The increased incidence of cardiovascular diseases (CVDs) has stimulated research for substances that could improve cardiovascular health. Among them, resveratrol (RES), a polyphenolic compound ...notably present in grapes and red wine, has been involved in the "French paradox". RES is known for its antioxidant and anti-inflammatory properties and for its ability to upregulate endothelial NO synthase (eNOS). RES was able to scavenge (•)OH/O₂(•-) and peroxyl radicals, which can limit the lipid peroxidation processes. Moreover, in bovine aortic endothelial cells (BAEC) under glucose-induced oxidative stress, RES restored the activity of dimethylargininedimethylaminohydrolase (DDAH), an enzyme that degrades an endogenous inhibitor of eNOS named asymmetric dimethylarginine (ADMA). Thus, RES could improve (•)NO availability and decrease the endothelial dysfunction observed in diabetes. Preclinical studies have made it possible to identify molecular targets (SIRT-1, AMPK, Nrf2, NFκB…); however, there are limited human clinical trials, and difficulties in the interpretation of results arise from the use of high-dose RES supplements in research studies, whereas low RES concentrations are present in red wine. The discussions on potential beneficial effects of RES in CVDs (atherosclerosis, hypertension, stroke, myocardial infarction, heart failure) should compare the results of preclinical studies with those of clinical trials.
Abstract This review aims at describing the beneficial properties of melatonin related to its antioxidant effects. Oxidative stress, i.e., an imbalance between the production of reactive oxygen ...species and antioxidant defences, is involved in several pathological conditions such as cardiovascular or neurological disease, and in aging. Therefore, research for antioxidants has developed. However, classical antioxidants often failed to exhibit beneficial effects, especially in metabolic diseases. Melatonin has been shown as a specific antioxidant due to its amphiphilic feature that allows it to cross physiological barriers, thereby reducing oxidative damage in both lipid and aqueous cell environments. Studies on the antioxidant action of melatonin are reported, with a special mention to water gamma radiolysis as a method to produce oxygen-derived free radicals, and on structure–activity relationships of melatonin derivatives. Mass spectrometry-based techniques have been developed to identify melatonin oxidation products. Besides its ability to scavenge several radical species, melatonin regulates the activity of antioxidant enzymes (indirect antioxidant properties). Efficient detection methods confirmed the presence of melatonin in several plant products. Therapeutic potential of melatonin relies either on increasing melatonin dietary intake or on supplementation with supraphysiological dosages. Clinical trials showed that melatonin could be efficient in preventing cell damage, as well under acute (sepsis, asphyxia in newborns) as under chronic (metabolic and neurodegenerative diseases, cancer, inflammation, aging). Its global action on oxidative stress, together with its rhythmicity that plays a role in several metabolic functions, lead melatonin to be of great interest for future clinical research in order to improve public health.
Clinical, genetic, and medical evidence has shown the inflammatory vasculitis aspect of Behçet’s Disease (BD). Whereas oxysterols are vital factors in inflammation and oxidative stress, it is still ...unknown whether they are involved in the pathophysiology of BD. The current study aims to explore the profile of oxysterols in plasma of BD patients. Thirty patients diagnosed with BD and forty healthy controls matched for age and gender were included. Results showed that the cholestane-3β,5α,6β-triol, 27-hydroxycholesterol (27-OHC) and cholestanol levels were higher in BD than controls. In addition, plasma levels of 7-ketocholesterol (7-KC) and 25-hydroxycholesterol (25-OHC) were lower in BD patient. However, levels of 24S-hydroxycholesterol (24-OHC) did not significantly differ. For BD patients, the plasma 7-KC level was negatively correlated with the BD activity index (BDAI) while 27-OHC was positively correlated with high-sensitivity C-reactive protein (hs-CRP) in patients with active course of the disease. According to ROC analysis, a remarkable increase in the area under the curve (AUC) with a higher sensitivity (Se) and specificity (Sp) for 7-KC, 25-OHC and 27-OHC combined markers was observed. The present study indicated that the identification of the predictive value of these three-selected biomarkers related to oxidative stress and inflammation in patients should lead to a better identification of the etiological mechanism of BD.
•High levels of cholestane-3β,5α,6β-triol, 27-OHC and cholestanol in BD patients.•7KC plasma level was negatively correlated with the BD activity index.•Plasma level of 27-OHC was positively correlated with hs-CRP in active disease.•7-KC, 25-OHC and 27-OHC combined markers could predict BD.
Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged ...seizures and require urgent administration of antiepileptic drugs. Refractory status epilepticus requires anesthetics drugs and may lead to brain injury with molecular and cellular alterations (eg, inflammation, and neuronal and astroglial injury) that could induce neurologic sequels and further development of epilepsy. Outcome scores based on demographic, clinical, and electroencephalography (EEG) condition are available, allowing prediction of the risk of mortality, but the severity of brain injury in survivors is poorly evaluated. New biomarkers are needed to predict with higher accuracy the outcome of patients admitted with status in an intensive care unit. Here, we summarize the findings of studies from patients and animal models of status epilepticus. Specific protein markers can be detected in the cerebrospinal fluid and the blood. One of the first described markers of neuronal death is the neuron‐specific enolase. Gliosis resulting from inflammatory responses after status can be detected through the increase of S100‐beta, or some cytokines, like the High Mobility Group Box 1. Other proteins, like progranulin may reflect the neuroprotective mechanisms resulting from the brain adaptation to excitotoxicity. These new biomarkers aim to prospectively identify the severity and development of disability, and subsequent epilepsy of patients with status. We discuss the advantages and disadvantages of each biomarker, by evaluating their brain specificity, stability in the fluids, and sensitivity to external interferences, such as hemolysis. Finally, we emphasize the need for further development and validation of such biomarkers in order to better assess patients with severe status epilepticus.
: Melatonin (N‐acetyl‐5‐hydroxytryptamine) is a pineal hormone widely known for its antioxidant properties, both in vivo and by direct capture of free radicals in vitro. Although some metabolites ...and oxidation products of melatonin have been identified, the molecular mechanism by which melatonin exerts its antioxidant properties has not been totally unravelled. This study investigated the reaction mechanism of oxidation of melatonin by radio‐induced reactive oxygen species, generated by gamma radiolysis of water for aqueous solutions of melatonin (from 20 to 200 μm), in the presence or absence of molecular oxygen. The hydroxyl radical was found to be the unique species able to initiate the oxidation process, leading to three main products, e.g. N1‐acetyl‐N2‐formyl‐5‐methoxykynurenin (AFMK), N1‐acetyl‐5‐methoxykynurenin (AMK) and hydroxymelatonin (HO‐MLT). The generation of AFMK and HO‐MLT strongly depended on the presence of molecular oxygen in solution: AFMK was the major product in aerated solutions (84%), whereas HO‐MLT was favoured in the absence of oxygen (86%). Concentrations of AMK remained quite low, and AMK was proposed to result from a chemical hydrolysis of AFMK in solution. A K‐value of 1.1 × 10−4 was calculated for this equilibrium. Both hydrogen peroxide and superoxide dismutase had no effect on the radio‐induced oxidation of melatonin, in good accordance for the second case with the poor reactivity of the superoxide anion towards melatonin. Finally, a reaction mechanism was proposed for the oxidation of melatonin in vitro.
Background and purpose
There is a need for accurate biomarkers to monitor electroencephalography (EEG) activity and assess seizure risk in patients with acute brain injury. Seizure recurrence may ...lead to cellular alterations and subsequent neurological sequelae. Whether neuron‐specific enolase (NSE) and S100‐beta (S100B), brain injury biomarkers, can reflect EEG activity and help to evaluate the seizure risk was investigated.
Methods
Eleven patients, admitted to an intensive care unit for refractory status epilepticus, who underwent a minimum of 3 days of continuous EEG concomitantly with daily serum NSE and S100B assays were included. At 103 days the relationships between serum NSE and S100B levels and two EEG scores able to monitor the seizure risk were investigated. Biochemical biomarker thresholds able to predict seizure recurrence were sought.
Results
Only NSE levels positively correlated with EEG scores. Similar temporal dynamics were observed for the time courses of EEG scores and NSE levels. NSE levels above 17 ng/ml were associated with seizure in 71% of patients. An increase of more than 15% of NSE levels was associated with seizure recurrence in 80% of patients.
Conclusions
Our study highlights the potential of NSE as a biomarker of EEG activity and to assess the risk of seizure recurrence.
Whether neuron‐specific enolase (NSE) and S100‐beta, brain injury biomarkers, can reflect electroencephalography (EEG) activity and help to evaluate seizure risk was investigated. Only NSE levels positively correlated with EEG scores and were able to monitor the seizure risk. An increase of more than 15% of NSE levels was associated with a seizure recurrence in 80% of patients.
Hepatic fibrosis is a major consequence of chronic liver disease such as non-alcoholic steatohepatitis which is undergoing a dramatic evolution given the obesity progression worldwide, and has no ...treatment to date. Hepatic stellate cells (HSCs) play a key role in the fibrosis process, because in chronic liver damage, they transdifferentiate from a "quiescent" to an "activated" phenotype responsible for most the collagen deposition in liver tissue. Here, using a diet-induced liver fibrosis murine model (choline-deficient amino acid-defined, high fat diet), we characterized a specific population of HSCs organized as clusters presenting simultaneously hypertrophy of retinoid droplets, quiescent and activated HSC markers. We showed that hypertrophied HSCs co-localized with fibrosis areas in space and time. Importantly, we reported the existence of this phenotype and its association with collagen deposition in three other mouse fibrosis models, including CCl
-induced fibrosis model. Moreover, we have also shown its relevance in human liver fibrosis associated with different etiologies (obesity, non-alcoholic steatohepatitis, viral hepatitis C and alcoholism). In particular, we have demonstrated a significant positive correlation between the stage of liver fibrosis and HSC hypertrophy in a cohort of obese patients with hepatic fibrosis. These results lead us to conclude that hypertrophied HSCs are closely associated with hepatic fibrosis in a metabolic disease context and may represent a new marker of metabolic liver disease progression.
Abstract
Objectives
Inhibition of the organic cation transporter-2 renal tubule transporter by dolutegravir leads to serum creatinine increase. Serum cystatin C is a non-organic cation ...transporter-2-dependent marker, possibly enabling glomerular filtration rate (GFR) estimation under dolutegravir. Our goal was to evaluate the changes in creatinine- and cystatin C-based estimated GFR values before and after dolutegravir initiation.
Methods
Creatinine and cystatin measurements were carried out on frozen plasma samples from HIV-1-infected patients, before and after dolutegravir initiation, between October 2016 and March 2017 at Pitié-Salpêtrière Hospital. CKD-EPI equations were used to estimate mean GFR from creatinine and cystatin C values. Variations were analysed by paired t-test.
Results
Forty-four patients were included median age = 48 years (IQR 36–58) and median CD4 count = 592 cells/mm3 (IQR 388–728), including 6 ART-naive patients and 38 on switch strategies 72% with viral load <50 copies/mL and median ART duration = 13 years (IQR 5–20). Before dolutegravir initiation (median time = 41 days), 19 patients (43%) had creatinine-based estimated GFR <90 mL/min/1.73 m2 and 11 (25%) had cystatin C-based estimated GFR <90 mL/min/1.73 m2. After dolutegravir initiation, serum creatinine values significantly increased (+8.6 μmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated estimated GFR significantly decreased (−7.7 mL/min/1.73 m2, 95% CI −10.4; −5.1, P < 0.001). In contrast, there was no significant change in cystatin C value variation and associated estimated GFR. The same results were observed regardless of renal function at baseline.
Conclusions
Creatinine values increased after dolutegravir initiation, whereas no change was observed for cystatin C values. Use of cystatin C may enable better understanding of plasma creatinine fluctuations after dolutegravir initiation, particularly in high-risk renal patients.
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