Purpose:The purpose of this study was to extensively evaluate the efficacy of integrin αvβ3 antagonists for the treatment of experimental dry eye (EDE).Methods:Vitronectin, an αvβ3 ligand, was used to induce tumor necrosis factor-α gene expression in human THP-1 macrophages. To induce EDE, C57BL/6 mice were housed in a low-humidity controlled environment chamber and injected subcutaneously with scopolamine for 7 days. Subsequently, αvβ3 antagonists, including RGDfD, c(RGDfD), c(RGDiD), c(RGDfK), ATN-161, SB273005, and cilengitide, were administered topically to EDE animals under controlled environment chamber conditions. Corneal epithelial damage in EDE was assessed by fluorescein staining. The density of conjunctival goblet cells and secretion of tears was measured by period acid–Schiff staining and phenol red-impregnated cotton threads, respectively. Inflammation markers, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-17A, and metalloproteinase (MMP)-9, in the pooled cornea and conjunctiva tissues were examined by real-time polymerase chain reaction.Results:The inhibitory effects of αvβ3 antagonists on the vitronectin-induced tumor necrosis factor-α gene expression and integrin-mediated inflammatory signaling were validated in THP-1 macrophages. αvβ3 antagonists ameliorated the impairment of the corneal epithelial barrier with varying therapeutic efficacies, compared with vehicle-treated mice. c(RGDfD) and c(RGDiD) significantly protected against goblet cell loss, tear reduction, and proinflammatory gene expression in EDE.Conclusions:Topical applications of αvβ3 antagonists yield therapeutic benefits in EDE by promoting corneal epithelial defect healing and reducing inflammation. Antagonistic targeting αvβ3 may be a novel promising strategy to treat patients with dry eye disease.

01 Jan 2023·Neuroscience Letters

Neuroprotective effect of thyroid hormones on methamphetamine-induced neurotoxicity via cell surface receptors

Article

Author: Seyedhosseini Tamijani, Seyedeh Masoumeh ; Ahmadiani, Abolhassan ; Beirami, Elmira ; Dargahi, Leila ; Dargahi, Saina

Thyroid hormones (THs) have an essential role in normal brain development and function. Methamphetamine (MA) is a widely abused psychostimulant that induces irreversible damages to neuronal cells. In the current study, we used rat primary hippocampal neurons (PHNs) to investigate the neuroprotective effect of THs against MA neurotoxicity. PHNs were prepared from 18-day rat embryos and cell viability was assessed using MTT assay, following treatment with various concentrations of MA, T3, T4 or tetrac, an integrin αvβ3 cell surface receptor antagonist. Our results showed that 7 mM MA induced an approximately 50 % reduction in the PHNs viability. Treatment with 800 nM T3 or 8 μM T4 protected PHNs against MA toxicity, an effect which was blocked in the presence of tetrac. These findings suggest that THs protect PHNs against MA-induced cell death by the activation of integrin αvβ3 cell surface receptors. So, targeting integrin αvβ3 receptors or using THs can be considered as promising therapeutic strategies to overcome MA neurotoxicity.

06 Sep 2022·Molecular Cancer Therapeutics

Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

Article

Author: Marullo, Rossella ; Zamponi, Nahuel ; Díaz Flaqué, María C. ; Mulvey, Erin ; Revuelta, Maria V. ; Cremaschi, Graciela A. ; Cerchietti, Leandro ; Magro, Cynthia ; Phillip, Jude M. ; Ruan, Jia ; Debernardi, Mercedes ; Cayrol, Florencia ; Sterle, Helena ; Paulazo, Alejandra

AbstractBexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVβ3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an αVβ3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVβ3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin αVβ3 inhibitors as part of CTCL regimens based on bexarotene administration.Teaser:Inhibiting αVβ3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.

100 Deals associated with Integrin αvβ3 targeting CAR-T(Virginia)

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	US	University of Virginia	18 Apr 2023
Melanoma	Preclinical	US	University of Virginia	18 Apr 2023

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