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Metabolic syndrome (MetS) represents a cluster of diseases that includes diabetes and insulin resistance. A combination of these metabolic disorders damages liver function. We hypothesized here that histone deacetylase 1 (HDAC1) inhibits fibroblast growth factor 21 (FGF21) expression through histone deacetylation, thereby accentuating liver injury in rats with MetS. MetS rats induced by a high-fat diet were monitored weekly for blood pressure and body weight measurement. The changes of hepatic injury parameters were also measured. The pathological changes in the liver were observed by HE staining and oil red O staining. We found that HDAC1 was increased in the liver of rats with MetS, while sh-HDAC1 reduced blood pressure, body weight, and hepatic injury parameters. Improvement of structural pathological alterations and reduction of lipid deposition were observed after HDAC1 inhibition. Notably, HDAC1 inhibited FGF21 expression through histone deacetylation. The hepatoprotective effects of sh-HDAC1 on rats were reversed by adenovirus-mediated knockdown of FGF21. Moreover, methyltransferase-like 3 (METTL3) mediated the N6-methyladenosine (m6A) modification of HDAC1 mRNA and increased its binding to IGF2BP2. Consistently, sh-METTL3 inhibited HDAC1 and increased FGF21 expression, thereby ameliorating liver injury in MetS rats. This study discovered that HDAC1 is capable of managing liver injury in MetS. Targeting HDAC1 may be an optimal treatment for MetS-related liver injury. Key words: METTL3, IGF2BP2, HDAC1, FGF21, metabolic syndrome, liver injury, Introduction Metabolic syndrome (MetS), also known as syndrome X, insulin resistance (IR), etc., is defined by World Health Organization as a pathological condition characterized by abdominal obesity, hypertension, as well [...]

In order to analyze the differences in functional genes of Bifidobacterium pseudocatenulatum. Comparative genomics analysis was performed on 104 strains of Bifidobacterium pseudocatenulatum isolated from China, Japan and America. The results showed that the number of coding sequences of Japanese isolates were significantly higher than Chinese and American isolates in genome level (P<0.01).Phylogenetic tree based on core gene and average nucleotide identity clustering heat map showed that strains isolated from the same country were more similar. The results of functional gene annotation further showed that the isolation could affect the functional genes distribution of strains. The annotation of carbohydrate active enzymes revealed that 15 carbohydrate active enzymes had regional differences. The number of antibiotic resistance genes and adhesion virulence factors carried by Chinese isolates were more abundant than Japanese isolates by the annotation of antibiotic resistance genes database and virulence factors database. The number of Replication\recombination\repair and phage associated mobile genetic elements carried by the Chinese and Japanese isolates were different from American isolates. In this study, it was found that the location of strains will affect the functional genes of Bifidobacterium pseudocatenulatum, and Bifidobacterium pseudocatenulatum in different locations have different functional genes. This study provides theoretical basis for the analysis of the functional differences of Bifidobacterium pseudocatenulatum. [ABSTRACT FROM AUTHOR]

Aims: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. Methods: CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open‐label, 2‐period cross‐over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. Results: After a loading dose, the AUC0‐t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0‐t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28‐fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. Conclusions: CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs. [ABSTRACT FROM AUTHOR]

Background: The associations of cardiovascular autonomic neuropathy (CAN) with diabetic nephropathy and heart disease remain elusive. The aim of this study was to explore the correlations of CAN with urinary albumin excretion rate (UAER) and cardiac function in patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 225 T2DM patients were assigned into CAN and non-CAN groups using cardiovascular reflex tests (CARTs). They were divided into macroalbuminuria, microalbuminuria and normoalbuminuria groups according to urinary albumin/creatinine ratio (UACR), or left ventricular diastolic dysfunction and normal groups based on left ventricular peak E/A velocity ratio (E/A). The correlations of CAN with albuminuria and left ventricular diastolic dysfunction, and the predictive values of UACR and E/A were analyzed., Results: Compared with non-CAN group, CAN group had older age, longer T2DM duration, higher serum urine acid (SUA) level, UACR, systolic and diastolic pressure differences between supine and standing positions, and lower other CARTs parameters and E/A (P<0.001). Macroalbuminuria group had largest positional systolic and diastolic pressure differences, and lowest other CARTs parameters (P<0.001). Compared with normal group, left ventricular diastolic dysfunction group had larger positional systolic and diastolic pressure differences, and lower other CARTs parameters (P<0.001). CAN in T2DM patients was positively correlated with albuminuria and left ventricular diastolic dysfunction (P<0.001). Age, SUA, UACR and E/A were independent predictive factors (P=0.031, P=0.005, P<0.001, P<0.001). UACR and E/A had high predictive values., Conclusions: In T2DM patients, CAN is positively correlated with declined UAER and cardiac function. UACR and E/A have high predictive values.

Inflammasomes are innate immune sensors and receptors that play key pathological roles in the development and progression of numerous diseases. Recent studies have shown that NLRP3 inflammasomes are critical in the pathology of diseases with a high impact on public health, such as musculoskeletal disorders. Musculoskeletal disorders, mainly caused or aggravated by work and the surrounding environment, are locomotor system disorders such as muscles, joints, bones, as well as diseases associated with neurological and circulatory system injuries. Activation of NLRP3 inflammasomes can induce inflammation and pyroptosis, leading to further bodily harm. Therefore, investigating the mechanism and function of NLRP3 inflammasomes, holds great significance and importance for the prevention and treatment of musculoskeletal disorders. This review provides a summary of the activation pathway and mechanism of NLRP3 inflammasomes, and analyzes the role in musculoskeletal disorders such as sarcopenia, osteoporosis and arthritis, with the aim to facilitate the treatment of musculoskeletal disorders.

Aims: Vicagrel, a novel antiplatelet prodrug to overcome the residual high platelet reactivity of clopidogrel induced by inactive metabolism and cytochrome P450 (CYP) 2C19 polymorphisms, provides favourable antiplatelet inhibition in healthy volunteers. However, its antiplatelet effect and safety in patients with coronary artery disease (CAD) are unclear., Methods and Results: This was a multicentre, randomized, double-blind, triple-dummy, dose-exploring phase II trial comparing the antiplatelet activity and safety of vicagrel at different doses vs. those of clopidogrel in patients with CAD undergoing percutaneous coronary intervention (PCI). The primary endpoint was inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (%IPA) after loading and maintenance doses (LD/MD) at 28 days. Safety endpoints included adverse events (AEs) and Bleeding Academic Research Consortium-defined any bleeding. Pharmacokinetic (PK) profiles and the influence of CYP2C19 polymorphisms were explored in subgroup analysis. Two hundred and seventy-nine patients diagnosed with stable CAD (51.97%), unstable angina (40.86%), and myocardial infarction (7.17%) were randomized to receive vicagrel 20/5 mg (LD/MD), 24/6 mg, or 30/7.5 mg or clopidogrel 300/75 mg in combination with aspirin. %IPAs on Day 28 were 30.19%, 35.02%, 45.61%, and 32.55% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, and were comparable across all groups (P = 0.0694). The plasma concentration of the vicagrel active metabolite M15-2 had a similar area under curve and Tmax to those of clopidogrel. There were no significant differences in AEs (4.35%, 0%, 1.45%, and 5.56% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, P = 0.6667) or any bleeding (13.04%, 14.06%, 11.59%, and 11.11% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, P = 0.95) across four groups. %IPAs and PK profiles of vicagrel did not vary significantly among different CYP2C19 metabolizers., Conclusion: Vicagrel had comparable antiplatelet effect and safety to clopidogrel in patients with CAD undergoing PCI., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Cordycepin (known as 3-deoxyadenosine, CRD), a natural product from the valuable traditional Chinese medicine Cordyceps militaris, has been reported to improve cognitive function and modulate neuroprotective effects on the central nervous system (CNS). However, the modulating mechanisms of cordycepin on information processing in hippocampal CA1 pyramidal neurons are not fully understood. To clarify how cordycepin modulates synaptic responses of pyramidal neurons in rat hippocampal CA1 region, we conducted an electrophysiological experiment using whole-cell patch-clamp technique. The spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs, respectively) and the spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) recorded by this technique evaluated pure single or multi-synapse responses and enabled us to accurately quantify how cordycepin influenced the pre and postsynaptic aspects of synaptic transmission. The present results showed that cordycepin significantly decreased the frequency of both glutamatergic and GABAergic postsynaptic currents without affecting the amplitude, while these inhibitory effects were antagonized by the A 1 adenosine receptor antagonist (DPCPX), but not the A 2A (ZM 241385), A 2B (MRS1754) and A 3 (MRS1191) adenosine receptor antagonists. Taken together, our results suggested that cordycepin had a clear presynaptic effect on glutamatergic and GABAergic transmission, and provided novel evidence that cordycepin suppresses the synaptic transmission through the activation of A 1 AR., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)