Polyunsaturated fatty acids balance affects platelet NOX2 activity in patients with liver cirrhosis

BackgroundNADPH-oxidase-2 up-regulation has been suggested in liver damage perpetuation via an oxidative stress-mediated mechanism. n-6/n-3 polyunsaturated fatty acids ratio derangement has been reported in liver disease.AimTo explore polyunsaturated fatty acids balance and its interplay with platelet oxidative stress in liver cirrhosis.MethodsA cross-sectional study in 51 cirrhotic patients and sex- and age-matched controls was performed. Serum polyunsaturated fatty acids and oxidative stress markers (urinary isoprostanes and serum soluble NADPH-oxidase-2-derived peptide) were measured. The effect on platelet oxidative stress of n-6/n-3 polyunsaturated fatty acids ratio in vitro and in vivo (1-week supplementation with 3 g/daily n-3-polyunsaturated fatty acids) was tested.ResultsCompared to controls, cirrhotic patients had significantly higher n-6/n-3 polyunsaturated fatty acids ratio. n-6/n-3 polyunsaturated fatty acids ratio correlated significantly with disease severity and oxidative stress markers. In vitro experiments showed that in Child–Pugh C patients’ platelets incubation with low n-6/n-3 polyunsaturated fatty acids ratio resulted in dose-dependent decrease of radical oxigen species (−39%), isoprostanes (−25%) and NADPH-oxidase-2 regulation (−51%). n-3 polyunsaturated fatty acids supplemented patients showed significant oxidative stress indexes reduction.ConclusionsIn cirrhosis, n-6/n-3 polyunsaturated fatty acids imbalance up-regulates platelet NADPH-oxidase-2 with ensuing oxidative stress. Further study to evaluate if n-3 supplementation may reduce disease progression is warranted.     

Inequalities in enrollment of women and racial minorities in trials testing uric acid lowering drugs

AimsWe investigated sex and racial inequalities in clinical trials testing serum uric acid (SUA) lowering drugs and analyzed the temporal trends of participation among the pre-specified demographic groups.Data were collected from publications of clinical trials testing SUA-lowering drugs. Linear regression analysis was performed to assess the relation between drug approval year and proportion of women and minorities enrolled in clinical studies.Data synthesisThe mean percentage enrollment of women in clinical trials significantly decreased over the time (r = −0.43, P-value = 0.02). Moreover, there was a statistically significant difference in mean percentage enrollment of women among trials testing different SUA-lowering drugs, with the highest representation in rasburicase (71.1%) and the lowest representation of women in dotinurad (0.8%). Over the time, also the mean percentage enrollment of racial minorities decreased, passing from 8.7% to 2.2% in a 10-year period.Women were proportionally underrepresented compared with their share of the population with asymptomatic hyperuricemia, overall (participation-to-prevalence ratio (PPR) = 0.34), in trials testing xanthine oxiase inhibitors (PPR = 0.38) and uricosurics (PPR = 0.29), and in trials with febuxostat, allopurinol, pegloticase, halofenate/arhalofenate, verinurad, lesinurad and dotinurad. Women were proportionally underreppresented also compared with their share of the population with gout, overall (PPR = 0.69) and in trials testing XOIs (PPR = 0.69), uricosurics (PPR = 0.68), and all SUA-lowering drugs excepted for rasburicase, pegloticase and topiroxostat.ConclusionsOur analysis shows that women and racial and ethnical minorities are underrepresented in controlled clinical trials testing SUA-lowering drugs, with similar pattern across drug classes.     

The incorporation and release of glucose oxidase and interleukin 2 from a bead formed macroporous hydrophilic polymer matrix

Freeze-thaw photopolymerization at low temperature of a mixed solution of 2-hydroxyethyl methacrylate (HEMA), ethylene glycol dimethacrylate (EDM), and either glucose oxidase (GOx) or interleukin 2 (IL-2) around frozen ice crystals has been used to generate a bead-formed macroporous hydrophilic matrix with potential for immobilization and sustained release. The mean equilibrium acetate buffer content (EBC) of unloaded p-HEMA beads at room temperature and controlled humidity was ~72%. The incorporation of GOx into beads significantly increased the EBC to ~76%. The release of GOx was characterized by a short initial burst release which declined rapidly until by day 14 no further biologically active enzyme release could be detected. Bead size had no significant effect on the total mean cumulative release of GOx at room temperature. Since only ~ 4% of the original therapeutic load of GOx was released over 14 days a substantial proportion of biologically active enzyme had become associated with the hydrogel matrix surface generating a bead formed immobilised enzyme system. Total cumulative release profiles for IL-2 were almost linear and maintained for at least 16 days. In absolute terms, the proportion of the original theoretical incorporated load subsequently released over this period was low. However, such a low level sustained release of IL-2 may lend itself therapeutically to a reduction in unwanted non-specific systemic activity.     

内皮素-NADPH氧化酶途径和心肌钙调控蛋白：心律失常和心衰治疗药物的新靶点

心肌雷诺定受体2是一种心肌细胞钙释放通道,对心肌Ca2＋循环起着至关重要的作用。该受体的功能受心肌钙调控蛋白FKBP12.6、SERCA2a和CASQ2等的影响,而此类蛋白的表达又与内皮素-NADPH氧化酶（ET-NOX）途径有关。ET-NOX途径和心肌钙调控蛋白的异常均会导致心律失常和心衰。因此,ET-NOX途径中各成员以及心肌钙调控蛋白有可能成为治疗心律失常和心衰的新靶标。综述了心肌钙调控蛋白和ET-NOX途径在正常心肌兴奋收缩耦联过程及病理过程中的作用,并介绍了相关的在研抗心律失常药物。     

Identification of biomarkers for essential hypertension based on metabolomics

AimEssential hypertension (EH) is one of the most important public health problems worldwide. However, the pathogenesis of EH is unclear and early diagnostic methods are lacking. Metabolomics demonstrates great potential for biomarker discovery and the mechanistic exploration of metabolic diseases.Data synthesisThis review included human and animal metabolomics studies related to EH in the PubMed and Web of Science databases between February 1996 and May 2020. The study designs, EH standards, and reported metabolic biomarkers were systematically examined and compared. The pathway analysis was conducted through the online software MetaboAnalyst 4.0.Twenty-two human studies and fifteen animal studies were included in this systematic review. There were many frequently reported biomarkers with consistent trends (e.g., pyruvate, lactic acid, valine, and tryptophan) in human and animal studies, and thus had potential as biomarkers of EH. In addition, several shared metabolic pathways, including alanine, aspartate, and glutamate metabolism, aminoacyl-tRNA biosynthesis, and arginine biosynthesis, were identified in human and animal metabolomics studies. These biomarkers and pathways, closely related to insulin resistance, the inflammatory state, and impaired nitric oxide production, were demonstrated to contribute to EH development.ConclusionsThis study summarized valuable metabolic biomarkers and pathways that could offer opportunities for the early diagnosis or prediction of EH and the discovery of the metabolic mechanisms of EH.     

Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase

Excessive activity of NADPH oxidase (Nox) is considered to be of importance for the progress of diabetic nephropathy. The aim of the study was to elucidate the effect of melatonin, known for its nephroprotective properties, on Nox activity under diabetic conditions. The experiments were performed on three groups of animals: (i) untreated lean (?/+) Zucker diabetic fatty (ZDF) rats; (ii) untreated obese diabetic (fa/fa) ZDF rats; and (iii) ZDF fa/fa rats treated with melatonin (20 mg/L) in drinking water. Urinary albumin excretion was measured weekly. After 4 wk of the treatment, the following parameters were determined in kidney cortex: Nox activity, expression of subunits of the enzyme, their phosphorylation and subcellular distribution. Histological studies were also performed. Compared to ?/+ controls, ZDF fa/fa rats exhibited increased renal Nox activity, augmented expression of Nox4 and p47^phox subunits, elevated level of p47^phox phosphorylation, and enlarged phospho‐p47^phox and p67^phox content in membrane. Melatonin administration to ZDF fa/fa rats resulted in the improvement of renal functions, as manifested by considerable attenuation of albuminuria and some amelioration of structural abnormalities. The treatment turned out to nearly normalize Nox activity, which was accompanied by considerably lowered expression and diminished membrane distribution of regulatory subunits, that is, phospho‐p47^phox and p67^phox. Thus, it is concluded that: (i) melatonin beneficial action against diabetic nephropathy involves attenuation of the excessive activity of Nox; and (ii) the mechanism of melatonin inhibitory effect on Nox is based on the mitigation of expression and membrane translocation of its regulatory subunits.     

An expert opinion on safinamide in Parkinson's disease

Background: Dopamine replacement therapies (levodopa, dopamine receptor agonists, anticholinergics, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors) remain the cornerstones of therapeutic interventions for Parkinson's disease (PD). Despite the treatment options for PD symptoms, a cure remains elusive. An optimal treatment would be one that combined relief in both motor and nonmotor symptoms with neuroprotective properties. Safinamide is an investigational drug for PD currently in development as add-on therapy to both dopamine agonists and levodopa. Safinamide is a unique molecule with a novel mode of action, targeting both dopaminergic and glutaminergic systems, and potentially provides motor symptom control. Preliminary results from experimental models suggest potential neuroprotective effects. Studies on the potential effects on nonmotor symptoms are ongoing. Objective: To review the mechanism of action and pharmacokinetics, and to evaluate the available clinical safety and efficacy results of safinamide. Methods: A search of the electronic database MEDLINE (PubMed, no time limits) was performed on 14 December 2007. The full text of all citations was obtained for review. Furthermore, two abstracts on safinamide published as proceedings of a European conference were reviewed. Results/conclusion: Safinamide is a promising investigational drug for PD with a novel mode of action. Early reports confirm the potential efficacy of safinamide in PD. Further studies on potential effects on cognition and neuroprotection are needed.