Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice

Manigrasso, Michaele B.; Rabbani, Piul S.; Egaña-Gorroño, Lander; Quadri, Nosirudeen; Frye, Laura; Zhou, Boyan; Reverdatto, Sergey; Ramirez, Lisa; Dansereau, Stephen; Pan, Jinhong; Li, Huilin; D’Agati, Vivette D.; Ramasamy, Ravichandran; DeVita, Robert J.; Shekhtman, Alexander; Schmidt, Ann Marie

doi:10.1126/scitranslmed.abf7084

Cited by 39 publications

(37 citation statements)

References 95 publications

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“…Numerous studies have underscored that the RAGE ligands may bind on multiple and discrete domains of the extracellular V, C1, and C2-type Ig domains (99,100). On account of these findings by multiple research groups, it is plausible that targeting the RAGE-DIAPH1 interaction may represent a superior approach to capture the signaling impact of the multiple RAGE ligands through blocking downstream events; in this context, administration of the chemical probe, RAGE229, which binds to the cytoplasmic domain of RAGE and blocks interaction with DIAPH1, to mice blocks delayed type hypersensitivity inflammation, cardiac ischemia (diabetic mice), type 1 and type 2-diabetes like kidney disease and improves wound healing in mice with type 2-like diabetes (33,34). Time will tell if stopping the cycle of RAGE/DIAPH1-dependent dysregulation of glucose and lipid metabolism, through this small molecule approach, may be translated to benefit for human subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Roles for RAGE and DIAPH1 in these processes were demonstrated through studies using a new class of RAGE-DIAPH1 antagonists (33,34). Specifically, these small molecules bind to the cytoplasmic tail of RAGE and block the RAGE tail interaction with DIAPH1; this has been illustrated directly using in vitro binding assays as well as FRET assays (34). A representative small molecule antagonist of RAGE/DIAPH1 was shown to suppress uptake of oxLDL and foam cell formation in wild-type RAGE-expressing macrophages (35).…”

Section: Rage/diaph1 and Foam Cell Formationmentioning

confidence: 99%

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Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) – Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

Arivazhagan

López‐Díez

Shekhtman

et al. 2022

Front. Cardiovasc. Med.

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Obesity and non-alcoholic fatty liver disease (NAFLD) are on the rise world-wide; despite fervent advocacy for healthier diets and enhanced physical activity, these disorders persist unabated and, long-term, are major causes of morbidity and mortality. Numerous fundamental biochemical and molecular pathways participate in these events at incipient, mid- and advanced stages during atherogenesis and impaired regression of established atherosclerosis. It is proposed that upon the consumption of high fat/high sugar diets, the production of receptor for advanced glycation end products (RAGE) ligands, advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs), contribute to the development of foam cells, endothelial injury, vascular inflammation, and, ultimately, atherosclerosis and its consequences. RAGE/Diaphanous-1 (DIAPH1) increases macrophage foam cell formation; decreases cholesterol efflux and causes foam cells to produce and release damage associated molecular patterns (DAMPs) molecules, which are also ligands of RAGE. DAMPs stimulate upregulation of Interferon Regulatory Factor 7 (IRF7) in macrophages, which exacerbates vascular inflammation and further perturbs cholesterol metabolism. Obesity and NAFLD, characterized by the upregulation of AGEs, ALEs and DAMPs in the target tissues, contribute to insulin resistance, hyperglycemia and type two diabetes. Once in motion, a vicious cycle of RAGE ligand production and exacerbation of RAGE/DIAPH1 signaling ensues, which, if left unchecked, augments cardiometabolic disease and its consequences. This Review focuses on RAGE/DIAPH1 and its role in perturbation of metabolism and processes that converge to augur cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Section: Rage/diaph1 and Foam Cell Formationmentioning

confidence: 99%

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) – Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

Arivazhagan

López‐Díez

Shekhtman

et al. 2022

Front. Cardiovasc. Med.

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“…These include: anti-RAGE antibodies, sRAGE, and RAGE inhibitors; FPSZM1, a specific and potent chemical inhibitor of AGE receptor, which could improve diabetic nephropathy [ 96 ] and Aβ-mediated brain disorder [ 97 ]; Azeliragon, an oral small molecule antagonist of RAGE in Phase 3 development for mild cognitive impairment [ 98 ]. Small molecules are also in development to inhibit Diaphanous.1, the intracellular RAGE adaptor [ 99 ]. Inhibiting oxidative stress and inflammation in tissues by blocking the interaction of AGEs with RAGE is another new way to inhibit the process of late glycation.…”

Section: Inhibitors Of Agesmentioning

confidence: 99%

Research Advances on the Damage Mechanism of Skin Glycation and Related Inhibitors

Zheng

et al. 2022

Nutrients

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Our skin is an organ with the largest contact area between the human body and the external environment. Skin aging is affected directly by both endogenous factors and exogenous factors (e.g., UV exposure). Skin saccharification, a non-enzymatic reaction between proteins, e.g., dermal collagen and naturally occurring reducing sugars, is one of the basic root causes of endogenous skin aging. During the reaction, a series of complicated glycation products produced at different reaction stages and pathways are usually collectively referred to as advanced glycation end products (AGEs). AGEs cause cellular dysfunction through the modification of intracellular molecules and accumulate in tissues with aging. AGEs are also associated with a variety of age-related diseases, such as diabetes, cardiovascular disease, renal failure (uremia), and Alzheimer’s disease. AGEs accumulate in the skin with age and are amplified through exogenous factors, e.g., ultraviolet radiation, resulting in wrinkles, loss of elasticity, dull yellowing, and other skin problems. This article focuses on the damage mechanism of glucose and its glycation products on the skin by summarizing the biochemical characteristics, compositions, as well as processes of the production and elimination of AGEs. One of the important parts of this article would be to summarize the current AGEs inhibitors to gain insight into the anti-glycation mechanism of the skin and the development of promising natural products with anti-glycation effects.

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“…This novel screening strategy of searching for molecules able to block protein–protein interactions has been demonstrated to be successful to inhibit the RAGE-mediated expression of inflammatory genes in diabetes complications[ 88 , 89 ] and atherosclerosis[ 90 ].…”

Section: Therapeutic Potential Of the Rage/ages Axis In Tumor Biologymentioning

confidence: 99%

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider

Rojas¹,

Lindner²,

Schneider³

et al. 2022

World J Gastroenterol

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Compelling evidence derived from clinical and experimental research has demonstrated the crucial contribution of chronic inflammation in the development of neoplasms, including gallbladder cancer. In this regard, data derived from clinical and experimental studies have demonstrated that the receptor of advanced glycation end-products (RAGE)/AGEs axis plays an important role in the onset of a crucial and long-lasting inflammatory milieu, thus supporting tumor growth and development. AGEs are formed in biological systems or foods, and food-derived AGEs, also known as dietary AGEs are known to contribute to the systemic pool of AGEs. Once they bind to RAGE, the activation of multiple and crucial signaling pathways are triggered, thus favoring the secretion of several proinflammatory cytokines also involved in the promotion of gallbladder cancer invasion and migration. In the present review, we aimed to highlight the relevance of the association between high dietary AGEs intakes and high risk for gallbladder cancer, and emerging data supporting that dietary intervention to reduce gallbladder cancer risk is a very attractive approach that deserves much more research efforts.

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Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice

Abstract: Small-molecule antagonism of RAGE-DIAPH1 reduces diabetes-related complications in mice.

Cited by 39 publications

References 95 publications

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) – Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) – Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

Research Advances on the Damage Mechanism of Skin Glycation and Related Inhibitors

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider

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