RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice.

Joshi, Aditi; Wu, Ying; Deng, Songyan; Preston-Hurlburt, Paula; Forbes, Josephine M.; Herold, Kevan C.

doi:10.1016/j.clim.2022.109165

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…In particular, levels of IL‐1β, IL‐6, and TNF‐α were reduced. Azeliragon also reduced serum cytokines in mice to improve xenograft rejection by T cells, with reduction in levels of IL‐1β, IL‐10, and IL‐17A [31] . Such studies indicate that inhibiting interactions between RAGE and its ligands can affect the downward stream of proinflammatory cytokine production and thus attenuate negative pathological inflammatory pathways.…”

Section: Discussionmentioning

confidence: 88%

“…Azeliragon also reduced serum cytokines in mice to improve xenograft rejection by T cells, with reduction in levels of IL-1β, IL-10, and IL-17A. [31] Such studies indicate that inhibiting interactions between RAGE and its ligands can affect the downward stream of proinflammatory cytokine production and thus attenuate negative pathological inflammatory pathways. The parallel reduction of cytokine production by peptoids in cell culture suggests that they possess potential to affect inflammation-associated disease states.…”

Section: Discussionmentioning

confidence: 91%

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Modulating the RAGE‐Induced Inflammatory Response: Peptoids as RAGE Antagonists

Waugh,

Wolf,

Turner

et al. 2023

ChemBioChem

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While the primary pathology of Alzheimer’s disease (AD) is defined by brain deposition of amyloid‑β (Aβ) plaques and tau neurofibrillary tangles, chronic inflammation has emerged as an important factor in AD etiology. Upregulated cell surface expression of the receptor for advanced glycation end‐products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including Aβ aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD‐associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood‐brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic Aβ, a ligand that binds the V‐domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide‐induced pro‐inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid‐based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 91%

Modulating the RAGE‐Induced Inflammatory Response: Peptoids as RAGE Antagonists

Waugh,

Wolf,

Turner

et al. 2023

ChemBioChem

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“…The V-domain of RAGE is the main binding area between RAGE and DAMPs [14]. Several small molecule inhibitors target the RAGE-V structural domain, such as FPS-ZM1, HMGB1-derived Peptide, and Azeliragon (TTP488), which can bind to various DAMPs, including HMGB1, and have been validated in several systems [15][16][17][18]. In this paper, we applied two antagonists, TFA, the peptide salt of the small peptide antagonist RAGE antagonist peptide (RAP) [19], and FPS-ZM1 [17], a small molecule inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the HMGB1/RAGE axis protects against cisplatin-induced ototoxicity via suppression of inflammation and oxidative stress

Qiao,

Li,

Zheng

et al. 2024

Int. J. Biol. Sci.

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As an anti-tumor drug widely used in the clinic, cisplatin is limited by its ototoxic side effects associated with various factors, including inflammatory responses. Receptor for Advanced Glycation Endproducts (RAGE) recognizes damage-associated molecular patterns (DAMPs) and promotes stress and inflammation. This study intended to determine the potential behavior of the HMGB1/RAGE axis after cisplatin injury and whether it has a protective effect after inhibiting this pathway. We used FPS-ZM1, a RAGE inhibitor, to modulate the axis of HMGB1/RAGE in neonatal mouse cochlear explants and C57BL/6 mice in vivo . Apoptosis was identified by Annexin V-FITC/PI assay, Cleaved Caspase-3, and TUNEL staining. Reactive oxygen species (ROS) level was assessed by MitoSOX Red and CellROX Green assay. The expression of proteins associated with the HMGB1/RAGE axis and apoptosis was observed by western blotting. The expression of inflammatory cytokines was evaluated by qPCR. The protective effect of HMGB1/RAGE knockdown was also assessed on cisplatin-induced ototoxicity. These results demonstrated that cisplatin could activate the HMGB1/RAGE pathway in cochlear hair cells and release inflammatory factors. Pretreatment with FPS-ZM1 alleviated cisplatin-induced ototoxicity in vivo and in vitro . Knocking down HMGB1 and RAGE achieved specific protective effects. Altogether, inhibiting HMGB1/RAGE axis can reverse the increase of ROS accumulation, the activation of apoptosis, and the production of inflammatory reactions after cisplatin injury. FPS-ZM1 could resist the ototoxicity of cisplatin by suppressing the HMGB1/RAGE signal pathway, and it may be considered the new otoprotective potential strategy for hearing loss.

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Pathological role of RAGE underlying progression of various diseases: its potential as biomarker and therapeutic target

Sarkar

2024

Naunyn-Schmiedeberg's Arch Pharmacol

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RAGE antagonism with azeliragon improves xenograft rejection by T cells in humanized mice.

Cited by 5 publications

References 38 publications

Modulating the RAGE‐Induced Inflammatory Response: Peptoids as RAGE Antagonists

Modulating the RAGE‐Induced Inflammatory Response: Peptoids as RAGE Antagonists

Inhibition of the HMGB1/RAGE axis protects against cisplatin-induced ototoxicity via suppression of inflammation and oxidative stress

Pathological role of RAGE underlying progression of various diseases: its potential as biomarker and therapeutic target

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