•CPB leads to inflammatory responses and oxidative stress.•PON1 is decreased in systemic inflammation and ischemia, like that during CPB is.•Glucocorticoids counteract oxidative stress by up ...regulating PON1 gene expression.•Methylprednisolone doesn't have significant effects on PON1 activity during CPB.
Cardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role whose activity is decreased in systemic inflammation and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by upregulating PON1 gene expression. The authors aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB.
Prospective, randomized, controlled clinical trial.
The University Medical Center Ljubljana, Slovenia.
Forty adult patients who underwent complex cardiac surgery on CPB between February 2016 and December 2017 were randomized into methylprednisolone and control groups (n = 20 each).
Patients in the methylprednisolone group received 1 g of methylprednisolone in the CPB priming solution, whereas patients in the control group were not given methylprednisolone during CPB.
The effect of methylprednisolone from the CPB priming solution was compared with standard care during CPB on PON1 activity until postoperative day 5. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed also. No significant differences were found between study groups for PON1 activity, high-density lipoprotein, and low-density lipoprotein in any of the measurement intervals (p > 0.016). The methylprednisolone group had significantly lower tumor necrosis factor alpha (p < 0.001) and interleukin-6 (p < 0.001), as well as C-reactive protein and procalcitonin (p < 0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and tumor necrosis factor alpha, interleukin-6, and CPB duration.
Methylprednisolone does not influence PON1 activity during cardiac surgery on CPB.
Organophosphates (OPs) are a class of chemicals commonly used in agriculture as pesticides, that can often lead to severe toxicity in humans. Paraoxonase-1 (PON1) belongs to a family of A-esterases ...and hydrolyses several OPs while also serving other biological roles. Two main genetic polymorphisms have been shown to affect enzymatic ability; an A > G transition in the 192nd position (192 Q/R, rs662), and an A > T at codon 55 (55 M/L, rs854560). In this review, we searched PubMed for relevant articles published from its inception till June 2018 and included publications from 1996 to 2018. We aimed to address the distribution of the polymorphisms in various populations, the way they affect enzymatic activity and the possible use of PON1 as a biomarker. The polymorphisms present great heterogeneity between populations, with the data being clearer over 192 Q/R, and this heterogeneity is related to the phylogenetic origins of each population. Concerning enzymatic activity, the different genotypes react better or worse to different OP substrates, with studies presenting a variety of findings. Detecting the “paraoxonase status” of an individual -referring to PON1 function- seems to be important in predicting OP toxicity, as studies have shown that some specific-genotype individuals present symptoms of toxicity in higher rates than others. We are strongly convinced that in order for the scientific community to reach a consensus over which polymorphisms confer susceptibility to toxicity and whether PON1 can eventually be used as a biomarker, more studies need to be carried out, since the data thus far does not seem to reach a universal conclusion.
Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are ...produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.
Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.
Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na
-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.
The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.
Current blood biomarkers are suboptimal in detecting drug‐induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of ...14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA‐122 (miR‐122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S‐transferase α, alpha‐fetoprotein, arginase‐1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin‐5, macrophage colony‐stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell‐derived chemotaxin‐2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR‐122, and there was a surprisingly wide inter‐ and intra‐individual variability of miR‐122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver‐related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End‐Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR‐122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.
Some previous studies already explored associations between paraoxonase 1 (PON1) polymorphisms and atherosclerotic cardiovascular diseases (ASCVD), with conflicting findings. Here, we aimed to better ...analyze the relationship between PON1 polymorphisms and ASCVD in a larger combined population by performing a meta-analysis.
We searched Pubmed, Embase and Web of Science for related articles. We calculated odds ratio (OR) and 95% confidence interval (CI) to estimate whether there are genetic associations between PON1 polymorphisms and ASCVD.
One hundred and nine studies were included for this meta-analysis. The PON1 rs854560 (17,220 cases and 18,570 controls, recessive comparison: OR = 0.83, 95%CI 0.72–0.96) and rs662 (30,717 cases and 54,894 controls, dominant comparison: OR = 0.82, 95% CI 0.77–0.89; recessive comparison: OR = 1.17, 95% CI 1.07–1.28; allele comparison: OR = 0.85, 95% CI 0.81–0.90) polymorphisms were both found to be significantly associated with susceptibility to ASCVD in general population. Subgroup analyses by ethnicity revealed similar significant findings for rs854560 polymorphism only in East Asians, while similar positive findings for rs662 polymorphism were observed in Caucasians, East Asians and South Asians. Subgroup analyses by type of disease indicated that the significant findings for rs854560 polymorphism were mainly driven by the ischemic stroke (IS) subgroup, whereas the positive results for rs662 polymorphism were mainly driven by the coronary artery disease (CAD) subgroup.
In summary, this meta-analysis proved that PON1 rs854560 polymorphism could be used to identify individual with elevated susceptibility to IS, whereas rs662 polymorphism could be used to identify individual with elevated susceptibility to CAD.
Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we ...examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis.
We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation.
Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells.
Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver.
Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.
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•Restoration of HNF4A via mRNA delivery improves functions of fibrotic primary hepatocytes from both mice and humans.•The mRNA encapsulated in lipid nanoparticles can be delivered into hepatocytes of the fibrotic liver.•Lipid nanoparticle-mediated HNF4A mRNA delivery ameliorates fibrosis and cirrhosis in different chronic liver injury models.•Paraoxonase 1, a therapeutic target of HNF4A, contributes to anti-fibrotic effects of HNF4A.•HNF4A mRNA delivery affects macrophage infiltration and polarization as well as hepatic stellate cell activation.
Organophosphate insecticides (OPs) are one of the pesticides commonly used in agricultural activities either to eradicate or to protect crops from insect attacks. Aside from the advantages proposed, ...this OPs substance also brings some worrisome threats for individual and population. Shallot farmworkers in Brebes Regency are population at risk to OPs exposure. The activity levels of Butyrylcholinesterase (BuChE) and paraoxonase 1 (PON1) in blood play important roles as a biomarker of exposure as well to measure the occurrence of OPs exposure in a human body and as a biomarker of susceptibility as well to measure the level of detoxifying OPs. The aim of this study was to analyse the correlation between levels of BuChE and PON1 activities amongst shallot farmworkers. A cross-sectional study was conducted on 88 male subjects selected randomly from Dukuhlo Village in Brebes Regency, Indonesia, occupationally exposed to OPs from April to May 2017. Using a structured questionnaire, a survey was carried out based on sociodemographic characteristics. Blood samples were collected to determine the levels of BuChE and PON1 activity. These samples were then analysed at laboratories of Cito in Tegal and Gaky, Undip in Semarang. Furthermore, data were analysed systematically using univariate and bivariate (a Spearman’s Rank test). A significant correlation was found between these both variables (p=0.025 and rho=0.238) with slightly moderate positive relationship. To sum up, farmworkers with higher PON1 activity may have a better chance of detoxifying the acute effect of OPs exposure. A further research is needed to identify correlation between PON1 activity, levels of thyroid hormones, and OPs metabolites in urine.
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