Berberine Inhibits HIV Protease Inhibitor-Induced Inflammatory Response by Modulating ER Stress Signaling Pathways in Murine Macrophages |
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Authors: | Weibin Zha Guang Liang Jian Xiao Elaine J Studer Phillip B Hylemon William M Pandak Jr Guangji Wang Xiaokun Li Huiping Zhou |
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Institution: | 1. Department of Microbiology & Immunology and Internal Medicine/Gastroenterology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.; 2. China Pharmaceutical University, Nanjing, China.; 3. School of Pharmacy, Wenzhou Medical College, Wenzhou, China.;University of Maryland School of Pharmacy, United States of America |
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Abstract: | BackgroundHIV protease inhibitor (PI)-induced inflammatory response plays an important role in HIV PI-associated dyslipidemia and cardiovascular complications. This study examined the effect of berberine, a traditional herb medicine, on HIV PI-induced inflammatory response and further investigated the underlying cellular/molecular mechanisms in macrophages.Methodology and Principal FindingsCultured mouse J774A.1 macrophages and primary mouse macrophages were used in this study. The expression of TNF-α and IL-6 were detected by real-time RT-PCR and ELISA. Activations of ER stress and ERK signaling pathways were determined by Western blot analysis. Immunofluorescent staining was used to determine the intracellular localization of RNA binding protein HuR. RNA-pull down assay was used to determine the association of HuR with endogenous TNF-α and IL-6. Berberine significantly inhibited HIV PI-induced TNF-α and IL-6 expression by modulating ER stress signaling pathways and subsequent ERK activation, in turn preventing the accumulation of the RNA binding protein HuR in cytosol and inhibiting the binding of HuR to the 3′-UTRs of TNF-α and IL-6 in macrophages.Conclusions and SignificanceInhibition of ER stress represents a key mechanism by which berberine prevents HIV PI-induced inflammatory response. Our findings provide a new insight into the molecular mechanisms of berberine and show the potential application of berberine as a complimentary therapeutic agent for HIV infection. |
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