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Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation.

ABSTRACT: An increase in the prevalence of the drug-resistant Mycobacteria tuberculosis necessitates developing new types of anti-tuberculosis drugs. Here, we found that phloretin, a naturally-occurring flavonoid, has anti-mycobacterial effects on H37Rv, multi-drug-, and extensively drug-resistant clinical isolates, with minimum inhibitory concentrations of 182 and 364 ?M, respectively. Since Mycobacteria cause lung inflammation that contributes to tuberculosis pathogenesis, anti-inflammatory effects of phloretin in interferon-?-stimulated MRC-5 human lung fibroblasts and lipopolysaccharide (LPS)-stimulated dendritic cells were investigated. The release of interleukin (IL)-1?, IL-12, and tumor necrosis factor (TNF)-? was inhibited by phloretin. The mRNA levels of IL-1?, IL-6, IL-12, TNF-?, and matrix metalloproteinase-1, as well as p38 mitogen-activated protein kinase and extracellular signal-regulated kinase phosphorylation, were suppressed. A mouse in vivo study of LPS-stimulated lung inflammation showed that phloretin effectively suppressed the levels of TNF-?, IL-1?, and IL-6 in lung tissue with low cytotoxicity. Phloretin was found to bind M. tuberculosis ?-ketoacyl acyl carrier protein synthase III (mtKASIII) with high affinity (7.221 × 10? M-1); a binding model showed hydrogen bonding of A-ring 2'-hydroxy and B-ring 4-hydroxy groups of phloretin with Asn261 and Cys122 of mtKASIII, implying that mtKASIII can be a potential target protein. Therefore, phloretin can be a useful dietary natural product with anti-tuberculosis benefits.

SUBMITTER: Jeon D

PROVIDER: S-EPMC6155841 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation.

Jeon Dasom D Jeong Min-Cheol MC Jnawali Hum Nath HN Kwak Chulhee C Ryoo Sungwon S Jung In Duk ID Kim Yangmee Y

Molecules (Basel, Switzerland) 20170122 1

An increase in the prevalence of the drug-resistant <i>Mycobacteria tuberculosis</i> necessitates developing new types of anti-tuberculosis drugs. Here, we found that phloretin, a naturally-occurring flavonoid, has anti-mycobacterial effects on H37Rv, multi-drug-, and extensively drug-resistant clinical isolates, with minimum inhibitory concentrations of 182 and 364 μM, respectively. Since <i>Mycobacteria</i> cause lung inflammation that contributes to tuberculosis pathogenesis, anti-inflammator ...[more]

PMID: 28117761

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Project description:BackgroundHost immune response is a critical component in tumorigenesis and immune escape. Radiation is widely used for glioblastoma (GBM) and can induce marked tissue inflammation and substantially alter host immune response. However, the role of myeloperoxidase (MPO), a key enzyme in inflammation and host immune response, in tumorigenesis after radiotherapy is unclear. In this study, we aimed to determine how post-radiation MPO activity influences GBM and outcome.MethodsWe injected C57BL/6J or MPO-knockout mice with 005 mouse GBM stem cells intracranially. To observe MPO's effects on post-radiation tumor progression, we then irradiated the head with 10 Gy unfractionated and treated the mice with a specific MPO inhibitor, 4-aminobenzoic acid hydrazide (ABAH), or vehicle as control. We performed semi-quantitative longitudinal molecular MRI, enzymatic assays and flow cytometry to assess changes in inflammatory response and tumor size, and tracked survival. We also performed cell culture experiments in murine and human GBM cells to determine the effect of MPO on these cells.ResultsBrain irradiation increased the number of monocytes/macrophages and neutrophils, and boosted MPO activity by ten-fold in the glioma microenvironment. However, MPO inhibition dampened radiation-induced inflammation, demonstrating decreased MPO-specific signal on molecular MRI and attenuated neutrophil and inflammatory monocyte/macrophage recruitment to the glioma. Compared to saline-treated mice, both ABAH-treated and MPO-knockout mice had accelerated tumor growth and reduced survival. We further confirmed that MPO decreased tumor cell viability and proliferation in cell cultures.ConclusionLocal radiation to the brain initiated an acute systemic inflammatory response with increased MPO-carrying cells both in the periphery and the GBM, resulting in increased MPO activity in the tumor microenvironment. Inhibition or absence of MPO activity increased tumor growth and decreased host survival, revealing that elevated MPO activity after radiation has an anti-tumor role.

Dataset Information

Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation.

Publications

Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation.

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