Plasma metabolites and risk of myocardial infarction: a bidirectional Mendelian randomization study.

BACKGROUND: Myocardial infarction (MI) is a critical cardiovascular event with multifaceted etiology, involving several genetic and environmental factors. It is essential to understand the function of plasma metabolites in the development of MI and unravel its complex pathogenesis. METHODS: This study employed a bidirectional Mendelian randomization (MR) approach to investigate the causal relationships between plasma metabolites and MI risk. We used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa. In addition, the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite (1400 metabolites) and MI (20,917 individuals with MI and 440,906 individuals without MI) susceptibility. Inverse variance weighted was the primary method for estimating causal effects. MR estimates are expressed as beta coefficients or odds ratio (OR) with 95% CI. RESULTS: We identified 14 plasma metabolites associated with the occurrence of MI (P < 0.05), among which 8 plasma metabolites [propionylglycine levels (OR = 0.922, 95% CI: 0.881-0.965, P < 0.001), gamma-glutamylglycine levels (OR = 0.903, 95% CI: 0.861-0.948, P < 0.001), hexadecanedioate (C16-DC) levels (OR = 0.941, 95% CI: 0.911-0.973, P < 0.001), pentose acid levels (OR = 0.923, 95% CI: 0.877-0.972, P = 0.002), X-24546 levels (OR = 0.936, 95% CI: 0.902-0.971, P < 0.001), glycine levels (OR = 0.936, 95% CI: 0.909-0.964, P < 0.001), glycine to serine ratio (OR = 0.930, 95% CI: 0.888-0.974, P = 0.002), and mannose to trans-4-hydroxyproline ratio (OR = 0.912, 95% CI: 0.869-0.958, P < 0.001)] were correlated with a decreased risk of MI, whereas the remaining 6 plasma metabolites [1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) levels (OR = 1.051, 95% CI: 1.018-1.084, P = 0.002), behenoyl dihydrosphingomyelin (d18:0/22:0) levels (OR = 1.076, 95% CI: 1.027-1.128, P = 0.002), 1-stearoyl-2-docosahexaenoyl-GPE (18:0/22:6) levels (OR = 1.067, 95% CI: 1.027-1.109, P = 0.001), alpha-ketobutyrate levels (OR = 1.108, 95% CI: 1.041-1.180, P = 0.001), 5-acetylamino-6-formylamino-3-methyluracil levels (OR = 1.047, 95% CI: 1.019-1.076, P < 0.001), and N-acetylputrescine to (N (1) + N (8))-acetylspermidine ratio (OR = 1.045, 95% CI: 1.018-1.073, P < 0.001)] were associated with an increased risk of MI. Furthermore, we also observed that the mentioned relationships were unaffected by horizontal pleiotropy (P > 0.05). On the contrary, MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites (P > 0.05 for each comparison). CONCLUSIONS: Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI, among which 13 plasma metabolites have not been reported previously. These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.

Bioactive polycyclic polyprenylated acylphloroglucinols from Hypericum scabrum.

Eighteen polycyclic polyprenylated acylphloroglucinols were isolated from the whole plant of Hypericum scabrum Linn., including six new compounds (1-6). Their structures were elucidated by comprehensive spectroscopic analyses. The evaluation of their cytotoxic activities was carried out against SMMC-7721 and MGC-803 cell lines. We found that most tested compounds exhibited moderate cytotoxic activities against SMMC-7721 cell line except for 11 and 12, while compounds 1, 5-7, 13 and 16 also showed cytotoxic activities on MGC-803 cells. Besides, Bacillus subtilis, MRSA and MDPRA were also used to test inhibitory activity of these compounds. Our results showed that only compounds 12 and 13 presented weak inhibitory activity against Bacillus subtilis, while compounds 7, 13 and 14 also inhibited MRSA weakly.

Prevalence and Factors Associated with Concomitant Chinese Medicine Use by Rheumatoid Arthritis Patients in A Multi-Ethnic Asian Population.

OBJECTIVE: To determine the prevalence, factors associated with and patterns of concomitant Chinese medicine (CM) with Western treatment use among patients with rheumatoid arthritis (RA) in a tertiary referral centre (Singapore General Hospital) in Singapore. METHODS: We conducted a cross-sectional interviewer-administered survey of a consecutive sample of patients with RA in Singapore General Hospital centre regarding their CM use including data on patient demographics, disease characteristics, concomitant use of CM and reasons, concerns and disclosure patterns from March to August 2015. Univariate and multivariate logistic regression analyses were performed to determine the associations of CM use. RESULTS: Prevalence of CM use among the 258 patients surveyed (male: female 42: 216; Chinese: Malay: Indian 191: 29: 34; mean age: 61 years; mean duration of RA: 10 years) was 46.1% (119/258). On multivariate analysis, Chinese ethnicity (OR, 95% CI: 4.11, 1.49-11.36), Chinese speakers (OR, 95% CI: 2.35, 1.03-5.54), middle-income group (OR, 95% CI: 2.53, 1.01-6.31) and greater learned helplessness (OR, 95% CI: 1.13, 1.04-1.22) were significantly associated with CM use. More CM users disclosed their CM use to CM physicians (87.3%, 96/110), sought advice from them on treatment interactions (59.4%, 57/96) and how best to combine treatments (49.0%, 47/96) than did so with rheumatologists (42.0%, 50/119; 40.0%, 20/50; and 42.0%, 21/50, respectively). Forty-two percentage (29/69) of patients who concealed CM use from rheumatologists because their rheumatologists did not specifically enquire about CM use. CONCLUSIONS: Concomitant CM use among patients with RA treated in a tertiary referral centre in Singapore is high but voluntary disclosure is low. The associations identified can help doctors identify and enquire about CM use, minimizing potential adverse interactions.

Metabolite and Microbiome Profilings of Pickled Tea Elucidate the Role of Anaerobic Fermentation in Promoting High Levels of Gallic Acid Accumulation.

Gallic acid (GA) is an important active ingredient for its pharmacological activities. High levels of GA in tea can be obtained by anaerobic fermentation, but its mechanism is still unclear. Here, the profiles of metabolites and microbiomes in pickled tea were analyzed. The results showed that GA of pickled tea increased to 24.26 mg/g at 18 d after anaerobic fermentation, which was accompanied by the reducing levels of epicatechin gallate (ECG), epiafzelechin-3-O-gallate (EAG), and 7-galloylcatechin (7-GC) and the increasing relative abundances of Bacillus and other six bacterial genera. However, epigallocatechin gallate (EGCG) was basically stable during the whole fermentation process. These results suggested that EGCG contributes little to the GA formation during anaerobic fermentation, but ECG, EAG, and 7-GC should be the key precursors to form GA; moreover, bacteria, especially Bacillus, may be responsible for their bioconversion. It will establish an effective way to increase GA in tea production.

miR-145 Inhibits Th9 Cell Differentiation by Suppressing Activation of the PI3K/Akt/mTOR/p70S6K/HIF-1α Pathway in Malignant Ascites from Liver Cancer.

PURPOSE: Our previous experiments confirmed that T helper type 9 (Th9) cells were involved in the occurrence and development of malignant ascites caused by liver cancer. The current study investigated the mechanism underlying microRNA (miR-145)-mediated inhibition of Th9 cells in an malignant ascites model with liver cancer. MATERIALS AND METHODS: CD4+ T cells were induced to differentiate Th9 cells after transfection with miR-145 mimics or negative control. A malignant ascites mouse model was transfected with miR-145agomir or negative control. Th9 cells were detected by flow cytometry. Enzyme-linked immunosorbent assay was applied to detect the interleukin 9 (IL-9) cytokine and hypoxia-inducible factor 1 alpha (HIF-1α). RT-PCR was used to detect the expression of miR-145 and phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase/HIF-1α (PI3K/Akt/mTOR/p70S6K/HIF-1α) mRNA. Western blotting and immunofluorescence were performed to detect the expression of PI3K/Akt/mTOR/p70S6K/HIF-1α-related proteins. RESULTS: In vitro experiments showed that miR-145 inhibited Th9 cell polarization, HIF-1α expression, and PI3K/Akt/mTOR/p70S6K pathway activation. In the malignant ascites mouse model, miR-145 also demonstrated inhibitory effects on Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. CONCLUSION: miR-145 may inhibit Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. These findings suggest a novel therapeutic target for malignant ascites from liver cancer.

Prokaryotic expression and purification of Camellia sinensis polyphenol oxidase.

BACKGROUND: Polyphenol oxidase (PPO) causes the postharvest loss of fruits and vegetables but is also a key factor in the quality development of tea. However, there are no reports on engineered active plant PPO purified from prokaryotic cells. RESULTS: In this study the ppo gene of about 1800 bp from Camellia sinensis cv. Yihongzao was successfully cloned and expressed in Escherichia coli. The PPOs purified from both the soluble fraction and the inclusion bodies showed activity. In addition, 1.0 × 10(-7) mol L(-1) Cu(2+) and acidic conditions were found to be favourable for the engineered PPO catalysis of catechol oxidation. CONCLUSION: This paper represents the first report on C. sinensis ppo expression in E. coli and engineered active PPO purification. The results of the study provide a basis for the large-scale preparation and application of PPO.

The key DNA-binding residues in the C-terminal domain of Mycobacterium tuberculosis DNA gyrase A subunit (GyrA).

As only the type II topoisomerase is capable of introducing negative supercoiling, DNA gyrase is involved in crucial cellular processes. Although the other domains of DNA gyrase are better understood, the mechanism of DNA binding by the C-terminal domain of the DNA gyrase A subunit (GyrA-CTD) is less clear. Here, we investigated the DNA-binding sites in the GyrA-CTD of Mycobacterium tuberculosis gyrase through site-directed mutagenesis. The results show that Y577, R691 and R745 are among the key DNA-binding residues in M.tuberculosis GyrA-CTD, and that the third blade of the GyrA-CTD is the main DNA-binding region in M.tuberculosis DNA gyrase. The substitutions of Y577A, D669A, R691A, R745A and G729W led to the loss of supercoiling and relaxation activities, although they had a little effect on the drug-dependent DNA cleavage and decatenation activities, and had no effect on the ATPase activity. Taken together, these results showed that the GyrA-CTD is essential to DNA gyrase of M.tuberculosis, and promote the idea that the M.tuberculosis GyrA-CTD is a new potential target for drug design. It is the first time that the DNA-binding sites in GyrA-CTD have been identified.