The extract of buds of Chrysanthemum morifolium ramat alleviated UVB-induced skin photoaging by regulating MAPK and Nrf2/ARE pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum morifolium Ramat. is a commonly used Chinese herb and food homologous plant with traditional effects such as anti-inflammatory, antifebrile, antibacterial and antiviral. AIM OF STUDY: Photoaging is one of the main causes of accelerated skin aging. Chrysanthemum morifolium Ramat. has reported to alleviate photodamage. In this study, we investigated the protective effect of the extract of buds of Chrysanthemum morifolium Ramat. (CE) on UVB-induced photoaging and further mechanism. MATERIALS AND METHODS: The extract of buds of chrysanthemum was analyzed by HPLC-Q-TOF-MS/MS. Antioxidant activity was assessed by DPPH and ABTS assay. Cell viability examined by cell counting kit-8 assay. The ROS level was detected by fluorescent probe DCFH-DA. Protein expression evaluated by Western blotting. The skin tissue investigated by immunohistochemistry. RESULTS: CE significantly reversed the decrease of cell viability that induced by UVB in HaCaT and HFF-1 cells. Further analysis showed that CE alleviated photoaging by inhibiting the expression of mitogen-activated protein kinase (MAPK) and activating the NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway to promote the expression of antioxidant enzymes. Moreover, CE effectively improved the reduced skin hydration, disordered collagen and thickening epidermis caused by UVB in mice. CONCLUSIONS: All results demonstrated that CE had therapeutic effect on UVB-induced photoaging and provided theoretical basis for its further developing as a natural functional product with anti-photoaging effect.

Design, Synthesis, and Biological Evaluation for First GPX4 and CDK Dual Inhibitors.

The coexistence of ferroptosis and other modes of death has great advantages in the treatment of cancers. A series of glutathione peroxidase 4 (GPX4) and cyclin-dependent kinase (CDK) dual inhibitors were designed and synthesized, given the synergistic anticancer effect of ML162 (GPX4 inhibitor) in combination with indirubin-3'-oxime (IO) (CDK inhibitor). Compound B9 exhibited the highest potential cytotoxic activity against all four cell lines and displayed excellent inhibitory activity against GPX4 (IC50 = 542.5 ± 0.9 nM) and selective inhibition of CDK 4/6 (IC50 = 191.2 ± 8.7, 68.1 ± 1.4 nM). Mechanism research showed that B9 could simultaneously induce ferroptosis and arrest cells at the G1 phase in both MDA-MB-231 cells and HCT-116 cells. Compared with ML162 and IO, B9 showed much stronger cancer cell growth inhibition in vivo. These results proved that developing potent GPX4/CDK dual inhibitors is a promising strategy for the malignant cancer therapy.

Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer.

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 µM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer.

New N-oxide alkaloids from the stems of Sinomenium acutum.

Six new alkaloids (1-6) and six known alkaloids (7-12) were obtained from the stems of Sinomenium acutum. Among them, compounds 1-3 and 6 were four N-oxide alkaloids. The structures and absolute configurations of these new alkaloids were elucidated through comprehensive data of 1D and 2D NMR, HRESIMS and ECD spectra. All isolated compounds were evaluated in vitro for their inhibitory activities against nitric oxide (NO) production and inhibitory effects on AChE. Among them, the sinomenine N-oxide (9) was the most potent NO production inhibitor, with an IC50 value of 23.04 µM.