Dimethyl Cardamonin Exhibits Anti-inflammatory Effects via Interfering with the PI3K-PDK1-PKCα Signaling Pathway

Abstract

Consumption of herbal tea [flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae)] is associated with health beneficial effects against multiple diseases including diabetes, asthma, and inflammatory bowel disease. Emerging evidences have reported that High mobility group box 1 (HMGB1) is considered as a key “late” proinflammatory factor by its unique secretion pattern in aforementioned diseases. Dimethyl cardamonin (2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone, DMC) is a major ingredient of C. operculatus flower buds. In this study, the anti-inflammatory effects of DMC and its underlying molecular mechanisms were investigated on lipopolysaccharide (LPS)-induced macrophages. DMC notably suppressed the mRNA expressions of TNF-α, IL-1β, IL-6, and HMGB1, and also markedly decreased their productions in a time- and dose-dependent manner. Intriguingly, DMC could notably reduce LPS-stimulated HMGB1 secretion and its nucleo-cytoplasmic translocation. Furthermore, DMC dose-dependently inhibited the activation of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1), and protein kinase C alpha (PKCα). All these data demonstrated that DMC had anti-inflammatory effects through reducing both early (TNF-α, IL-1β, and IL-6) and late (HMGB1) cytokines expressions via interfering with the PI3K-PDK1-PKCα signaling pathway.

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

“…But in parallel, DMC was also shown to induce intracellular reactive oxygen species (ROS) production, thereby enhancing the phosphorylation levels of proteins p38 and c-Jun NH 2 -terminal kinase (JNK) in macrophage-like RAW264.7 cells [ 20 ]. In these cells, DMC potently attenuates LPS-induced inflammatory response via inhibition of Nuclear Factor kappa B (NFκB) activation and a potent inhibition of cytokines expression, such as tumor necrosis factor-α (TNFα), interleukin (IL)-1β and IL-6 [ 21 , 22 ]. But depending on the experimental conditions and cell types, inhibition or activation of nuclear factor erythroid 2-related factor 2 (Nrf2) have been reported with DMC.…”

“…In a mouse model of LPS-induced endotoxin shock, the anti-inflammatory activity of DMC was characterized by a suppression of the secretion of TNFα, IL-6 and IL-1β in the blood serum, likely due to the drug-induced blockade of NFκB activation [ 21 ]. Importantly, the drug was also found to suppress LPS-stimulated secretion and nucleocytoplasmic translocation of the protein high-mobility group box 1 (HMGB1), which is a prototypical alarmin protein (or damage-associated molecular pattern, DAMP) [ 22 ]. DMC dose-dependently inhibited the phosphorylation of HMGB1 and its interaction with the enzyme Protein Kinase C (PKC).…”

Regulation mechanism of PDK1 on macrophage metabolism and function

“…HMGB1 is an important mediator in late‐phase inflammation and the translocation of HMGB1 from nucleus to cytoplasm is accelerated by PI3K‐PDK1‐PKC signaling pathway. Both CKD712 and DMC have anti‐inflammatory effect and dose dependently inhibit PI3K, PDK1, and cPKC, respectively . A study involving 95% ethanol extracts of Dipterocarpaceae shows anti‐inflammatory effect on LPS‐treated macrophages by regulating IκBα, which in turn regulates the nuclear translocation of NF‐κB .…”

“…Macrophages are derived from monocytes of hematopoietic stem cells and are quite special in boosting adaptive and especially innate immunity . When tissues suffer from bacterial invasion, injury, cancer cell growth, or other harmful substances, macrophages are activated by cytokines to work as the first defense barrier through the following complex multifunctional mechanism.…”

“…Macrophages are derived from monocytes of hematopoietic stem cells and are quite special in boosting adaptive and especially innate immunity. [20][21][22][23] When tissues suffer from bacterial invasion, injury, cancer cell growth, or other harmful substances, macrophages are activated by cytokines to work as the first defense barrier through the following complex multifunctional mechanism. Migration: resident and peripheral macrophages are recruited to respond to foreign factors by chemokines, growth factors, adhesion molecules, and/or surface proteoglcans.…”