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.

Investigation of cationicity and structure of pseudin-2 analogues for enhanced bacterial selectivity and anti-inflammatory activity

“…The supernatants, in two-fold serial dilutions, were added to antibody capture pre-coated plates for 2 h at 25 °C. Inhibition of inflammatory cytokine release was determined using a sandwich ELISA assay as previously described 52 . To measure peptide-induced inhibition of expression of inflammatory cytokine mRNA and inflammation-related proteins, we performed reverse transcription polymerase chain reaction (RT-PCR) and western blot assays as previously described 25, 49 .…”

3,6‐Dihydroxyflavone Has Antituberculosis Activity and Suppresses Lung Inflammation

“…28 Mtb strains H 37 Rv (P887), MDR (M22, M23), and XDR (X24, X59) were mixed with liquid agarose and loaded into inlet wells at 37 C. Microfluidic agarose channels were formed and surrounded the liquid stock solution medium loading well. The anti-TB activity of 3,6-DHF and 3,6,3 0 ,4 0 -THF was measured against several Mtb strains as previously described.…”

“…H 37 Rv (P887) is a pan susceptible Mtb strain. 28 Immunoplate wells (SPL, Gyeonggi-do, Korea) were coated with antibodies against hTNFα, hIL-1β, and hIL-12. During incubation, the boundary area between the microfluidic agarose channels and the liquid medium loading wells was imaged to observe the bacterial growth at 1, 3, 5, 7, and 9 days using a 4X lens inverted microscope.…”

“…21,28 Sodium lauryl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) was conducted using 30 μg of protein per well. 21,28 Sodium lauryl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) was conducted using 30 μg of protein per well.…”

The Phytochemical Bergenin Enhances T Helper 1 Responses and Anti-Mycobacterial Immunity by Activating the MAP Kinase Pathway in Macrophages

“…In our efforts to characterize such compounds, we identified a large number of ethnomedical compounds that showed potent immunomodulatory activity (Chattopadhyay et al, 2012; Mukherjee et al, 2013; Jnawali et al, 2016; Lee and Suh, 2016; Gomez-Cansino et al, 2017). One of these compounds is bergenin, a tri-hydroxybenzoic acid or C-glycoside of 4-O-Methyl Gallic acid (Stanford et al, 1990; Narita et al, 1998; Patel et al, 2012) known as Paashaanbhed in Ayurveda.…”