title: Antituberculosis Activity of a Naturally Occurring Flavonoid, Isorhamnetin.
abstract: Isorhamnetin (1) is a naturally occurring flavonoid having anticancer and anti-inflammatory properties. The present study demonstrated that 1 had antimycobacterial effects on Mycobacterium tuberculosis H37Rv, multi-drug- and extensively drug-resistant clinical isolates with minimum inhibitory concentrations of 158 and 316 μM, respectively. Mycobacteria mainly affect the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis. We investigated the effects of 1 on interferon (IFN)-γ-stimulated human lung fibroblast MRC-5 cells. Isorhamnetin suppressed the release of tumor necrosis factor (TNF)-α and interleukin (IL)-12. A nontoxic dose of 1 reduced mRNA expression of TNF-α, IL-1β, IL-6, IL-12, and matrix metalloproteinase-1 in IFN-γ-stimulated cells. Isorhamnetin inhibited IFN-γ-mediated stimulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase and showed high-affinity binding to these kinases (binding constants: 4.46 × 10(6) M(-1) and 7.6 × 10(6) M(-1), respectively). The 4'-hydroxy group and the 3'-methoxy group of the B-ring and the 5-hydroxy group of the A-ring of 1 play key roles in these binding interactions. A mouse in vivo study of lipopolysaccharide-induced lung inflammation revealed that a nontoxic dose of 1 reduced the levels of IL-1β, IL-6, IL-12, and INF-γ in lung tissue. These data provide the first evidence that 1 could be developed as a potent antituberculosis drug.
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul, 143-701, South Korea.
authors.forename: Hum Nath
authors.initials: HN
authors.lastname: Jnawali
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul, 143-701, South Korea.
authors.forename: Dasom
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul, 143-701, South Korea.
authors.forename: Min-Cheol
authors.initials: MC
authors.lastname: Jeong
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul, 143-701, South Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul, 143-701, South Korea.
authors.forename: Bongwhan
authors.initials: B
authors.lastname: Jin
authors.affiliation: Korean Institute of Tuberculosis , Osong, Cheongju, 361-954, South Korea.
authors.forename: Sungweon
authors.initials: S
authors.lastname: Ryoo
authors.affiliation: Quantamatrix Inc., Seoul National University , Seoul, 151-742, South Korea.
authors.forename: Jungheon
authors.initials: J
authors.lastname: Yoo
authors.affiliation: Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University , Chungju, 380-701, South Korea.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.affiliation: Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University , Chungju, 380-701, South Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Immunology, Lab of Dendritic Cell Differentiation & Regulation, School of Medicine, Konkuk University , Chungju, 380-701, South Korea.
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Konkuk University , Seoul, 143-701, South Korea.
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000995:Antitubercular Agents; D005419:Flavonoids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C047368:3-methylquercetin; D007371:Interferon-gamma; D011794:Quercetin; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1