Dihydroaustrasulfone Alcohol (WA-25) Impedes Macrophage Foam Cell Formation by Regulating the Transforming Growth Factor-β1 Pathway

Abstract

Atherosclerosis is considered an inflammatory disease. However, clinically used anti-atherosclerotic drugs, such as simvastatin, have many side effects. Recently, several unique marine compounds have been isolated that possess a variety of bioactivities. In a previous study, we found a synthetic precursor of the marine compound (austrasulfone), which is dihydroaustrasulfone alcohol (WA-25), has anti-atherosclerotic effects in vivo. However, the detailed mechanisms remain unclear. Therefore, to clarify the mechanisms through which WA-25 exerts anti-atherosclerotic activity, we used RAW 264.7 macrophages as an in vitro model to evaluate the effects of WA-25. In lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, WA-25 significantly inhibited expression of the pro-inflammatory proteins, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In contrast, simvastatin increased the COX-2 expression compared to WA-25. In addition, WA-25 impedes foam cell formation and up-regulated the lysosomal and cyclic adenosine monophosphate (cAMP) signaling pathway. We also observed that transforming growth factor β1 (TGF-β1) was up-regulated by WA-25 and simvastatin in LPS-induced RAW 264.7 cells, and the promising anti-atherosclerosis effects of WA-25 were disrupted by blockade of TGF-β1 signaling. Besides, WA-25 might act through increasing lipolysis than through alteration of lipid export. Taken together, these data demonstrate that WA-25 may have potential as an anti-atherosclerotic drug with anti-inflammatory effects.

Nucleophosmin modulates the alleviation of atopic dermatitis caused by the marine-derived compound dihydroaustrasulfone alcohol

“…Our previous studies reported that WA-25 impedes the formation of foam cells, which would cause atherosclerosis by activating the transforming growth factor β1 (TGF-β1) pathway. 24 Interestingly, TGF-β1 inhibits AD in NC/Nga mice. 70 However, we also found that WA-25 inhibits angiogenesis.…”

“…Immunocytochemistry was performed using modified methods as previously described. 24 After treatment, RAW 264.7 cells were fixed with 4% paraformaldehyde in PBS buffer for 8 min and washed three times with PBS buffer. The cells were blocked with 4% normal goat serum dissolved in PBS containing 0.01% Triton X-100.…”

Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice

“…TGF-β1, a growth regulatory factor originating from multiple human epithelia, has various biological effects related to cellular proliferation and differentiation, deposition of extracellular matrix, and human immune responses [ 22 ]. TGF-β1 is a key cytokine that regulates cellular growth and controls the balance of extracellular matrix production and degradation [ 23 ].…”

The 1-Tosylpentan-3-one Protects against 6-Hydroxydopamine-Induced Neurotoxicity

“…Austrasulfone effectively decreases 6-OHDA-induced SH-SY5Y cell death. Furthermore, a previous study found that the intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, decreases the expression of proinflammatory cytokines such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), thus alleviating neuropathic pain and multiple sclerosis in rats regulating lipid metabolism in macrophages, and inhibiting restenosis [ 35 , 36 , 37 , 38 ]. The above results suggest that the bioactivity of austrasulfone and its intermediate, dihydroaustrasulfone, could be possibly related to their structures.…”