Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC) was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia.
BackgroundOverexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2).MethodsHTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression.ResultsTY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase.ConclusionsThese results indicate that TY-011 is a well-tolerated, orally active compound that targets mitosis and angiogenesis in tumor growth, and provides strong preclinical support for use as a therapeutic for human gastric cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0464-2) contains supplementary material, which is available to authorized users.
BF211, a bufalin (BF) derivative, exhibits stronger anti-cancer activity than BF but with potential cardiotoxicity. Fibroblast activation protein-α (FAPα) is a membrane-bound protease specifically expressed by carcinoma-associated fibroblasts, thus has been used for the selective delivery of anticancer agents. In this study, we used a FAPα-based prodrug strategy to synthesize a dipeptide (Z-Gly-Pro)-conjugated BF211 prodrug named BF211-03. BF211-03 was hydrolyzed by recombinant human FAPα (rhFAPα) and cleaved by homogenates of human colon cancer HCT-116 or human gastric cancer MGC-803 xenografts. In contrast, BF211-03 showed good stability in plasma and in the homogenates of FAPα-negative normal tissues, such as heart and kidney. In HCT-116 and MGC-803 cells with low levels of FAPα expression, BF211-03 displayed a lower in vitro cytotoxicity than BF211 with approximately 30 to 40-fold larger IC values, whereas in human breast cancer MDA-MB-435 cells with high levels of FAPα expression, the IC value difference between BF211-03 and BF211 was small (approximately 4-fold). Although the cytotoxicity of BF211-03 against tumor cells was dramatically decreased by the chemical decoration, it was restored after cleavage of BF211-03 by rhFAPα or tumor homogenate. In HCT-116 tumor-bearing nude mice, doubling the dose of BF211-03, compared with BF211, caused less weight loss, but showing similar inhibitive effects on tumor growth. Our results suggest that BF211-03 is converted to active BF211 in tumor tissues and exhibits anti-tumor activities in tumor-bearing nude mice. FAPα-targeted BF211-03 displays tumor selectivity and may be useful as a targeting agent to improve the safety profile of cytotoxic natural products for use in cancer therapy.
The excitation spectra of chlorophyll (Chl) fluorescence can be used to differentiate phytoplankton populations at phylum level in vivo and in situ within a few minutes. The investigated phytoplankton divisions (Dinophyta, Bacillariophyta, Chrysophyta, Cyanophyta, Cryptophyta, Chlorophyta) are each characterized by a specific composition of photosynthetic antenna pigments and, consequently, by a specific excitation spectrum of the Chl fluorescence. Norm excitation spectra (emission of 680 nm and excitation of 400-600 nm) of every division were obtained from several species per division by a F4500 fluorescence spectrophotometer. Fisher's linear discriminant analysis of the norm spectra shows that the divisions could be discriminated. The discrimination method, established by multivariate linear regression and weighted least squares, was used to differentiate the phytoplankton samples cultured in the laboratory and samples collected from the Jiaozhao Bay at division level. The correctly discriminated samples were more than 94% for single algal species ones, more than 84% for simulatively mixed ones, more than 83% for real mixed ones and 100% for samples collected from the Jiaozhou Bay for the dominant species. The method for phytoplankton differentiation described here can be applied to routine checking by fluorescence spectrophotometer, and benefit the monitoring and supervision tasks related to phytoplankton populations in the marine environments.
IntroductionThe Zhejiang coastal area is the most important fishery ground in East China Sea, located south of the Yangtze River Estuary. The previous studies on hypoxia and mechanisms mainly focused on the outer shelf and Yangtze River Estuary, and limited knowledge on the DO depletion and low DO information in this area.MethodsIn this study, the relationships among the DO spatial variation and depletion with nutrients, Chl-a, algal blooms, stratification were analyzed based on the investigation from July to August in 2020.Results and discussionThe results showed that, the DO contents were high in the surface water (4.6–11.8 mg/L) than in the bottom water (3.0-8.4 mg/L) with an increasing trend from nearshore to offshore in the surface layer, but opposite in the bottom. The vertical profile of DO showed that low DO concentrations (≤3.0 mg/L) started from the water depth of 12 m with a depth of 45 m. The low DO area appeared in the northeast and central Zhejiang coastal areas covering an area of 6,000 km2 and 4,000 km2, respectively. Our analysis indicated that the successive algal blooms (Chl-a > 40.0 μg/L) occurred in late June and during the investigation prepared the low DO pool for the hypoxia development. Stratification, generated from upper warm, light, diluted freshwater from the Yangtze River and the deeper cold, heavy, salty Taiwan Warm Current ceased the vertical convection of DO in the surface, and accelerated the hypoxia development. The hypoxia starting time was earlier and the duration was longer in this complicated area. The rising temperature, more frequency of algal blooms by global warming would likely to make this worse. Continued interdisciplinary research are badly needed to get a better view in the future.
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