Sesquiterpene lactones from Inula hupehensis inhibit nitric oxide production in RAW264.7 macrophages.

Phytochemical investigation of the aerial parts of Inula hupehensis Ling. led to the isolation and identification of 27 sesquiterpene lactones (1-27), including three new eudesmanolides (3-5), three new germacranolides (9-11), one new xanthanolide (16), two new carabrone derivatives (25-26), and 18 known sesquiterpene lactones. The structures were elucidated by extensive spectroscopic methods and comparison to previously reported spectroscopic data. All compounds were evaluated for their inhibitory effects against LPS-induced nitric oxide production in RAW264.7 macrophages, and compound 5 showed the strongest activity with the IC50 value of 3.2 ± 0.4 µM.

[Ozone Sensitivity Analysis and Control Strategy in Shijiazhuang City in July 2019].

The pollution characteristics of surface ozone and its response to meteorological factors were studied based on monitoring in July 2019 in Shijiazhuang City, China. Furthermore, the WRF-CMAQ model coupled with O3 isopleths (EKMA curves) were applied to explore the non-linear response relationship of O3 to precursors VOCs and NOx, aiming to identify a suitable precursor control strategy. The results showed that the days with the maximum daily 8-hour average ozone concentration (MDA8 O3) exceeded the standard by 70.9%. The nonattainment days were usually accompanied by higher temperature, lower relative humidity, and low winds, and the south and southeast winds occurred frequently. The O3 formation was in the strong VOC-limited regime in the urban area of Shijiazhuang, whereas it was in the NOx and VOCs transition regime in suburban areas. As for the urban area, under the condition of single NOx emission reduction, O3 pollution improved when continuous NOx emission reduction was higher than 50% during the nonattainment days. By contrast, during the non-polluted days, O3 concentrations would not rebound when the reduction ratio of NOx and VOCs was higher than 1. In conclusion, VOCs reduction should be the priority for emission reduction plans in urban areas, whereas all different NOx and VOCs ratios led to a decline in O3 concentration in the suburban areas, and a VOCs:NOx of 1:2 was recommended.

Tumor bud-derived CCL5 recruits fibroblasts and promotes colorectal cancer progression via CCR5-SLC25A24 signaling.

BACKGROUND: Tumor budding is included in the routine diagnosis of colorectal cancer (CRC) and is considered a tumor prognostic factor independent of TNM staging. This study aimed to identify the fibroblast-mediated effect of tumor bud-derived C-C chemokine ligand 5 (CCL5) on the tumor microenvironment (TME). METHODS: Recruitment assays and a human cytokine array were used to detect the main cytokines that CRC tumor buds secrete to recruit fibroblasts. siRNA transfection and inhibitor treatment were used to investigate the role of fibroblast CCL5 receptors in fibroblast recruitment. Subsequently, transcriptome sequencing was performed to explore the molecular changes occurring in fibroblasts upon stimulation with CCL5. Finally, clinical specimens and orthotopic xenograft mouse models were studied to explore the contribution of CCL5 to angiogenesis and collagen synthesis. RESULTS: Hematoxylin-eosin staining and immunochemistry revealed a higher number of fibroblasts at the invasive front of CRC tissue showing tumor budding than at sites without tumor budding. In vitro experiments demonstrated that CCL5 derived from tumor buds could recruit fibroblasts by acting on the CCR5 receptors on fibroblasts. Tumor bud-derived CCL5 could also positively regulate solute carrier family 25 member 24 (SLC25A24) expression in fibroblasts, potentially activating pAkt-pmTOR signaling. Moreover, CCL5 could increase the number of α-SMAhigh CD90high FAPlow fibroblasts and thus promote tumor angiogenesis by enhancing VEGFA expression and making fibroblasts transdifferentiate into vascular endothelial cells. Finally, the results also showed that CCL5 could promote collagen synthesis through fibroblasts, thus contributing to tumor progression. CONCLUSIONS: At the invasive front of CRC, tumor bud-derived CCL5 can recruit fibroblasts via CCR5-SLC25A24 signaling, further promoting angiogenesis and collagen synthesis via recruited fibroblasts, and eventually create a tumor-promoting microenvironment. Therefore, CCL5 may serve as a potential diagnostic marker and therapeutic target for tumor budding in CRC.

Pseudoguaianolides and guaianolides from Inula hupehensis as potential anti-inflammatory agents.

Eight new pseudoguaianolides (1-8), two new guaianolides (9 and 10), and 14 known sesquiterpenes were isolated from the aerial parts of Inula hupehensis. The structures were elucidated using spectroscopic methods and circular dichroism analysis. All compounds were tested for inhibitory activities against LPS-induced nitric oxide production in RAW264.7 macrophages. Compounds 13 and 22 were found to inhibit nitric oxide production potently, with IC50 values of 0.9 and 0.6 µM, respectively. Preliminary structure-activity relationships for these compounds are proposed.

MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly.

Tumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368-411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin ß1 and Talin-1, which facilitated to integrin ß1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.

Japonicones E-L, dimeric sesquiterpene lactones from Inula japonica Thunb.

Eight new dimeric sesquiterpene lactones (japonicones E-L, 1- 8), including a novel sesquiterpene dimer bearing a rare hydroperoxide group (japonicone E, 1), were isolated from the aerial part of Inula japonica Thunb. Their structures were determined mainly by the use of 1D and 2D NMR spectroscopic techniques including HSQC, (1)H-(1)H COSY, HMBC, and NOESY. All the isolates were tested for inhibitory effects against LPS-induced NO production in RAW264.7 macrophages. Among the compounds tested, japonicone F (2) showed the strongest activity with the IC(50) value of 4.1 microg/mL.

A new ent-kaurane type diterpenoid glycoside from Inula japonica Thunb.

A new ent-kaurane type diterpenoid glycoside, 17-O-beta-D-glucopyranosyl-16alpha-ent-kauran-19-oic acid (1), together with 17-hydroxy-16alpha-ent-kauran-19-oic acid (2), 16alpha,17-dihydroxyl-ent-kauran-19-oic acid (3), and 16alpha-hydroxy-17-acetoxy-ent-kauran-19-oic acid (4) were isolated from the aerial parts of Inula japonica Thunb. The structure of 1 was determined mainly by use of 1D and 2D NMR spectroscopic techniques including HSQC, (1)H-(1)H COSY, HMBC, and NOESY. In addition, 4 exhibited significant inhibitory activity on NO production in LPS-stimulated RAW264.7 cells with IC(50) value of 14.3 microg/mL.

Japonicones Q-T, four new dimeric sesquiterpene lactones from Inula japonica Thunb.

Four new dimeric sesquiterpene lactones (japonicones Q-T, 1-4) were isolated from the aerial part of Inula japonica Thunb., together with two known ones. Their structures were determined mainly by 1D and 2D NMR spectroscopic techniques including HSQC, (1)H-H COSY, HMBC, and NOESY. Herein, the inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages of 1-6 were evaluated; IC(50) values were tested as 8.5, 8.9, 4.3, 4.3, 4.2, and 9.2µM, respectively.

Phenylpropanoids and lignanoids from Euonymus acanthocarpus.

A new phenylpropanoid derivative (1), along with five phenylpropanoids (2-6), two monoepoxy lignans (8-9), one bisepoxy lignan (10), two cyclolignans (11-12), six neolignans (7, 13-17), two mixed lignan-neolignans (18-19), two lignan glycosides (20-21), and four flavonolignans (22-25), were isolated from the stems and twigs of Euonymus acanthocarpus. Compounds 2-3, 6-8, 12, and 14-25 were obtained from Celastraceae family for the first time, and compounds 5 and 9 were isolated from Euonymus genus for the first time. All the compounds were tested for cytotoxicity against SK-OV-3 and MCG-803 human tumor cell lines. Compounds 3, 10, 12, and 18 showed weak cytotoxicity against SK-OV-3 cell line, and compounds 3-4, 10-13, and 19 showed weak cytotoxicity against MCG-803 cell line.

Neojaponicone A, a bioactive sesquiterpene lactone dimer with an unprecedented carbon skeleton from Inula japonica.

Five new dimeric sesquiterpene lactones, neojaponicone A (1) and japonicones M-P (2-5) were isolated from the aerial part of Inula japonica. Neojaponicone A (1) has an unprecedented carbon skeleton with an unusual valerolactone system formed between a guaianolide and an eudesmane. The structure and absolute configuration of 1 were established by extensive analysis of spectroscopic data and computational approaches.