A small molecule UPR modulator for diabetes identified by high throughput screening

Marrocco, Valeria; Tran, Tuan Anh; Zhu, Siying; Choi, Seung Hyuk; Gamo, Ana M.; Li, Sijia; Fu, Qiangwei; Cunado, Marta Diez; Roland, Jason; Hull, Mitchell V.; Nguyên-Trân, Vân; Joseph, Sean B.; Chatterjee, Arnab K.; Rogers, Nikki Lynn; Tremblay, Matthew S.; Shen, Weijun

doi:10.1016/j.apsb.2021.05.018

Cited by 6 publications

(11 citation statements)

References 39 publications

(51 reference statements)

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“…To date, only a limited number of such compounds were identified, including 3HNA, 16 azoramide, 25 IBT21 26 and APC655. 27 Except for IBT21, antidiabetic effects of these compounds have been reported. 17 , 25 , 27 However, none of these new chemical chaperones were tested in a model of cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

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Endoplasmic Reticulum Chemical Chaperone 3‐Hydroxy‐2‐Naphthoic Acid Reduces Angiotensin II‐Induced Vascular Remodeling and Hypertension In Vivo and Protein Synthesis In Vitro

Cicalese

Torimoto

Okuno

et al. 2022

JAHA

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Background Investigations into alternative treatments for hypertension are necessary because current treatments cannot fully reduce the risk for the development of cardiovascular diseases. Chronic activation of unfolded protein response attributable to the endoplasmic reticulum stress has been proposed as a potential therapeutic target for hypertension and associated vascular remodeling. Triggered by the accumulation of misfolded proteins, chronic unfolded protein response leads to downstream signaling of cellular inflammation and dysfunction. Here, we have tested our hypothesis that a novel chemical chaperone, 3‐hydroxy‐2‐naphthoic acid (3HNA) can attenuate angiotensin II (AngII)‐induced vascular remodeling and hypertension. Methods and Results Mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension with or without 3HNA treatment. We found that injections of 3HNA prevented hypertension and increase in heart weight body weight ratio induced by AngII infusion. Histological assessment revealed that 3HNA treatment prevented vascular medial thickening as well as perivascular fibrosis in response to AngII infusion. In cultured vascular smooth muscle cells, 3HNA attenuated enhancement in protein synthesis induced by AngII. In vascular adventitial fibroblasts, 3HNA prevented induction of unfolded protein response markers. Conclusions We present evidence that a chemical chaperone 3HNA prevents vascular remodeling and hypertension in mice with AngII infusion, and 3HNA further prevents increase in protein synthesis in AngII‐stimulated vascular smooth muscle cells. Using 3HNA may represent a novel therapy for hypertension with multiple benefits by preserving protein homeostasis under cardiovascular stress.

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Section: Discussionmentioning

confidence: 99%

“… 27 Except for IBT21, antidiabetic effects of these compounds have been reported. 17 , 25 , 27 However, none of these new chemical chaperones were tested in a model of cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Chemical Chaperone 3‐Hydroxy‐2‐Naphthoic Acid Reduces Angiotensin II‐Induced Vascular Remodeling and Hypertension In Vivo and Protein Synthesis In Vitro

Cicalese

Torimoto

Okuno

et al. 2022

JAHA

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“…The misfolding and inhibition of protein folding in the endoplasmic reticulum (ER) lead to the aggregation of unfolded proteins, resulting in ER stress [103]. Li et al showed that the ER stress and unfolded protein response (UPR) accompanied by the accumulation of protein aggregates emerged as a significant pathway affected by aging, specifically in β cells.…”

Section: Inhibits Endoplasmic Reticulum Stress In the Pancreasmentioning

confidence: 99%

Ameliorative Effects of Gut Microbial Metabolite Urolithin A on Pancreatic Diseases

Xiao

Bian

et al. 2022

Nutrients

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Urolithin A (Uro A) is a dietary metabolite of the intestinal microbiota following the ingestion of plant-based food ingredients ellagitannins and ellagic acid in mammals. Accumulating studies have reported its multiple potential health benefits in a broad range of diseases, including cardiovascular disease, cancer, cognitive impairment, and diabetes. In particular, Uro A is safe via direct oral administration and is non-genotoxic. The pancreas plays a central role in regulating energy consumption and metabolism by secreting digestive enzymes and hormones. Numerous pathophysiological factors, such as inflammation, deficits of mitophagy, and endoplasmic reticulum stress, can negatively affect the pancreas, leading to pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes mellitus. Recent studies showed that Uro A activates autophagy and inhibits endoplasmic reticulum stress in the pancreas, thus decreasing oxidative stress, inflammation, and apoptosis. In this review, we summarize the knowledge of Uro A metabolism and biological activity in the gut, as well as the pathological features and mechanisms of common pancreatic diseases. Importantly, we focus on the potential activities of Uro A and the underlying mechanisms in ameliorating various pancreatic diseases via inhibiting inflammatory signaling pathways, activating autophagy, maintaining the mitochondrial function, and improving the immune microenvironment. It might present a novel nutritional strategy for the intervention and prevention of pancreatic diseases.

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“…Reduce hepatic glucose production; enhancing fatty acid β-oxidation; improve insulin resistance [214,215] Pantothenate kinase Increase fatty acid β-oxidation; improve insulin resistance [217] Stearoyl-CoA desaturase-1 (SCD) Increase fatty acid β-oxidation; improve insulin resistance [218] Hormone-sensitive lipase (HSL) Reduce circulating free fatty acids (FFA); improve insulin resistance [216] 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) Reduce glucocorticoid activity; improve insulin resistance [244] Thioredoxin-interacting protein (TXNIP) Reduce glucagon secretion of α-cells; improve insulin resistance [245] Adiponectin Preventing FFA accumulation; improve insulin resistance [248] α-glucosidase Reduce the breakdown of starch to glucose in the intestine; improve hyperglycemia [222] Fatty acid transport protein-2 (FATP-2) Reduce lipid absorption in the intestine; reduce lipid accumulation in β-cells [223,224] Glucagon-like peptide 1 (GLP-1) receptor Increase GLP1R activity; increase insulin secretion [232] Hepatocyte nuclear factor-4α (HNF4α) Increase the glucose sensitivity of β-cells; increase insulin secretion [235,236] Glucokinase Increase the glucose sensitivity of β-cells; increase insulin secretion [237] Glucose-6-phosphatase (G6P) Increase the glucose sensitivity of β-cells; increase insulin secretion [238] G-protein-coupled receptors (GPCRs or GPRs) Increase insulin secretion [239][240][241][242][243] Endoplasmic-reticulum (ER) stress Prevent functional β-cell loss [249,250] Mitochondria dysfunction Prevent functional β-cell loss [251] www.advanced-bio.com of glucagon from α-cells, and by testing the capacity of compounds to inhibit TXNIP expression, a small molecule named SRI-37330 was identified. Administration of SRI-37330 could significantly reduce the TXNIP expression, glucagon secretion, and hepatic glucose production in ob/ob mice.…”

Section: Therapeutic Strategies For T2dmmentioning

confidence: 99%

“…[248] ER stress and mitochondrial dysfunction caused by metabolic stress also contribute to β-cell loss in T2DM, and phenotypic screening could be used to discover hits that relieve ER stress and that resume mitochondrial homeostasis. [249][250][251] Additionally, HTS approaches have also aided in identifying potential T2DM drugs from new sources, such as plants and bacteria. [244,[252][253][254]…”

Section: Therapeutic Strategies For T2dmmentioning

confidence: 99%

The Application of High‐Throughput Approaches in Identifying Novel Therapeutic Targets and Agents to Treat Diabetes

Lim

2022

Advanced Biology

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An early example of HTS in drug development came from the identification of new antibiotics using 96-well microtiter plates, whereby fermentations of an established actinomycetes library were incubated with a panel of microorganisms, and after optimization, a screening capacity of 10 000 fermentation broths per week was achieved. [1] In the following decades, the rapid development of molecular biology techniques and advances in automated equipment have changed how new drugs are identified, and a variety of HTS-identified drugs have been approved to treat different diseases. [2] For a comprehensive list of HTS-identified drugs, please refer to the excellent review by Macarron et al. [2] High-throughput applications can also be combined with other unbiased "Omics" technologies used to study genomics, epigenomics, transcriptomics, proteomics, and metabolomics. [3] Diabetes is an incurable disease characterized by the inability of the body to maintain normoglycemia due to decreased sensitivity of various tissues to insulin and insufficient amounts of circulating insulin, a hormone produced by pancreatic β-cells. [4] Diabetes is associated with chronic complications, like macrovascular diseases (e.g., cardiovascular diseases) and microvascular diseases (e.g., damages in nerve, kidney, eye, and foot). [5,6] More than 537 million adults are currently living with diabetes, and this number is expected to increase to 693 million by 2045. In 2021, 6.7 million deaths worldwide were attributed to diabetes, [7] which made it the ninth leading cause of death. [8] Globally, the prevalence of diabetes also brings a heavy burden to healthcare systems, with an estimated expenditure of over 966 billion U.S. dollars per year. [7] Diabetes is generally categorized into two groups: Type I diabetes mellitus (T1DM) and Type II diabetes mellitus (T2DM), but there are still some cases that have different etiologies, such as gestational diabetes mellitus and monogenic diabetes. [9] Since the discovery of insulin in 1921, [10] significant progress has been made in diabetes pharmacotherapy and therapeutic technology; [11][12][13] however, since a permanent cure is unavailable, the discovery and development of anti-diabetic drugs is still at the forefront of diabetes research. With the rapid advancement in high-throughput omics technologies, combined with accumulated genome-wide association study (GWAS) data, a better understanding of diabetes pathophysiology may one day lead to the discovery of novel therapeutic targets. [14,15] This review will During the past decades, unprecedented progress in technologies has revolutionized traditional research methodologies. Among these, advances in highthroughput drug screening approaches have permitted the rapid identification of potential therapeutic agents from drug libraries that contain thousands or millions of molecules. Moreover, high-throughput-based therapeutic target discovery strategies can comprehensively interrogate relationships between biomolecules (e.g., gene, RNA, and protein) and diseas...

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A small molecule UPR modulator for diabetes identified by high throughput screening

Cited by 6 publications

References 39 publications

Endoplasmic Reticulum Chemical Chaperone 3‐Hydroxy‐2‐Naphthoic Acid Reduces Angiotensin II‐Induced Vascular Remodeling and Hypertension In Vivo and Protein Synthesis In Vitro

Endoplasmic Reticulum Chemical Chaperone 3‐Hydroxy‐2‐Naphthoic Acid Reduces Angiotensin II‐Induced Vascular Remodeling and Hypertension In Vivo and Protein Synthesis In Vitro

Ameliorative Effects of Gut Microbial Metabolite Urolithin A on Pancreatic Diseases

The Application of High‐Throughput Approaches in Identifying Novel Therapeutic Targets and Agents to Treat Diabetes

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