Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation

Kim, Jieun; Durai, Prasannavenkatesh; Jeon, Dasom; Jung, In Duk; Lee, Seung Jun; Park, Yeong‐Min; Kim, Yangmee

doi:10.3390/nu10070868

Cited by 48 publications

(43 citation statements)

References 35 publications

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“…Re-docking of the cocrystallized ligand (Pam 3 CSK 4 ) into the active site of TLR2/TLR1 heterodimer showed root mean square deviation (RMSD) less than 2 Å which propose the reliability of the docking protocol. 12 In addition to the hydrogen bond interactions, hydrophobic interaction with Phe312, Gln316 of TLR1 and Tyr376, Phe349 of TLR2 were observed. The best docked conformation was selected based on the cluster analysis, the binding energy and efficiency of the polar and non-polar interactions.…”

Section: Resultsmentioning

confidence: 98%

“…12 Measurement of Inflammatory Cytokine TNF-α in Pam 3 CSK 4 -Stimulated HEK293-hTLR2 Cells. 3,6-DHF was purchased from the Indofine Chemical Company (Hillsborough, NJ, USA) and purified using HPLC with an analytical Vydac C 18 column at Korea Basic Science Institute (KBSI, Ochang, Korea).…”

Section: Methodsmentioning

confidence: 99%

“…All 13 members are transmembrane proteins with intracellularly located Cterminal and the extracellular N-terminal that contain distinctive leucine-rich repeats which act as the ligand recognition domain. 11,12 In contrast, Pam 2 CSK 4 is a diacylated lipopeptide. 7 PAMPs and DAMPs are the molecules derived from microorganisms and from tissue injury, respectively.…”

Section: Introductionmentioning

confidence: 99%

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3,6‐Dihydroxyflavone: A Potent Inhibitor with Anti‐Inflammatory Activity Targeting Toll‐like Receptor 2

Balasubramanian

Kim

Son

et al. 2018

Bulletin Korean Chem Soc

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Toll-like receptors are membrane-bound proteins which plays a vital role in the regulation of innate immune response which is involved in various inflammatory disorders. 3,6-Dihydroxyflavone (3,6-DHF) is a known chemo preventive agent which is used in the treatment of various cancers including breast cancer and an effective JNK kinase inhibitor which can efficiently block the TLR2-mediated signaling pathways. In this current study, we have explored inhibition of 3,6-DHF in TLR2/TLR1 heterodimerization. We stimulated HEK cells by Pam 3 CSK 4 which specifically induced inflammation through TLR2/TLR1 binding. Secretion of the inflammatory cytokine in Pam 3 CSK 4 -induced HEK293-hTLR2 cells was considerably reduced by 3,6-DHF, implying that 3,6-DHF inhibited Pam 3 CSK 4 -induced TLR2/TLR1 signaling specifically. In addition, 3,6-DHF did not cause severe cytotoxicity against human embryonic kidney (HEK) cells at high concentration up to 100 μM. The binding affinity of 3,6-DHF to TLR2 and TLR1 was explored with 10 −5 affinity using bio-layer interferometry and molecular docking studies identified the important active site residues that participate in the inhibition of TLR2/TLR1 heterodimerization. Our results showed that 3,6-DHF inhibits TLR2-mediated inflammatory signaling by direct binding and the insights in designing more potent drug candidates by targeting the interacting crucial active site residues in TLR2/TLR1.

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Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3,6‐Dihydroxyflavone: A Potent Inhibitor with Anti‐Inflammatory Activity Targeting Toll‐like Receptor 2

Balasubramanian

Kim

Son

et al. 2018

Bulletin Korean Chem Soc

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“…Docking study revealed that the presence of a catechol function and 3′4′-dihydroxy groups on the B ring of polyphenols binds effectively with tyrosine and serine residues for its COX-2 inhibitory property (Castro, Valenzuela-Riffo, & Morales-Quintana, 2019;Kongpichitchoke et al, 2015 and TLR1 for being a more potent anti-inflammatory agent. The highly electrophilic α,β-unsaturated carbonyl moiety of phloretin, favors NF-κB inhibitory activity (Kim et al, 2018). Quercetin and its glycosylated derivatives, such as rutin and quercitrin (quercetin 3-rhamnoside), presence of a catechol group in the B ring makes it as a potent anti-inflammatory agent (Lago et al, 2014).…”

Section: Chemic Al Nature Of Pl Ant-ba S Ed P Olyphenol S and Antimentioning

confidence: 99%

The role of dietary polyphenols in inflammatory bowel disease: A possible clue on the molecular mechanisms involved in the prevention of immune and inflammatory reactions

2020

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Inflammatory bowel disease (IBD) is one of the major complications of the gastrointestinal tract, characterized by chronic inflammation, which disturbs the quality of life of the affected individuals. Genetic predisposition, immune, inflammatory, and enzyme-mediated signaling cascades are the primary mechanisms involved in the pathogenesis of the disease. Currently, the treatment strategy involves the maintenance of remission and induction of inflammation by anti-inflammatory agents and immune suppressants. Polyphenol-containing diets, including fruits and vegetables of regular use, possess anti-inflammatory, and antioxidant potential through the inhibition of major contributing pathways to IBD. This review discusses the role of these dietary polyphenols in downregulating the major signaling cascades in IBD. Our review encourages the development of nutritional strategies to improve the efficiency of current therapies for IBD and reduce the risks of side effects associated with conventional therapy. Practical applications At present, almost every third person in society is under stress and having chronic disorders like diabetes, arthritis, allergy, cardiovascular disease, IBD, etc. This insists on the direct/indirect role of changes in the lifestyle for such deterioration in society. This review would emphasize the medicinal value of polyphenols present in fruits and vegetables for chronic inflammatory disorders. This concept portrays the food components which have the potential to promote health, improve general well-being, and reduce the risk of IBD. We propose to add fruits with bioactive polyphenols in the regular diet to help in preventing the immune-mediated intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development.

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“…There has been a number of studies indicating the suppressive effect of different natural products (shinbaro3, curcumin, tanshinones, phloretin, xanthohumol, celastrol, garlic compounds etc.) on the different TLRs signaling (14,(23)(24)(25)(26). Additionally, several promising natural compounds (shinbaro3, curcumin, tanshinones) exert anti-inflammatory activities by suppressing TLR4/MyD88/NF-κB pathway.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of TLR4/TRIF/IRF3 Signaling Pathway by Curcumin in Breast Cancer Cells

et al. 2019

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Purpose: Toll-like receptor 4 (TLR4) is over-expressed in breast tumors and thus contributing to the tumor progression and metastasis. Natural products have drawn attention in cancer immunotherapy due to their various biological activities. Curcumin is well investigated in different types of cancer. However, the mechanisms underlying its anti-inflammatory actions have not been extensively elucidated. For this purpose, we explored the inhibitory effects of curcumin on lipopolysaccharide (LPS)-induced TLR4 dependent TRIF signaling pathway in two subtypes of breast cancer cell lines (MCF-7 and MDA-MB-231) in this study. Methods: In this context, the cytotoxicity of curcumin and LPS alone and the combination of curcumin with LPS on these cells was evaluated by WST-1 assay. The expression level of TLR4 and the release of type I interferon (IFN) levels were determined after treatment with curcumin and/or LPS by RT-PCR and ELISA analysis, respectively. Furthermore, the subcellular localization of TLR4 and interferon regulatory factor 3 (IRF3) were detected by immunofluorescence analysis. Results: Curcumin treatment suppressed breast cancer cells viabilities and the activation of TLR4-mediated TRIF signaling pathway by the downregulation of TLR4 and IRF3 expression levels and the inhibition of type I IFN (IFN-α/β) levels induced by LPS. However, curcumin was more efficient in MDA-MB-231 cells than MCF-7 cells owing to its greater inhibitory efficacy in the LPS- enhanced TLR4 signaling pathway. Furthermore, IFN-α/β levels induced by TLR4 and IRF3 were decreased in these cells following curcumin treatment. Conclusions: Consequently, these results demonstrated that the activation of LPS stimulated TLR4/TRIF/IRF3 signaling pathway was mediated by curcumin in breast cancer cells, in vitro. However, more studies are necessary to examine the curcumin’s anti-inflammatory activities on TLR4/MyD88/NF-κB as well as other signaling pathways downstream of TLRs in breast cancer.

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Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation

Cited by 48 publications

References 35 publications

3,6‐Dihydroxyflavone: A Potent Inhibitor with Anti‐Inflammatory Activity Targeting Toll‐like Receptor 2

3,6‐Dihydroxyflavone: A Potent Inhibitor with Anti‐Inflammatory Activity Targeting Toll‐like Receptor 2

The role of dietary polyphenols in inflammatory bowel disease: A possible clue on the molecular mechanisms involved in the prevention of immune and inflammatory reactions

Inhibition of TLR4/TRIF/IRF3 Signaling Pathway by Curcumin in Breast Cancer Cells

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