Effects of Se-enriched Chrysanthemum morifolium on lifespan and antioxidant defense-related gene expression of Drosophila melanogaster model.

Chrysanthemum morifolium is a well-known edible medicinal plant in Asia and some other regions. Content of selenium in Se-enriched C. morifolium (SeCM) is significantly higher than that in traditional C. morifolium (non-Se-enriched C. morifolium, TCM). In order to understand health effects of SeCM, its chemical composition, lifespan-prolonging activities, and impacts on antioxidant defense-related gene expressions of model organism D. melanogaster were systematically studied. A total of eight phenols, including luteolin-7-O-glucoside, linarin, luteolin, apigenin, diosmetin, acacetin, 3-caffeoylquinic acid and 4,5-dicaffeoylquinic acid, were identified in SeCM extract. Compared with TCM, SeCM exhibited superior antioxidant properties. Intake of SeCM dramatically reduced malondialdehyde level and increased activities of endogenous antioxidant enzymes in fruit flies. SeCM was able to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase and hydrogen peroxide catalase, and extend lifespans of fruit flies. Comparatively high antioxidant capacities and lifespan-prolonging activities of SeCM might be attributed to its abundant phenols and selenium, which probably ameliorated accumulation of free radicals and susceptibility to oxidative stress. These findings provide clues on further exploitation and utilization of Se-enriched C. morifolium. PRACTICAL APPLICATIONS: Chrysanthemum morifolium has been used for nutraceutical and curative purposes in China for thousands of years. Se-enriched C. morifolium typically contains more selenium than traditional C. morifolium, and is widely consumed in Asia and some other regions. Selenium is an essential micronutrient for humans, and selenium deficiency may result in several diseases such as myocardial infarction. SeCM is one of important selenium supplements. In this study, SeCM was found to upregulate gene expressions of Cu/Zn-superoxide dismutase, Mn-superoxide dismutase, and hydrogen peroxide catalase, and extend lifespans of experimental animals. These results provide supporting information for developing SeCM-based functional foods with distinct health benefits.

Phytochemicals in traditional Chinese medicine can treat gout by regulating intestinal flora through inactivating NLRP3 and inhibiting XOD activity.

OBJECTIVES: Gout is a common disease caused by hyperglycemia. Traditional drugs for gout have both good therapeutic effects and serious side effects. Traditional Chinese medicine (TCM) is one of the potential sources of modern medicine, and is the development of new drugs for many diseases, including gout. TCM is an indispensable part of gout treatment. Compared with anti-gout medication commonly used in clinic (e.g. the xanthine oxidase inhibitors allopurinol and febuxostat), traditional Chinese medicine has fewer side effects in the treatment of gout and can safely control serum uric acid and the level of inflammation. However, there have been few studies on how traditional Chinese medicine controls uric acid and inflammation levels in patients with gout. KEY FINDINGS: Herbs are a valuable resource in the search for new drugs to treat many diseases, including gout. Phytochemicals in TCM treatment of gout mainly includes two aspects, anti-inflammatory and reducing uric acid content. The anti-inflammatory mechanism is mainly through the inactivation of NF-κB and NLRP3 inflammasome to reduce the inflammatory response induced by uric acid crystals. The mechanism of lowering uric acid is mainly through inhibiting the activity of xanthine oxidase and up-regulating the expression of URAT1 and GLUT9.In recent years, the intestinal flora has become a new field of understanding diseases. It has been observed that the occurrence of gout is closely related to changes in the intestinal flora. Herbaceous plants contain fiber, polyphenols, polysaccharides and other active components. When taken orally, Chinese herbs act like prebiotics. After traditional Chinese medicine treatment, the abundance levels of Bifidobacterium, Lactobacillus, Bacteroidetes and Prevotella were increased, while the abundance of Proteus and the Firmicutes/Bacteroidetes ratio were decreased. Changes in the intestinal flora led to further changes in its metabolites, including short-chain fatty acids (SCFAs) and lipopolysaccharide (LPS), which ultimately down-regulate the TLR4/NF-κB inflammatory signaling pathway, up-regulate GLUT9 and URAT1 gene expression and inhibition of xanthine oxidase activity. Destruction of the intestinal barrier is also an important factor in the occurrence of gout. Disruption of the intestinal barrier allows LPS to enter the bloodstream and activates the expression of various inflammatory factors, which causes gout.

Natural substances derived from herbs or plants are promising sources of anticancer agents against colorectal cancer via triggering apoptosis.

OBJECTIVES: Nowadays, one of the most common gastrointestinal cancers is colorectal cancer (CRC). Chemotherapy is still one of the main methods to treat cancer. However, the currently available synthetic chemotherapy drugs often cause serious adverse reactions. Apoptosis is generally considered as an ideal way for induction the death of tumour cells without the body's inflammatory response, and it is reported that lots of natural agents could trigger various cancer cells to apoptosis. The overarching aim of this project was to elucidate the specific mechanisms by which natural substances induce apoptosis in CRC cells and to be used as an alternative therapeutic option in the future. KEY FINDINGS: The mechanisms for the pro-apoptotic effects of natural substances derived from herbs or plants include death receptor pathway, mitochondrial pathway, endoplasmic reticulum stress pathway, related signal transduction pathways (PI3K/Akt, MAPK, p53 signalling), and so on. SUMMARY: This paper updated this information regarding the anti-tumour effects of natural agents via induction of apoptosis against CRC, which would be beneficial for future new drug research regarding natural products from herbs or plants.

miR-6769b-5p targets CCND-1 to regulate proliferation in cadmium-treated placental trophoblasts: Association with the impairment of fetal growth.

Environmental cadmium (Cd) is positively associated with placental impairment and fetal growth retardation. Nevertheless, its potential mechanisms remain unclear. microRNAs (miRNAs) are known to influence placental development and fetal growth. This work was aimed to determine which miRNAs are involved in Cd-impaired placental and fetal development based on the mRNA and miRNA expression profiles analysis. As a result, gestational Cd exposure deceased fetal and placental weight, and reduced the protein level of PCNA in human and mouse placentae. Furthermore, the results of mRNA microarray showed that Cd-downregulated mRNAs were predictively correlated with several biological processes, including cell proliferation, differentiation and motility. In addition, the results of miRNA microarray and qPCR assay demonstrated that Cd significantly increased the level of miR-6769b-5p, miR-146b-5p and miR-452-5p. Integrated analysis of Cd-upregulated miRNAs predicted target genes and Cd-downregulated mRNAs found that overlapping mRNAs, such as CCND1, CDK13, RINT1 and CDC26 were also significantly associated with cell proliferation. Further experiments showed that miR-6769b-5p inhibitor, but not miR-146b-5p and miR-452-5p, markedly reversed Cd-downregulated the expression of proliferation-related mRNAs, and thereby restored Cd-decreased the proteins level of CCND1 and PCNA in human placental trophoblasts. Dual luciferase reporter assay further revealed that miR-6769b-5p directly targets CCND1. Finally, the case-control study demonstrated that increased miR-6769b-5p level and impaired cell proliferation were observed in small-for-gestational-age human placentae. In conclusion, miR-6769b-5p targets CCND-1 to regulate proliferation in Cd-treated placental trophoblasts, which is associated with the impairment of fetal growth. Our findings imply that placental miR-6769b-5p may be used as an epigenetic marker for environmental pollutants-caused fetal growth restriction and its late-onset chronic diseases.

Integrated analysis reveals distinct molecular, clinical, and immunological features of B7-H3 in acute myeloid leukemia.

The role of B7-H3 in acute myeloid leukemia (AML) is not fully understood. Two previous studies investigating its expression and significances in AML are partially different. In this study, we aimed to systematically characterize the genomic and immune landscape in AML patients with altered B7-H3 expression using multi-omics data in the public domain. We found significantly increased B7-H3 expression in AML compared to either other hematological malignancies or healthy controls. Clinically, high B7-H3 expression was associated with old age, TP53 mutations, wild-type WT1 and CEBPA, and the M3 and M5 FAB subtypes. Moreover, we observed that increased B7-H3 expression correlated significantly with a poor outcome of AML patients in four independent datasets. Gene set enrichment analysis (GSEA) revealed the enrichment of the "EMT" oncogenic gene signatures in high B7-H3 expressers. Further investigation suggested that B7-H3 was more likely to be associated with immune-suppressive cells (macrophages, neutrophils, dendritic cells, and Th17 cells). B7-H3 was also positively associated with a number of checkpoint genes, such as VISTA (B7-H5), CD80 (B7-1), CD86 (B7-2), and CD70. In summary, we uncovered distinct genomic and immunologic features associated with B7-H3 expression in AML. This may lead to a better understanding of the molecular mechanisms underlying B7-H3 dysregulation in AML and to the development of novel therapeutic strategies.

Population pharmacokinetic analysis of tacrolimus in Chinese myasthenia gravis patients.

The importance of tacrolimus in the treatment of myasthenia gravis (MG) as a substitute for corticosteroid-dependent immunosuppressive therapy is increasing. Thus far, however, no population pharmacokinetic (PopPK) analysis of tacrolimus in treating MG patients has been published. This article aimed to construct a PopPK model of tacrolimus for Chinese MG patients with the goal of improving its performance in MG treatment. A total of 253 trough concentration records were obtained from 83 Chinese MG patients. The effects of demographics, lifestyle and health status, biochemical test data, disease progression and treatment-related information (including co-administered medications) as covariates on the various parameters were investigated. The covariate selection was based on biological plausibility, clinical significance, statistical significance and reduction in inter-individual variability (IIV). Bootstrap and normalized prediction distribution error (NPDE) analysis were performed to validate the final model. A one-compartment PopPK model with first-order elimination and a fixed absorption phase was constructed. The estimated apparent oral clearance (CL/F) and apparent oral volume of distribution (V/F) were 3.6 L/h and 1700 L, respectively, in the MG patients. Hematocrit and blood urea nitrogen were identified as two covariates that significantly influenced the CL/F. Immunoglobulin treatment (PRO) also had the potential to influence V/F, which was consistent with the clinical observations and the high protein-binding property of tacrolimus. Other covariates including age, weight, gender and co-administered medications had no obvious influence on CL/F or V/F. The first PopPK model of tacrolimus in MG patients was established. The identified covariates were of biological plausibility and clinical importance to help individualize the dosing schedule in MG patients.

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α.

It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.

The Effects of Intra-Aortic Balloon Pumps on Mortality in Patients Undergoing High-Risk Coronary Revascularization: A Meta-Analysis of Randomized Controlled Trials of Coronary Artery Bypass Grafting and Stenting Era.

BACKGROUND: Intra-aortic balloon pumps (IABP) have generally been used for patients undergoing high-risk mechanical coronary revascularization. However, there is still insufficient evidence to determine whether they can improve outcomes in reperfusion therapy patients, mainly by percutaneous coronary intervention (PCI) with stenting or coronary artery bypass graft (CABG). This study was designed to determine the difference between high-risk mechanical coronary revascularization with and without IABPs on mortality, by performing a meta-analysis on randomized controlled trials of the current era. METHODS: Pubmed and Embase databases were searched from inception to May 2015. Unpublished data were obtained from the investigators. Randomized clinical trials of IABP and non-IABP in high-risk coronary revascularization procedures (PCI or CABG) were included. In the case of PCI procedures, stents should be used in more than 80% of patients. Numbers of events at the short-term and long-term follow-up were extracted. RESULTS: A total of 12 randomized trials enrolling 2155 patients were included. IABPs did not significantly decrease short-term mortality (relative risk (RR) 0.66; 95% CI, 0.42-1.01), or long-term mortality (RR 0.79; 95% CI, 0.47-1.35), with low heterogeneity across the studies. The findings remained stable in patients with acute myocardial infarction with or without cardiogenic shock. But in high-risk CABG patients, IABP was associated with reduced mortality (71 events in 846 patients; RR 0.40; 95%CI 0.25-0.67). CONCLUSION: In patients undergoing high-risk coronary revascularization, IABP did not significantly decrease mortality. But high-risk CABG patients may be benefit from IABP. Rigorous criteria should be applied to the use of IABPs.