promising class of diverse therapeutic agents with potential utility in a range of disorders. Their development and improvement might herald a new era of medical care that will be immensely advantageous to both patients and medical community as a whole. Additionally, this study encourages more research into these substances and their enhancement for use in pharmaceutical development.

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TSPA as a novel ATF6α translocation inducer efficiently ameliorates insulin sensitivity restoration and glucose homeostasis in db/db mice

Cited by 6 publications

References 30 publications

Endoplasmic Reticulum Stress in Metabolic Disorders

Endoplasmic Reticulum Stress in Metabolic Disorders

Differential unfolded protein response in skeletal muscle from non-diabetic glucose tolerant or intolerant patients with obesity before and after bariatric surgery

Significance of Triazole in Medicinal Chemistry: Advancement in Drug Design, Reward and Biological Activity

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