Red meat consumption and risk for dyslipidaemia and inflammation: A systematic review and meta-analysis.

Aim: The study (PROSPERO: CRD42021240905) aims to reveal the relationships among red meat, serum lipids and inflammatory biomarkers. Methods and results: PubMed, EMBASE and the Cochrane databases were explored through December 2021 to identify 574 studies about red meat and serum lipids markers including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP) or hypersensitive-CRP (hs-CRP). Finally, 20 randomized controlled trials (RCTs) involving 1001 people were included, red meat and serum lipid markers and their relevant information was extracted. The pooled standard mean difference (SMD) was obtained by applying a random-effects model, and subgroup analyses and meta-regression were employed to explain the heterogeneity. Compared with white meat or grain diets, the gross results showed that the consumption of red meat increased serum lipid concentrations like TG (0.29 mmol/L, 95% CI 0.14, 0.44,P<0.001), but did not significantly influence the TC (0.13 mmol/L, 95% CI -0.07, 0.33, P = 0.21), LDL-C (0.11 mmol/L, 95% CI -0.23, 0.45, P = 0.53), HDL-C (-0.07 mmol/L, 95% CI -0.31, 0.17, P = 0.57),CRP or hs-CRP (0.13 mmol/L, 95% CI -0.10, 0.37,P = 0.273). Conclusion: Our study provided evidence to the fact that red meat consumption affected serum lipids levels like TG, but almost had no effect on TC, LDL-C, HDL-C and CRP or hs-CRP. Such diets with red meat should be taken seriously to avoid the problem of high lipid profiles. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO], identifier [CRD42021240905].

Discovery of 4'-azido-2'-deoxy-2'-C-methyl cytidine and prodrugs thereof: a potent inhibitor of Hepatitis C virus replication.

4'-Azido-2'-deoxy-2'-methylcytidine (14) is a potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) value of 1.2 µM and showing moderate in vivo bioavailability in rat (F=14%). Here we describe the synthesis and biological evaluation of 4'-azido-2'-deoxy-2'-methylcytidine and prodrug derivatives thereof.

ß-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.

We report a series of ß-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. ß-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K(i) of 0.5 µM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC(50) 0.6 µM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative.

Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase.

2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5'-tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action.

The design, synthesis, and antiviral activity of monofluoro and difluoro analogues of 4'-azidocytidine against hepatitis C virus replication: the discovery of 4'-azido-2'-deoxy-2'-fluorocytidine and 4'-azido-2'-dideoxy-2',2'-difluorocytidine.

The discovery of 4'-azidocytidine (3) (R1479) (J. Biol. Chem. 2006, 281, 3793; Bioorg. Med. Chem. Lett. 2007, 17, 2570) as a potent inhibitor of RNA synthesis by NS5B (EC(50) = 1.28 microM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of several monofluoro and difluoro derivatives of 4'-azidocytidine. The most potent compounds in this series were 4'-azido-2'-deoxy-2',2'-difluorocytidine and 4'-azido-2'-deoxy-2'-fluoroarabinocytidine with antiviral EC(50) of 66 nM and 24 nM in the HCV replicon system, respectively. The structure-activity relationships within this series were discussed, which led to the discovery of these novel nucleoside analogues with the most potent compound, showing more than a 50-fold increase in antiviral potency as compared to 4'-azidocytidine (3).

The design, synthesis, and antiviral activity of 4'-azidocytidine analogues against hepatitis C virus replication: the discovery of 4'-azidoarabinocytidine.

4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.

Nucleoside analogs as anti-HBV agents.

Chronic hepatitis B virus (HBV) infection affects about 400 million people worldwide. The development of nucleoside analogs that inhibit HBV polymerase provides an important approach for treating HBV infection. The approval of lamivudine, adefovir and entecavir represents a cornerstone of hepatitis B therapy. However, the challenges from the resistance and the off-therapy viral rebound are still unmet, and there is a need of developing new therapeutic agents. This review will discuss the structure-activity relationship of the most significant anti-HBV nucleoside analogs and the latest development in the field.

[Effect of primary percutaneous coronary intervention on plasma B-type natriuretic peptide in patients with acute myocardial infarction].

OBJECTIVE: To observe the effect of primary percutaneous coronary intervention (PCI) on plasma B-type natriuretc peptide (BNP) in patients with acute myocardial infarction (AMI). METHODS: Thirty-eight patients with AMI were divided into two groups for PCI (n=26) and conventional treatment (n=12). The plasma BNP levels were measured by fluorescence immunoassay (FIA) in these patients immediately, 24 h, 7 d, and 30 days after admission, and the infarct-related coronary arteries (IRA) were treated only with emergency interventional therapy in PCI group. RESULTS: BNP of the patients in the PCI and conventional treatment group B increased immediately and 24 h after admission, but there was no significant difference between the two groups (243.74+/-75.68 vs 228.65+/-82.32 and 283.42+/-88.66 vs 275.48+/-89.67, P>0.05). BNP in PCI group decreased but that in conventional treatment group increased 7 days after admission, showing significant difference between them (203.63+/-59.42 vs 388.74+/-108.52, P<0.05 ). BNP remained significantly lower in the PCI group than in the other group 30 days after admission (96.31+/-43.22 vs 237.66+/-75.48, P<0.01). Emergency PCI for different IRA resulted in the significant difference in BNP between the patients, and intervention of the left anterior descending artery (LAD) resulted in more obvious BNP reduction in comparison with that due to interventional of the right coronary artery (RCA) and left circumflex coronary artery (LCX). The changes in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic dimension (LVEDD) were correlated to the changes of BNP. The mean BNP in the 3 fatal cases was nearly 10-fold higher than the normal level. CONCLUSIONS: BNP of AMI patients decreases on days 7 and 30 after reperfusion therapy with primary PCI, and the reduction can be more obvious 30 days after admission.

Validation of microdialysis sampling for oral availability studies by means of a new ganciclovir prodrug.

Microdialysis sampling was validated for oral availability studies using ganciclovir (9-(1, 3-dihydroxy-2-propoxymethyl) guanine) and a ganciclovir prodrug (9-(1-L-valyloxy-3-octadecanoyloxy-prop-2-oxymethyl) guanine). Three different techniques were used in the study; microdialysis, blood and urinesampling. The oral uptake (11+/-2%) and the urinary recovery (106+/-5%) were determined. Animals given ganciclovir subcutaneously were subject either to microdialysis and blood sampling or to microdialysis alone. There was no significant difference between microdialysis and blood sampling in terms of blood concentration data, CL, Vd, half-life or AUC by means of Student's t-test. The oral bioavailability of the prodrug was 40+/-7% estimated from microdialysis sampling data and 48+/-4% estimated from urine sampling data. It is concluded that microdialysis is a valid method to use in pharmacokinetic studies of oral availability as well as for basic pharmacokinetic parameter estimation.