Atherosclerosis (AS) is associated with high morbidity and mortality, thus imposing a growing burden on modern society. Herb‐derived bicyclol (BIC) is a versatile bioactive compound that can be used ...to treat AS. However, its efficacy in AS is not yet described. Here, it is shown that BIC normalizes gut microflora dysbiosis induced by a high fat diet in Apoe(−/−) mice. Metagenome‐wide association study analysis verifies that the modulation on carbohydrate‐active enzymes and short‐chain fatty acid generating genes in gut flora is among the mechanisms. The gut healthiness, especially the gut immunity and integrity, is restored by BIC intervention, leading to improved systemic immune cell dynamic and liver functions. Accordingly, the endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are alleviated by BIC to lessen the plaque onset. Moreover, it is proved that the therapeutic effect of BIC on AS is transmissible by fecal microbiota transplantation. The current study, for the first time, demonstrates the antiatherosclerotic effects of BIC and shows that its therapeutic value can at least partially be attributed to its manipulation of gut microbiota.
Bicyclol (BIC) effectively modulates the composition, function, and production of endogenous metabolites of gut microbiota. The gut health reinstated by BIC benefits systemic immune cell dynamics and liver functions, leading to improved chronic inflammation and hypercholesterolemia. Consequently, endothelial activation, macrophage infiltration, and cholesterol ester accumulation in the aortic arch are attenuated, causing less plaque onset.
PIWI-interacting RNAs (piRNAs) are a complex class of small non-coding RNAs which specifically interact with the PIWI protein to play important roles in germline development and somatic tissues. ...Aberrant expressions of piRNAs have been recently found in a variety of malignant tumors and associated with cancer hallmarks. However, current methods of analyzing piRNAs are limited to reverse transcription quantitative polymerase chain reaction and next generation sequencing. In this study, we have developed a universal catalytic hybridization assembly system (uniCHA) to quantify piRNAs as well as microRNAs. The system simply comprises two universal hairpin DNA strands and one starting hairpin DNA which can be tailored by a simple rule to bind different piRNA and miRNA targets. The uniCHA system was proved to be able to analyze various piRNAs and miRNAs at the same reaction condition with low leakage and high sensitivity of pM level. With this system, we have detected piR-651 and miR-1246 in 106 particles μL−1 MCF-7 cell-secreted exosomes, and successfully performed a direct plasma biopsy to diagnose breast cancer with sensitivity and specificity both at 100% in cohorts of 21 breast cancer patients and 13 healthy controls. This universal biosensing system provides a simple and efficient strategy in analyzing multiple piRNA/miRNA biomarkers in complicated biological samples, indicating its potential of clinical application in cancer diagnostics.
Display omitted
•A universal catalytic hairpin assembly system for detection of RNA has been set up.•The system has successfully analyzed PIWI-interacting RNAs in buffer, exosomes and human plasma.•The direct breast cancer plasma biopsy by the system has achieved high accuracy.
Many clinical trials have demonstrated that statins convey protective effects against atherosclerosis independent of cholesterol-lowering capacities. Other evidence indicates that pyroptosis, a type ...of programmed cell death, is likely involved in atherosclerosis, but the effects and mechanisms of statins on pyroptosis must be further revealed.
Here, we explored the effects and mechanisms of atorvastatin on pyroptosis in human vascular endothelial cells by quantitative real-time polymerase chain reaction and Western blot analyses.
Atorvastatin upregulated long non-coding RNA (lncRNA) NEXN-AS1 and the expression of NEXN at both the mRNA and protein levels in a concentration- and time-dependent manner. Atorvastatin inhibited pyroptosis by decreasing the expression levels of the canonical inflammasome pathway biomarkers NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 at both the mRNA and protein levels. The promotion effects of atorvastatin on NEXN-AS1 and NEXN expression could be significantly abolished by knockdown of lncRNA NEXN-AS1 or NEXN, and its inhibitory effects on pyroptosis were also markedly offset by knock-down of lncRNA NEXN-AS1 or interference of NEXN.
These results demonstrated that atorvastatin regulated pyroptosis via the lncRNA NEXN-AS1-NEXN pathway, which provides a new insight into the mechanism of how atorvastatin promotes non-lipid-lower effects against the development of atherosclerosis and gives new directions on how to reverse atherosclerosis.
Display omitted
•Atorvastatin upregulates lncRNA NEXN-AS1 and NEXN in EC.•Atorvastatin inhibits the canonical inflammasome pathway biomarkers of pyroptosis.•Both the above effects can be abolished by knockdown of lncRNA NEXN-AS1 or NEXN.
The outbreak of 2019 novel coronavirus (2019-nCoV) pneumonia was reported in Wuhan, Hubei Province, China in December 2019 and has spread internationally. This article discusses how radiology ...departments can most effectively respond to this public health emergency.
Studies have examined the association between parental body mass index (BMI) and autism spectrum disorder (ASD) in offspring, with inconsistent results, especially regarding maternal obesity, ...overweight and underweight. Cochrane Library, EMBASE, PubMed and PsycINFO databases were searched up to March 2018 for relevant observational studies with no language restriction. Our literature search identified 13 eligible studies for meta-analysis (involving 943,293 children and 30,337 cases). For maternal BMI (13 studies), both maternal obesity OR 1.41 (95% CI 1.19–1.67) and maternal overweight OR 1.16 (95% CI 1.05–1.27) were significantly associated with ASD, while maternal underweight was not associated with ASD OR 1.08 (95% CI 0.98–1.20). For paternal BMI (three studies), no association was found (paternal obesity: OR 1.28, 95% CI 0.94–1.74; overweight: OR 1.07, 95% CI 0.99–1.15; underweight: OR 1.12, 95% CI 0.87–1.44). Pooled estimates were robust in sensitivity analysis and subgroup analyses. Publication bias may exist for studies assessing maternal BMI and ASD risk, but the filled estimates were not altered. Relative to normal weight, maternal obesity and overweight were significantly associated with increased ASD risk, while maternal underweight was not associated with ASD. Although no association between paternal BMI and ASD was found, current evidence is limited (three studies). Future studies are warranted to address more confounding factors and to identify potential mediators of the association, but pre-pregnancy weight control is suggested.
Epithelial‐mesenchymal transition (EMT) is a physiological process that has been recognized to occur during the progression of an increasingly large number of human diseases, including liver ...fibrosis, cirrhosis, and hepatocellular carcinoma. The activation of transforming growth factor β (TGF‐β) signaling is considered a critical event during EMT, and efforts have been made to screen small molecules that interfere with the TGF‐β signaling pathway during EMT. Here we report the identification of sorafenib, a clinical agent that inhibits TGF‐β signaling. When applied to AML12 cells and primary hepatocytes, sorafenib strikingly suppressed TGF‐β1‐induced EMT and apoptosis. Additionally, sorafenib inhibited TGF‐β1‐induced signal transducer and activator of transcription 3 phosphorylation. We further present in vitro evidence that sorafenib ameliorates the proapoptotic and profibrotic effects of TGF‐β1 in mouse primary hepatocytes, suggesting that this drug exerts a protective effect on hepatocytes and has therapeutic potential for the treatment of liver fibrosis. (HEPATOLOGY 2011;)
We sought to explore the prevalence and immediate clinical implications of acute myocardial injury in a cohort of patients with COVID-19 in a region of China where medical resources are less stressed ...than in Wuhan (the epicentre of the pandemic).
We prospectively assessed the medical records, laboratory results, chest CT images and use of medication in a cohort of patients presenting to two designated covid-19 treatment centres in Sichuan, China. Outcomes of interest included death, admission to an intensive care unit (ICU), need for mechanical ventilation, treatment with vasoactive agents and classification of disease severity. Acute myocardial injury was defined by a value of high-sensitivity troponin T (hs-TnT) greater than the normal upper limit.
A total of 101 cases were enrolled from January to 10 March 2020 (average age 49 years, IQR 34-62 years). Acute myocardial injury was present in 15.8% of patients, nearly half of whom had a hs-TnT value fivefold greater than the normal upper limit. Patients with acute myocardial injury were older, with a higher prevalence of pre-existing cardiovascular disease and more likely to require ICU admission (62.5% vs 24.7%, p=0.003), mechanical ventilation (43.5% vs 4.7%, p<0.001) and treatment with vasoactive agents (31.2% vs 0%, p<0.001). Log hs-TnT was associated with disease severity (OR 6.63, 95% CI 2.24 to 19.65), and all of the three deaths occurred in patients with acute myocardial injury.
Acute myocardial injury is common in patients with COVID-19 and is associated with adverse prognosis.
Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)‐mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis ...and development. However, the molecular mechanism by which NAMPT contributes to HBV‐associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV‐positive HCC tissues compared with HBV‐negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV‐positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV‐associated HCC cells, while NAMPT‐insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element‐binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis‐related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV‐induced HCC progression through the activation of SREBP1‐triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV‐associated HCC patients.
NAMPT was upregulated in HBV‐positive HCC tissues and activated SREBP1 by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis‐related genes and the production of intracellular lipids and cholesterol, and ultimately the malignant progression in HBV‐associated HCC cells.
Ubiquitin-specific protease 14 (USP14) is one of the major proteasome-associated deubiquitinating enzymes critical for proteome homeostasis. However, substrates of USP14 remain largely unknown, ...hindering the understanding of its functional roles. Here we conduct a comprehensive proteome, ubiquitinome and interactome analysis for USP14 substrate screening. Bioinformatics analysis reveals broad new potential roles of USP14, especially in lipid and carbohydrate metabolism. Among the potential substrates identified, we show that fatty acid synthase (FASN), a key enzyme involved in hepatic lipogenesis, is a bona fide substrate of USP14. USP14 directly interacts with and increases FASN stability. As a result, overexpression of USP14 promotes liver triglyceride accumulation in C57BL/6 mice, whereas genetic ablation or pharmacological inhibition of USP14 ameliorates hepatosteatosis, hyperglycemia and insulin resistance in obese mice. In conclusion, our findings reveal for the first time an indispensable role of USP14 in hepatosteatosis through FASN stabilization.
Glutaminase regulates glutaminolysis to promote cancer cell proliferation. However, the mechanism underlying glutaminase activity regulation is largely unknown. Here, we demonstrate that kidney-type ...glutaminase (GLS) is highly expressed in human pancreatic ductal adenocarcinoma (PDAC) specimens with correspondingly upregulated glutamine dependence for PDAC cell proliferation. Upon oxidative stress, the succinyl-coenzyme A (CoA) synthetase ADP-forming subunit β (SUCLA2) phosphorylated by p38 mitogen-activated protein kinase (MAPK) at S79 dissociates from GLS, resulting in enhanced GLS K311 succinylation, oligomerization, and activity. Activated GLS increases glutaminolysis and the production of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, thereby counteracting oxidative stress and promoting tumor cell survival and tumor growth in mice. In addition, the levels of SUCLA2 pS79 and GLS K311 succinylation, which were mutually correlated, were positively associated with advanced stages of PDAC and poor prognosis for patients. Our findings reveal critical regulation of GLS by SUCLA2-coupled GLS succinylation regulation and underscore the regulatory role of metabolites in glutaminolysis and PDAC development.
•GLS is upregulated in human pancreatic ductal adenocarcinoma•GLS K311 succinylation enhances the oligomerization and activity of GLS•p38-phosphorylated SUCLA2 dissociates from GLS and promotes GLS K311 succinylation•GLS succinylation promotes glutaminolysis and tumor growth
Tong et al. demonstrate that oxidative stress removes GLS-associated SUCLA2 to catalyze succinyl-CoA. This dissociation enhances succinyl-CoA-dependent GLS K311 succinylation and activity, leading to increased production of NADPH and GSH against oxidative-stress-induced ROS production and apoptosis and promoting tumor cell proliferation and tumor growth in mice.
PDF
