Dual Role of 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone in Inhibiting High-Mobility Group Box 1 Secretion and Blocking Its Pro-inflammatory Activity in Hepatic Inflammation

Yu, Wanguo; He, Hao; Qian, Jie; Lü, Yanhua

doi:10.1021/jf504527r

Cited by 16 publications

(11 citation statements)

References 50 publications

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“…4 ). Thus, our own in silico analysis of the interaction of DMC with HMGB1 corroborates the initial observations made with a simpler model of HMGB1 Box-B [ 24 ]. At present, the direct binding of DMC to HMGB1 is based only on molecular models; it will necessitate an experimental validation.…”

Section: Molecular Targets Of Dmcsupporting

confidence: 86%

“…DMC dose-dependently inhibited the phosphorylation of HMGB1 and its interaction with the enzyme Protein Kinase C (PKC). The drug efficiently blocked the pro-inflammatory activity of HMGB1 [ 24 ]. This key property is further discussed below, as HMGB1 is considered a direct molecular target of DMC.…”

Section: Anti-inflammatory Activitiesmentioning

confidence: 99%

“…It has been reported that DMC can inhibit HMGB1 secretion and block the pro-inflammatory activity of the protein in a model of LPS-stimulated hepatic inflammation. Not only the drug dose-dependently inhibited the mRNA expression of HMGB1 and the extracellular protein release from activated liver macrophages but it also reduced the phosphorylation of downstream signaling proteins such as PI3K, PKCα and PDK1 [ 24 ]. The authors showed that the drug blocked the nucleocytoplasmic translocation of HMGB1 through the suppression of HMGB1 phosphorylation.…”

Section: Molecular Targets Of Dmcmentioning

confidence: 99%

“…A direct interaction of DMC with HMGB1 was proposed based on molecular modeling using a small protein motif (Box-B only) of HMGB1. The docking analysis suggested that DMC binds to Box-B via H-bonding interactions with specific amino acid residues (notably Arg-91, Ser-94, Lys-90) and multiple hydrophobic contacts [ 24 ]. Subsequently, the same authors demonstrated that DMC had anti-inflammatory effects through reducing HMGB1 expression (and expression of both early cytokines) (TNF-α, IL-1β, and IL-6) via interfering with the PI3K-PDK1-PKCα signaling pathway [ 22 ].…”

Section: Molecular Targets Of Dmcmentioning

confidence: 99%

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Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

Bailly

Vergoten

2020

Life Sciences

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Dimethyl cardamonin (DMC) has been isolated from diverse plants, notably from Cleistocalyx operculatus . We have reviewed the pharmacological properties of this natural product which displays anti-inflammatory, anti-hyperglycemic and anti-cancer properties. The pharmacological activities essentially derive from the capacity of DMC to interact with the protein targets HMGB1 and AMPK. Upon binding to HMGB1, DMC inhibits the nucleocytoplasmic transfer of the protein and its extracellular secretion, thereby blocking its alarmin function. DMC also binds to the AMP site of AMPK to activate phospho-AMPK and then to trigger downstream signals leading to the anti-inflammatory and anti-hyperglycemic effects. AMPK activation by DMC reinforces inhibition of HMGB1, to further reduce the release of the alarmin protein, likely contributing to the anticancer effects. The characterization of a tight control of DMC over the AMPK-HMGB1 axis not only helps to explain the known activities of DMC but also suggests opportunities to use this chalcone to treat other pathological conditions such as the acute respiratory distress syndrome (which affects patients with COVID-19). DMC structural analogues are also evoked.

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Section: Molecular Targets Of Dmcsupporting

confidence: 86%

Section: Anti-inflammatory Activitiesmentioning

confidence: 99%

Section: Molecular Targets Of Dmcmentioning

confidence: 99%

Section: Molecular Targets Of Dmcmentioning

confidence: 99%

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Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

Bailly

Vergoten

2020

Life Sciences

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“…Long-term dietary supplementation intervention is important for humans at risk of developing adiposity [1617]. Teas have long been considered as a dietary component [18].…”

Section: Introductionmentioning

confidence: 99%

Fumigaclavine C attenuates adipogenesis in 3T3-L1 adipocytes and ameliorates lipid accumulation in high-fat diet-induced obese mice

Chen

et al. 2019

Korean J Physiol Pharmacol

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Fumigaclavine C (FC), an active indole alkaloid, is obtained from endophytic Aspergillus terreus (strain No. FC118) by the root of Rhizophora stylosa (Rhizophoraceae). This study is designed to evaluate whether FC has anti-adipogenic effects in 3T3-L1 adipocytes and whether it ameliorates lipid accumulation in high-fat diet (HFD)-induced obese mice. FC notably increased the levels of glycerol in the culture supernatants and markedly reduced lipid accumulation in 3T3-L1 adipocytes. FC differentially inhibited the expressions of adipogenesis-related genes, including the peroxisome proliferator-activated receptor proteins, CCAAT/enhancer-binding proteins, and sterol regulatory element-binding proteins. FC markedly reduced the expressions of lipid synthesis-related genes, such as the fatty acid binding protein, lipoprotein lipase, and fatty acid synthase. Furthermore, FC significantly increased the expressions of lipolysis-related genes, such as the hormone-sensitive lipase, Aquaporin-7, and adipose triglyceride lipase. In HFD-induced obese mice, intraperitoneal injections of FC decreased both the body weight and visceral adipose tissue weight. FC administration significantly reduced lipid accumulation. Moreover, FC could dose-dependently and differentially regulate the expressions of lipid metabolism-related transcription factors. All these data indicated that FC exhibited anti-obesity effects through modulating adipogenesis and lipolysis.

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Total Syntheses of 4′,6′‐Dimethoxy‐2'‐Hydroxy‐3′,5′‐Dimethylchalcone Derivatives

Lee

Park

2020

Bulletin Korean Chem Soc

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Chalcone derivatives afford several pharmacological activities. However, a general synthetic method for 2',4'‐dihydroxy‐6'‐methoxy‐3',5'‐dimethylchalcone (DMC) derivatives has not been reported thus far. To address this, the preparation of 4',6'‐dimethoxy‐2'‐hydroxy‐3',5'‐dimethylchalcone (MDMC) derivatives, modified compounds of DMC, in excellent overall yields is reported herein. These compounds have recently attracted growing attention due to their various pharmacological activities. Di‐O‐methyl‐dimethylphloroacetophenone, the key intermediate containing the B‐ring moiety, was fabricated by four efficient reaction steps from commercially available phloroglucinol in a 50.1% isolated yield overall. Our synthetic route, which constructs the chalcone skeleton in the final stage via a Claisen–Schmidt condensation of the key intermediate with the desired benzaldehyde derivative, can rapidly produce a vast library of DMC derivatives.

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Dual Role of 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone in Inhibiting High-Mobility Group Box 1 Secretion and Blocking Its Pro-inflammatory Activity in Hepatic Inflammation

Cited by 16 publications

References 50 publications

Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

Fumigaclavine C attenuates adipogenesis in 3T3-L1 adipocytes and ameliorates lipid accumulation in high-fat diet-induced obese mice

Total Syntheses of 4′,6′‐Dimethoxy‐2'‐Hydroxy‐3′,5′‐Dimethylchalcone Derivatives

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