Centipeda minima and 6-O-angeloylplenolin enhance the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

BACKGROUND: Chemotherapeutic agents including cisplatin, gemcitabine, and pemetrexed, significantly enhance the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) by increasing PD-L1 expression and potentiating T cell cytotoxicity. However, the low response rate and adverse effects limit the application of chemotherapy/ICI combinations in patients. METHODS: We screened for medicinal herbs that could perturb PD-L1 expression and enhance T cell cytotoxicity in the presence of anti-PD-L1 antibody, and investigated the underlying mechanisms. RESULTS: We found that the aqueous extracts of Centipeda minima (CM) significantly enhanced the cancer cell-killing activity and granzyme B expression level of CD8+ T cells, in the presence of anti-PD-L1 antibody. Both CM and its active component 6-O-angeloylplenolin (6-OAP) upregulated PD-L1 expression by suppressing GSK-3ß-ß-TRCP-mediated ubiquitination and degradation. CM and 6-OAP significantly enhanced ICI-induced reduction of tumor burden and prolongation of overall survival of mice bearing NSCLC cells, accompanied by upregulation of PD-L1 and increase of CD8+ T cell infiltration. CM also exhibited anti-NSCLC activity in cells and in a patient-derived xenograft mouse model. CONCLUSIONS: These data demonstrated that the induced expression of PD-L1 and enhancement of CD8+ T cell cytotoxicity underlay the beneficial effects of 6-OAP-rich CM in NSCLCs, providing a clinically available and safe medicinal herb for combined use with ICIs to treat this deadly disease.

Combined metabolomic and transcriptomic analysis reveals key components of OsCIPK17 overexpression improves drought tolerance in rice.

Oryza Sativa is one of the most important food crops in China, which is easily affected by drought during its growth and development. As a member of the calcium signaling pathway, CBL-interacting protein kinase (CIPK) plays an important role in plant growth and development as well as environmental stress. However, there is no report on the function and mechanism of OsCIPK17 in rice drought resistance. We combined transcriptional and metabonomic analysis to clarify the specific mechanism of OsCIPK17 in response to rice drought tolerance. The results showed that OsCIPK17 improved drought resistance of rice by regulating deep roots under drought stress; Response to drought by regulating the energy metabolism pathway and controlling the accumulation of citric acid in the tricarboxylic acid (TCA) cycle; Our exogenous experiments also proved that OsCIPK17 responds to citric acid, and this process involves the auxin metabolism pathway; Exogenous citric acid can improve the drought resistance of overexpression plants. Our research reveals that OsCIPK17 positively regulates rice drought resistance and participates in the accumulation of citric acid in the TCA cycle, providing new insights for rice drought resistance.

Cytotoxic and Anti-Inflammatory Sesquiterpenes from the Whole Plants of Centipeda minima.

Sixteen new sesquiterpene lactones (1-16) along with 13 known analogues (17-29) were isolated from the whole plants of Centipeda minima. The structures of 1-16 were delineated by the combination of NMR spectroscopic experiments, HRESIMS, single-crystal X-ray diffraction analyses, and ECD spectra. Compounds 23-26 showed potent cytotoxicity against Hela, HCT-116, and HepG2 cells with IC50 values of 0.8-2.6, 0.4-3.3, and 1.1-2.6 µM, respectively. Compounds 8, 15, and 24 exhibited significant inhibitory activity on the production of nitric oxide in the lipopolysaccharide-activated RAW 264.7 mouse macrophage cell line, with IC50 values ranging from 0.1 to 0.2 µM.

Antioxidation and Cytoprotection of Acteoside and Its Derivatives: Comparison and Mechanistic Chemistry.

The study tried to explore the role of sugar-residues and mechanisms of phenolic phenylpropanoid antioxidants. Acteoside, along with its apioside forsythoside B and rhamnoside poliumoside, were comparatively investigated using various antioxidant assays. In three electron-transfer (ET)-based assays (FRAP, CUPRAC, PTIO•-scavenging at pH 4.5), the relative antioxidant levels roughly ruled as: acteoside >forsythoside B > poliumoside. Such order was also observed in H⁺-transfer-involved PTIO•-scavenging assay at pH 7.4, and in three multiple-pathway-involved radical-scavenging assays, i.e., ABTS⁺•-scavenging, DPPH•-scavenging, and •O2--scavenging. In UV-vis spectra, each of them displayed a red-shift at 335→364 nm and two weak peaks (480 and 719 nm), when mixed with Fe2+; however, acteoside gave the weakest absorption. In Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF-MS/MS) analysis, no radical-adduct-formation (RAF) peak was found. MTT assay revealed that poliumoside exhibited the highest viability of oxidative-stressed bone marrow-derived mesenchymal stem cells. In conclusion, acteoside, forsythoside B, and poliumoside may be involved in multiple-pathways to exert the antioxidant action, including ET, H⁺-transfer, or Fe2+-chelating, but not RAF. The ET and H⁺-transfer may be hindered by rhamnosyl and apiosyl moieties; however, the Fe2+-chelating potential can be enhanced by two sugar-residues (especially rhamnosyl moiety). The general effect of rhamnosyl and apiosyl moieties is to improve the antioxidant or cytoprotective effects.

Two new cyclic dipeptides from Rhinocladiella sp. lgt-3, a fungal endophyte isolated from Tripterygium wilfordii Hook.

Two new cyclic dipeptides, rhinocladin A (1) and rhinocladin B (2), were isolated from a fungal endophyte (Rhinocladiella sp. lgt-3) of Tripterygium wilfordii Hook. Their structures were elucidated by 1D and 2D NMR spectra. The monoamine oxidase inhibitory activity of 1 and 2 was also evaluated.