Skin delivery of synthetic benzoyl pterostilbenes suppresses atopic dermatitis-like inflammation through the inhibition of keratinocyte and macrophage activation.

Atopic dermatitis (AD) is one of the most common skin autoimmune diseases needing continuous anti-inflammatory management. Pterostilbene is reported to exhibit anti-inflammatory activity with higher bioavailability and stability than its parent compound, resveratrol. In this study, a series of synthetic pterostilbene analogs were designed by the hybridization of pterostilbene with chalcones or benzoyl chloride. Seventeen analogs derived from pterostilbene were synthesized with differences in the positions of hydroxyl, methoxyl, or fluoro moieties. These compounds were screened by the inhibitory effect on the overexpressed Th2-associated cytokines/chemokines in the activated human keratinocytes (HaCaT). The anti-IL-5 and anti-CCL5 activity of these compounds led to the identification of three effective compounds: 3a ((E)- 4-(3,5-dimethoxystyryl)phenyl benzoate), 3d ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-methoxybenzoate), and 3g ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-fluorobenzoate). These benzoyl pterostilbenes also significantly decreased Th1/Th17-associated proinflammatory mediators in the activated macrophages (differentiated THP-1). The result showed that the conditioned medium of benzoyl pterostilbene-treated macrophages reduced the phosphorylated STAT3 in the keratinocytes, indicating the blockade of crosstalk between resident and immune cells. Compounds 3d and 3g generally showed greater skin absorption than 3a. The flux of 3g across barrier-defective skins mimicking the AD skin was 3-fold higher than that of across intact skin. The dinitrochlorobenzene (DNCB)-induced AD mouse model manifested that topical delivery with 3g improved the pathological signs through inhibiting cytokines/chemokines (IL-5, TNF-α, CCL17, and CCL22) and macrophage recruitment. The epidermal thickness was reduced from 76 to 55 µm after topical 3g delivery. The therapeutic activity of 3g was comparable to that of tacrolimus (TAC) used as a positive control. The benzoyl pterostilbenes attenuated the inflammation via the MAPK and c-Jun signaling. Furthermore, this study provided experimental evidence of benzoyl pterostilbene analogs for therapeutic potential on AD.

Sophoraflavanone G from Sophora flavescens induces apoptosis in triple-negative breast cancer cells.

BACKGROUND: A compound isolated from Sophora flavescens-sophoraflavanone G (SG)-showed anti-tumor and anti-inflammatory properties. We previously demonstrated that SG promoted apoptosis in human leukemia HL-60 cells. In the present study, we investigated the effects of SG on apoptosis in human breast cancer MDA-MB-231 cells, and explored the underlying molecular mechanisms. METHODS: MDA-MB-231 cells were treated with various SG concentrations, and cell viability was evaluated by MTT assay. Apoptotic signal proteins were detected by western blotting, and cell apoptosis was assessed using flow cytometry. RESULTS: Our results demonstrated that SG induced nuclear condensation, DNA fragmentation, reactive oxygen species production, and increased cell apoptosis in MDA-MB-231 cells. SG also suppressed migration and invasion, likely via blockage of the MAPK pathway. In the apoptotic signaling pathway, SG increased cleaved caspase-8, caspase-3, and caspase-9. SG treatment also decreased Bcl-2 and Bcl-xL expression, increased Bax expression, and prompted release of more cytochrome c from mitochondria to the cytoplasm in MDA-MB-231 cells. CONCLUSION: Overall, our findings suggest that SG might increase apoptosis, and decrease migration and invasion, in MDA-MB-231 cells through suppression of a MAPK-related pathway.

Sophoraflavanone G Induces Apoptosis in Human Leukemia Cells and Blocks MAPK Activation.

Sophoraflavanone G (SG) was isolated from Sophora flavescens. Previously, we have found that SG is able to suppress the inflammatory response in lipopolysaccharide-stimulated RAW 264.7 macrophages. This study aimed to evaluate the effects of SG on apoptosis, and explore its molecular mechanism in human leukemia HL-60 cells. HL-60 cells were treated with various concentrations of SG (3-30 [Formula: see text]M). The viability of the HL-60 cells was assessed using the MTT method, and the nuclear condensation indicative of apoptosis was observed by DAPI fluorescence staining. In addition, apoptotic signal proteins were examined using Western blotting. The results showed that apoptosis, including DNA fragmentation and nuclear condensation, increased significantly in SG-treated HL-60 cells. SG activated caspase-3 and caspase-9, and downregulated Bcl-2 and Bcl-xL. SG also upregulated Bax and released cytochrome c from the mitochondria into the cytoplasm, enabling apoptosis via the mitochondrially-mediated "intrinsic" pathway. Additionally, SG was able to cleave poly (ADP-ribose) polymerase 1 and activate mitogen-activated protein kinase (MAPK) pathways. These results suggest that SG might increase the effect of apoptosis on HL-60 cells through caspase-3 activation, mitochondrial-mediated pathways, and the MAPK pathway.