Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice
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RESEARCH ARTICLE
Open Access
Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice Kai Lu1, O. Hans Iwenofu1, Rita Mitra2, Xiaokui Mo3, Partha Sarathi Dasgupta4 and Sujit Basu1,5*
Abstract Background: Although vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2–3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated. Methods: CIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo. Results: Significant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice. (Continued on next page)
* Correspondence: [email protected] 1 Department of Pathology, Ohio State University, Hamilton Hall (H166), 1645 Neil Avenue, Columbus, OH 43210, USA 5 Division of Medical Oncology, Department of Internal Medicine, Ohio State University, Columbus, OH 43210, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory
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