Naringenin exerts anticancer effects by inducing tumor cell death and inhibiting angiogenesis in malignant melanoma.

Malignant melanoma is one of the most deadly skin cancer, due to its aggressive proliferation and metastasis. Naringenin, abundantly present in citrus fruits, has widely studied in cancer therapy. In this study, we investigated whether naringenin also has anticancer effects against B16F10 murine and SK-MEL-28 human melanoma cells. Moreover, we assessed the effects of naringenin treatment on angiogenesis of HUVECs and ex vivo sprouting of microvessels.Naringenin inhibited tumor cell proliferation and migration in a dose-dependent manner in B16F10 and SK-MEL-28 cells, which is supported by the results that phosphorylation of ERK1/2 and JNK MAPK decreased. Furthermore, naringenin induced cell apoptosis. Western blot analysisshowed naringenin treatment significantly upregulated the protein expression of activated cas3 and PARP in B16F10 and SK-MEL-28 cells. In addition, in vitro and ex vivo angiogenesis assays demonstrated that naringenin treatment potently suppressed EC migration, tube formation, and sprouting of microvessels. RT-PCR analysis showed that naringenin treatment significantly reduced the mRNA expression of Tie2, but did not inhibit the expression of Ang2. In conclusion, present study demonstrates the anticancer effects of naringenin by its induction of tumor cell death and inhibition of angiogenesis in malignant melanoma, suggesting that naringenin has potential as a safe and effective therapeutic agent to treat melanoma.

Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model.

Diosmetin, a citrus flavonoid, has a variety of therapeutic properties such as antibacterial, anti-inflammatory and antioxidant effects. However, the effect of diosmetin on atopic dermatitis (AD) development has not been reported. This study thus aims to investigate whether diosmetin possesses inhibitory effects on AD development. A dinitrochlorobenzene (DNCB)-induced AD mouse model was used to evaluate the effects of diosmetin on AD development. Treatment with diosmetin significantly reduced the dermatitis score, thickness of epidermis and dermis and number of mast cells in comparison with the untreated group. Furthermore, immunohistochemical analysis using an anti-F4/80 antibody demonstrated that diosmetin significantly suppressed macrophage infiltration into the AD lesion. It was observed that the levels of pro-inflammatory cytokines (TNF-α, IL-4 and IL-1ß) in skin lesion decreased in response to treatment with diosmetin. In addition, the anti-inflammatory effect of diosmetin was evaluated in LPS- or IL-4-induced a mouse macrophage cell line (raw 264.7). Diosmetin inhibited the production of nitric oxide and decreased the expression of inducible nitric oxide synthase (iNOS). Diosmetin not only suppressed the phosphorylation of MAP kinase (ERK 1/2, p38 and JNK) but the activation of JAK/STAT signaling. The mRNA analysis demonstrated that diosmetin also reduced the level of inflammatory cytokines such as IL-1ß and IL-6. Collectively, these results demonstrate that diosmetin exhibits the inhibitory effect on AD, suggesting that diosmetin may be a potential therapeutic agent for this atopic disorder.

Diosmetin inhibits tumor development and block tumor angiogenesis in skin cancer.

Diosmetin is a natural flavonoid obtained from citrus fruits and some medicinal herbs. Previous studies have reported the anti-cancer activity of diosmetin in some types of tumors. However, it is still unclear whether diosmetin exerts anti-cancer effects, particularly anti-angiogenic effects, in skin cancer. In this study, we used B16F10 melanoma cells and human umbilical vein endothelial cells to investigate the inhibitory effect of diosmetin on cell proliferation, migration and tube formation in vitro. Rat aorta ring assays were performed to determine the effect of diosmetin on ECs sprouting ex vivo. Furthermore, a B16F10 mouse melanoma model was used to observe the effect of diosmetin on tumor growth, angiogenesis, and metastasis in vivo. Our results showed that diosmetin not only suppressed tumor cell proliferation and migration but also induced cell apoptosis via the caspase pathway in B16F10 cells, and potently inhibited tube formation and cell migration in HUVECs. Rat aorta ring assays showed that diosmetin attenuated the ECs sprouting. Moreover, the mouse melanoma model showed that diosmetin significantly delayed tumor growth by inhibiting tumor vessels sprouting and expansion during tumor progression. Notably, diosmetin induced the normalization of tumor vasculature through the downregulation of angiopoietin-2 and the improvement of pericyte coverage, leading to suppression of metastasis formation in lungs and lymph nodes. In conclusion, our results demonstrate that diosmetin suppresses tumor progression and metastasis by inducing tumor cell death and inhibiting tumor angiogenesis as well as normalizing the defective tumor vasculature, suggesting that diosmetin is a potential adjuvant chemotherapy agent.