Doo Suk Lee

Water soluble extracts from Actinidia arguta, PG102, attenuates house dust mite-induced murine atopic dermatitis by inhibiting the mTOR pathway with Treg generation.

ETHNOPHARMACOLOGICAL RELEVANCE Actinidia arguta is widespread in northeastern Asia, being found in Siberia, Korea, Japan, and northern China. These fruits have been documented to regulate the uncontrolled heat of body resulting in various allergic diseases in the Korean traditional medicine. PG102, a water-soluble extract from an edible fruit, A. arguta, has been previously shown to control various factors involved in allergic pathogenesis. AIM OF THE STUDY In this study, we investigated whether PG102 prevents chronic allergic reactions via the generation of Tregs, which play a preventive role in the pathogenesis of allergic disease. METHODS AND RESULTS In dust mite extract-induced chronic atopic dermatitis, orally administered PG102 inhibited symptoms of dermatitis, including ear swelling and erythema, and decreased lymphocyte infiltration into the inflamed region. Moreover, PG102 reduced inflammatory T cell responses and increased the expression levels of Foxp3 and other Treg-related genes. PG102 treatment enhanced the induction of CD4+Foxp3+ Tregs from naive CD4+CD62L+ T cells, probably via the inhibition of mTOR activation and the phosphorylation of STAT5 rather than using the TGF-β signaling pathway. CONCLUSION PG102 may have potential as an orally active immunosuppressor for preventing chronic inflammatory diseases.

Dehydrodiconiferyl Alcohol Inhibits Osteoclast Differentiation and Ovariectomy-Induced Bone Loss through Acting as an Estrogen Receptor Agonist

Estrogen deficiency after menopause increases bone loss by activating RANKL-induced osteoclast differentiation. Dehydrodiconiferyl alcohol (DHCA), a lignan originally isolated from Cucurbita moschata, has been thought to be a phytoestrogen based on its structure. In this study, we tested whether DHCA could affect RANKL-induced osteoclastogenesis in vitro and ovariectomy-induced bone loss in vivo. In RAW264.7 cells, DHCA inhibited RANKL-induced differentiation of osteoclasts. Consistently, expression of the six osteoclastogenic genes induced by RANKL was down-regulated. DHCA was also shown to suppress the NF-κB and p38 MAPK signaling pathways by activating AMPK. Data from transient transfection assays suggested that DHCA might activate the estrogen receptor signaling pathway. Effects of DHCA on RANKL-induced osteoclastogenesis were reduced when cells were treated with specific siRNA to ERα, but not to ERβ. Interestingly, DHCA was predicted from molecular docking simulation to bind to both ERα and ERβ. Indeed, data from an estrogen receptor competition assay revealed that DHCA acted as an agonist on both estrogen receptors. In the ovariectomized (Ovx) mouse model, DHCA prevented Ovx-induced bone loss by inhibiting osteoclastogenesis. Taken together, our results suggest that DHCA may be developed as an efficient therapeutic for osteoporosis by regulating osteoclastogenesis through its estrogenic effects.

Effective suppression of nitric oxide production by HX106N through transcriptional control of heme oxygenase-1

Heme oxygenase-1 (HO-1) has been suggested to be a key neuroprotective enzyme because of its widespread distribution in the brain as well as its strong antioxidative effects. HX106N, a water-soluble botanical formulation, has previously been demonstrated to prevent amyloid β-induced memory impairment and oxidative stress in mice by upregulating HO-1 levels. In this study, the underlying molecular mechanisms of HX106N-induced HO-1 expression were investigated using BV-2 cells, a murine microglial cell line, and primary microglia. Treatment with HX106N induced the expression of HO-1 at the transcriptional level through the stress-responsive element-containing enhancer present in the ho-1 promoter. Nuclear factor E2-related factor 2 (Nrf2) was activated in cells treated with HX106N. The results from knockdown assay showed that small interfering RNA of Nrf2 attenuated HX106N-mediated HO-1 expression. Pharmacological inhibitors of p38 and JNK mitogen-activated protein kinases suppressed the HX106N-mediated induction of HO-1. The NF-κB signaling pathway was activated by HX106N and played a role in HX106N-induced HO-1 expression. Furthermore, HO-1 and one of its by-products during the enzymatic degradation of heme, CO, were found to be involved in HX106N-mediated suppression of NO production. Taken together, these data indicate that HX106N exerts potent antioxidative effects by increasing the expression of HO-1 through multiple signaling pathways, leading to the suppression of NO production.