The discovery of water-soluble indazole derivatives as potent microtubule polymerization inhibitors.

Taking a previously discovered indazole derivative 1 as a lead, systematic structural modifications were performed with an indazole core at the 1- and 6-positions to improve its aqueous solubility. Among the designed indazole derivatives, 6-methylpyridin-3-yl indazole derivative 8l and 1H-indol-4-yl indazole derivative 8m exhibited high potency in the low nanomolar range against A549, Huh-7, and T24 cancer cells, including Taxol-resistant variant cells (A549/Tax). As a hydrochloride salt, 8l exhibited much improved aqueous solubility, and its log P value fell into a favorable range. In mechanistic studies, 8l impeded tubulin polymerization through interacting with the colchicine site, resulting in cell cycle arrest and cellular apoptosis. In addition, compared to lead compound 1, 8l reduced cell migration and led to more potent inhibition of tumor growth in vivo without apparent toxicity. In summary, indazole derivative 8l could work as a potential anticancer agent and deserves further investigation for cancer therapy.

Total Saponin Fraction of Dioscorea Nipponica Makino Improves Gouty Arthritis Symptoms in Rats via M1/M2 Polarization of Monocytes and Macrophages Mediated by Arachidonic Acid Signaling.

OBJECTIVE: To explore the mechanism of effects of total saponin fraction from Dioscorea Nipponica Makino (TSDN) on M1/M2 polarization of monocytes/macrophages and arachidonic acid (AA) pathway in rats with gouty arthritis (GA). METHODS: Seventy-two Sprague Dawley rats were randomly divided into 4 groups (n=18 in each): normal, model, TSDN at 160 mg/kg, and celecoxib at 43.3 mg/kg. Monosodium urate crystal (MSU) was injected into the rats' ankle joints to induce an experimental GA model. Blood and tissue samples were collected on the 3rd, 5th, and 8th days of drug administration. Histopathological changes in the synovium of joints were observed via hematoxylin and eosin (HE) staining. The expression levels of arachidonic acid (AA) signaling pathway were assessed via real-time polymerase chain reaction (qPCR) and Western blot. Flow cytometry was used to determine the proportion of M1 and M2 macrophages in the peripheral blood. An enzyme-linked immunosorbent assay (ELISA) was used to detect interleukine (IL)-1 ß, tumor necrosis factor-alpha (TNF-α), IL-4, IL-10, prostaglandin E2 (PGE2), and leukotriene B4 (LTB4). RESULTS: HE staining showed that TSDN improved the synovial tissue. qPCR and Western blot showed that on the 3rd, 5th and 8th days of drug administration, TSDN reduced the mRNA and protein expressions of cyclooxygenase (COX)2, microsomal prostaglandin E synthase-1 derived eicosanoids (mPGES-1), 5-lipoxygenase (5-LOX), recombinant human mothers against decapentaplegic homolog 3 (Smad3), nucleotide-binding oligomerization domain-like receptor protein 3 (NALP3), and inducible nitric oxide synthase (iNOS) in rats' ankle synovial tissues (P<0.01). TSDN decreased COX1 mRNA and protein expression on 3rd and 5th day of drug administration and raised it on the 8th day (both P<0.01). It lowered CD68 protein expression on days 3 (P<0.01), as well as mRNA and protein expression on days 5 and 8 (P<0.01). On the 3rd, 5th, and 8th days of drug administration, TSDN elevated the mRNA and protein expression of Arg1 and CD163 (P<0.01). Flow cytometry results showed that TSDN decreased the percentage of M1 macrophages while increasing the percentage of M2 in peripheral blood (P<0.05 or P<0.01). ELISA results showed that on the 3rd, 5th, and 8th days of drug administration, TSDN decreased serum levels of IL-1 ß, TNF-α, and LTB4 (P<0.01), as well as PGE2 levels on days 3rd and 8th days (P<0.05 or P<0.01); on day 8 of administration, TSDN increased IL-4 serum levels and enhanced IL-10 contents on days 5 and 8 (P<0.05 or P<0.01). CONCLUSION: The anti-inflammatory effect of TSDN on rats with GA may be achieved by influencing M1/M2 polarization through AA signaling pathway.

STAT1-induced regulation of lncRNA ZFPM2-AS1 predicts poor prognosis and contributes to hepatocellular carcinoma progression via the miR-653/GOLM1 axis.

Long noncoding RNAs (lncRNAs) have drawn growing attention owing to their important effects in various tumors, including hepatocellular carcinoma (HCC). Recently, a newly identified lncRNA, ZFPM2 antisense RNA 1 (ZFPM2-AS1), was reported to serve as an oncogene in gastric cancer. However, its function in tumors remains largely unknown. In this study, we identified ZFPM2-AS1 as a novel HCC-related lncRNA, which was observed to be distinctly upregulated in HCC tissues and associated with shorter overall survival. Luciferase reporter and chromatin immunoprecipitation assays suggested that overexpression of ZFPM2-AS1 was induced by STAT1. Functional investigations suggested that the inhibition of ZFPM2-AS1 suppressed cell proliferation, metastasis, cell cycle progression while accelerated cell apoptosis. Mechanistic studies showed that there were two binding sites of miR-653 within the sequence of ZFPM2-AS1 and the levels of ZFPM2-AS1 were negatively correlated with miR-653. In addition, ZFPM2-AS1 could reverse the suppressor effects of miR-653 on the proliferation and metastasis of HCC cells by the modulation of GOLM1, a target gene of miR-653. To conclude, we provided a better understanding of the interaction mechanism between ZFPM2-AS-miR-653-GOLM1 axis, which may help develop prognostic biomarkers and therapeutic target for HCC.

Mass spectrometry-based metabolomics in health and medical science: a systematic review.

Metabolomics is the study of the investigation of small molecules derived from cellular and organism metabolism, which reflects the outcomes of the complex network of biochemical reactions in living systems. As the most recent member of the omics family, there has been notable progress in metabolomics in the last decade, mainly driven by the improvement in mass spectrometry (MS). MS-based metabolomic strategies in modern health and medical science studies provide innovative tools for novel diagnostic and prognostic approaches, as well as an augmented role in drug development, nutrition science, toxicology, and forensic science. In the present review, we not only introduce the application of MS-based metabolomics in the above fields, but also discuss the MS analysis technologies commonly used in metabolomics and the application of metabolomics in precision medicine, and further explore the challenges and perspectives of metabolomics in the field of health and medical science, which are expected to make a little contribution to the better development of metabolomics.

Twist-related protein 1 negatively regulated osteoblastic transdifferentiation of human aortic valve interstitial cells by directly inhibiting runt-related transcription factor 2.

OBJECTIVE: Valve calcification involves transdifferentiation of valve interstitial cells (VICs) into osteoblasts. Twist-related protein 1 (TWIST1) has been established as a negative regulator of osteoblast differentiation in both mouse and human mesenchymal stem cells, but its function in human aortic VICs is unknown. In our study, we determined the mechanism of TWIST1 action in regulating osteoblastic transdifferentiation of human aortic VICs. METHODS: Human calcified and noncalcified aortic valves were examined for TWIST1 expression. Human aortic VICs were isolated and cultured. RESULTS: The data showed that calcified aortic valves express lower levels of TWIST1. In vitro experiments showed that TWIST1 overexpression inhibited the transdifferentiation of VICs into osteoblasts by decreasing the expression of runt-related transcription factor 2 (RUNX2) and its downstream osteoblastic markers. Through chromatin immunoprecipitation and dual luciferase assays, we found that TWIST1 repressed the expression of RUNX2 by directly binding to an E-box located at -820 bp of the RUNX2 P2 promoter region and inhibiting its activity. CONCLUSIONS: Our study results suggest that TWIST1 could play an important role in preventing human aortic valve calcification by negatively regulating osteoblastic transdifferentiation of human aortic VICs through direct inhibition of RUNX2.

Performance of EuroSCORE II in patients who have undergone heart valve surgery: a multicentre study in a Chinese population.

OBJECTIVES: The EuroSCORE II is an updated version of the EuroSCORE. This multicentre study validated the EuroSCORE II and logistic EuroSCORE in Chinese patients who underwent heart valve surgery. METHODS: A total of 11 170 adult patients underwent heart valve surgery from January 2008 to December 2011. Model discrimination and calibration were assessed for both EuroSCORE II and logistic EuroSCORE. The patients were divided into three subgroups according to the weight of the procedures, and the performance of EuroSCORE II for each group was assessed. A correlation analysis was performed for operative complications and EuroSCORE II. RESULTS: The in-hospital mortality of this series was 2.02% (226 of 11 170), and the predicted mortality rate was 2.62±5.75% by EuroSCORE II and 2.55±6.51% by logistic EuroSCORE (LES). The C-statistics of EuroSCORE II and LES were 0.72 [95% confidence interval (CI) 0.69-0.75] and 0.67 (95% CI 0.63-0.70), respectively. Both models failed the Hosmer-Lemeshow goodness-of-fit test, with a P<0.05. According to the weight of the procedure, the isolated non-CABG subgroup had the best discrimination (C-statistics: 0.76 in the non-CABG group, 0.67 in the 2 procedures group and 0.73 in the 3+ procedures group). The complication ratio was strongly related to the EuroSCORE II-predicted mortality (Pearson correlation coefficient: 0.90 for ARDS, 0.97 for acute renal failure, 0.97 for prolonged ventilation and 0.94 for a prolonged ICU stay). CONCLUSIONS: EuroSCORE II was an improvement upon its original logistic model for Chinese patients who underwent heart valve surgery, particularly for a single-valve procedure. The EuroSCORE II-predicted mortality correlated with the operative complications.

The use of intra-aortic balloon pump in patients undergoing heart valve replacement: outcome and risk analysis.

BACKGROUND AND AIM OF THE STUDY: Intra-aortic balloon pump (IABP) in heart valve surgical patients is associated with a higher mortality than coronary artery bypass grafting (CABG). The study aim was to analyze the early outcome of heart valve surgical patients requiring IABP support, and to assess the risk factors for early mortality. METHODS: Among a cohort of 5,786 patients undergoing heart valve replacement without CABG, 81 (1.4%) required IABP support. Data from these latter patients were collected and analyzed retrospectively, and univariate and multivariate logistic regression were applied to identify risk factors for early mortality in patients requiring IABP support. RESULTS: IABP was inserted in 30 patients intraoperatively, and in 51 patients postoperatively. The overall mortality was 50.6%. Mortality in the intraoperative IABP subgroup was significantly lower than in the postoperative IABP subgroup (26.7% versus 64.7%, p = 0.001). The independent risk factors for early mortality were: age increasing by 10 years (OR 1.906, 95% CI: 1.165-3.116, p = 0.010) and pulmonary hypertension (OR 4.153, 95% CI: 1.380-12.499, p = 0.011). Intraoperative IABP insertion (OR 0.297, 95% CI: 0.100-0.876, p = 0.028) was identified as a protective factor compared to postoperative insertion. CONCLUSION: The mortality of patients requiring IABP support after heart valve replacement was high. The efficacy of intraoperative IABP insertion was better than a postoperative mandatory use. Clearly, more attention should be paid to older patients or those with pulmonary hypertension, who may benefit less from IABP.