Unraveling the parahormetic mechanism underlying the health-protecting effects of grapeseed procyanidins.

Proanthocyanidins (PACs), the predominant constituents within Grape Seed Extract (GSE), are intricate compounds composed of interconnected flavan-3-ol units. Renowned for their health-affirming properties, PACs offer a shield against a spectrum of inflammation associated diseases, such as diabetes, obesity, degenerations and possibly cancer. While monomeric and dimeric PACs undergo some absorption within the gastrointestinal tract, their larger oligomeric and polymeric counterparts are not bioavailable. However, higher molecular weight PACs engage with the colonic microbiota, fostering the production of bioavailable metabolites that undergo metabolic processes, culminating in the emergence of bioactive agents capable of modulating physiological processes. Within this investigation, a GSE enriched with polymeric PACs was employed to explore in detail their impact. Through comprehensive analysis, the present study unequivocally verified the gastrointestinal-mediated transformation of medium to high molecular weight polymeric PACs, thereby establishing the bioaccessibility of a principal catabolite termed 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL). Notably, our findings, encompassing cell biology, chemistry and proteomics, converge to the proposal of the notion of the capacity of VL to activate, upon oxidation to the corresponding quinone, the nuclear factor E2-related factor 2 (Nrf2) pathway-an intricate process that incites cellular defenses and mitigates stress-induced responses, such as a challenge brought by TNFα. This mechanistic paradigm seamlessly aligns with the concept of para-hormesis, ultimately orchestrating the resilience to stress and the preservation of cellular redox equilibrium and homeostasis as benchmarks of health.

A dual attack on the peroxide bond. The common principle of peroxidatic cysteine or selenocysteine residues.

The (seleno)cysteine residues in some protein families react with hydroperoxides with rate constants far beyond those of fully dissociated low molecular weight thiol or selenol compounds. In case of the glutathione peroxidases, we could demonstrate that high rate constants are achieved by a proton transfer from the chalcogenol to a residue of the active site [Orian et al. Free Radic. Biol. Med. 87 (2015)]. We extended this study to three more protein families (OxyR, GAPDH and Prx). According to DFT calculations, a proton transfer from the active site chalcogenol to a residue within the active site is a prerequisite for both, creating a chalcogenolate that attacks one oxygen of the hydroperoxide substrate and combining the delocalized proton with the remaining OH or OR, respectively, to create an ideal leaving group. The "parking postions" of the delocalized proton differ between the protein families. It is the ring nitrogen of tryptophan in GPx, a histidine in GAPDH and OxyR and a threonine in Prx. The basic principle, however, is common to all four families of proteins. We, thus, conclude that the principle outlined in this investigation offers a convincing explanation for how a cysteine residue can become peroxidatic.

Chronobiology of acute pancreatitis in a single Italian centre.

OBJECTIVE: Seasonal variation may occur in many different diseases hence influencing awareness in clinical practice. This study aimed to establish seasonal variations of acute pancreatitis by using a validated chronobiological analysis. PATIENTS AND METHODS: All cases of acute pancreatitis consecutively observed in fifteen years, i.e., from January 2003 to December 2017, at St. Anna University Hospital of Ferrara, Italy, were included in this study. Accurate statistical and logistic regression analyses were applied to our database. RESULTS: A total number of 1883 consecutive cases of acute pancreatitis were observed. A significant peak was identified in the summer period (p=0.014). Patient stratification, according to age, showed that elderly people had an increased incidence of acute pancreatitis in autumn and summer (being the biliary stone disease the main cause, p=0.011) vs. other seasons (p=0.003). Mortality occurred more prominently in males vs. females, although the latter gender was more prone to acute pancreatitis (p=0.017). CONCLUSIONS: In a single centre of Northern East of Italy, we demonstrated that acute pancreatitis had a clear seasonal variation with a prominent incidence during summer. Various associated factors could contribute to this chronobiological pattern, including gender, age, and biliary stone disease.

Costs of irritable bowel syndrome in European countries with universal healthcare coverage: a meta-analysis.

OBJECTIVE: To provide an overall estimate of the direct, indirect and total costs of irritable bowel syndrome (IBS) for the adult population of the European countries with universal healthcare coverage. MATERIALS AND METHODS: We searched MedLine and Scopus databases (up to September 2018) to identify the European studies that evaluated the economic impact of IBS. Mean annual direct, indirect and total per-capita IBS costs were estimated using random-effect single-group meta-analyses of continuous data. All analyses were stratified by payer category (governments, insurance, societal), and the results were expressed as summary mean and 95% CI. RESULTS: A total of 24 studies were included in the meta-analyses. Only two studies evaluated IBS costs in Italy. The pooled summary of direct IBS per-capita cost, obtained from 23 European datasets (n=15,157), was €1837/year (95% CI: 1480-2195), with large differences across payers (from €1183 to €3358, in countries with publicly-funded and insurance-based health systems, respectively). The mean indirect cost, extracted from 13 datasets (n=3978), was €2314/year (95% CI: 1811-2817), again with wide differences across payers. Finally, the meta-analysis estimating the total annual cost, based upon 11 European datasets (n=2757), yielded a summary estimate of €2889/year (95% CI: 2318-3460) per patient, ranging from €1602 (insurance-based health systems) to €3909 (studies adopting a societal perspective). CONCLUSIONS: Considering a conservative estimate of 2,736,700 Italian adults affected by the syndrome, the minimum costs due to IBS in Italy - likely underestimated - range from 6 to 8 billion euro per year. Given the substantial economic burden for patients, healthcare systems and society, IBS should be included among the priorities of the public health agenda.

Kaposi's sarcoma after T-cell costimulation blockade with abatacept in rheumatoid arthritis: a case report.

WHAT IS KNOWN AND OBJECTIVE: Kaposi's sarcoma (KS) is a malignant neoplasm caused by HHV-8, a pathogen that leads to endothelial cell transformation when host defences are weakened. CASE DESCRIPTION: Here we report the first case of KS during treatment with abatacept, a biologic agent targeting T-cell costimulation. The patient was a 64-year-old female with rheumatoid arthritis who developed multiple firm, purple-reddish nodules on the dorsal aspect of the right hand. Histological examination confirmed KS. WHAT IS NEW AND CONCLUSION: Although a direct causal relationship between KS development and abatacept treatment cannot be proved, we hypothesize a role for costimulation blockade.

Effects of moderate beer consumption on health and disease: A consensus document.

A large evidence-based review on the effects of a moderate consumption of beer on human health has been conducted by an international panel of experts who reached a full consensus on the present document. Low-moderate (up to 1 drink per day in women, up to 2 in men), non-bingeing beer consumption, reduces the risk of cardiovascular disease. This effect is similar to that of wine, at comparable alcohol amounts. Epidemiological studies suggest that moderate consumption of either beer or wine may confer greater cardiovascular protection than spirits. Although specific data on beer are not conclusive, observational studies seem to indicate that low-moderate alcohol consumption is associated with a reduced risk of developing neurodegenerative disease. There is no evidence that beer drinking is different from other types of alcoholic beverages in respect to risk for some cancers. Evidence consistently suggests a J-shaped relationship between alcohol consumption (including beer) and all-cause mortality, with lower risk for moderate alcohol consumers than for abstainers or heavy drinkers. Unless they are at high risk for alcohol-related cancers or alcohol dependency, there is no reason to discourage healthy adults who are already regular light-moderate beer consumers from continuing. Consumption of beer, at any dosage, is not recommended for children, adolescents, pregnant women, individuals at risk to develop alcoholism, those with cardiomyopathy, cardiac arrhythmias, depression, liver and pancreatic diseases, or anyone engaged in actions that require concentration, skill or coordination. In conclusion, although heavy and excessive beer consumption exerts deleterious effects on the human body, with increased disease risks on many organs and is associated to significant social problems such as addiction, accidents, violence and crime, data reported in this document show evidence for no harm of moderate beer consumption for major chronic conditions and some benefit against cardiovascular disease.

Active galaxies. A fast and long-lived outflow from the supermassive black hole in NGC 5548.

Supermassive black holes in the nuclei of active galaxies expel large amounts of matter through powerful winds of ionized gas. The archetypal active galaxy NGC 5548 has been studied for decades, and high-resolution x-ray and ultraviolet (UV) observations have previously shown a persistent ionized outflow. An observing campaign in 2013 with six space observatories shows the nucleus to be obscured by a long-lasting, clumpy stream of ionized gas not seen before. It blocks 90% of the soft x-ray emission and causes simultaneous deep, broad UV absorption troughs. The outflow velocities of this gas are up to five times faster than those in the persistent outflow, and, at a distance of only a few light days from the nucleus, it may likely originate from the accretion disk.

Efficacy and safety of duloxetine in fibromyalgia.

Fibromyalgia is a chronic disorder of uncertain aetiology, more common in women than in man, characterized by widespread pain, muscle tenderness and decreased pain threshold to pressure and other stimuli. The pathophysiology of fibromyalgia is still unknown, but some evidences suggest that abnormalities in central monoaminergic transmission might play an important role. These abnormalities include dysfunction in both serotonin (5-HT) and norepinephrine (NE) systems. In addition, fibromyalgia frequently presents in comorbidity with depression and anxiety disorders. On these basis antidepressants are the most widely studied drugs and, probably the most effective therapy of fibromyalgia. Until now amitriptyline, a tricyclic antidepressant, was considered the most effective, with some evidence of efficacy for other antidepressant such as the SSRI fluoxetine and sertraline. Here we review the efficacy and safety of duloxetine, a SNRI antidepressant, in the management of fibromyalgia.

Sudden progression from impaired glucose tolerance to type 2 diabetes after discontinuation of administration of anti-tumor necrosis factor-alpha antibody infliximab.

We present the case of a 45-year-old man with psoriasis and psoriatic arthritis and concomitant impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). In this patient, refractory to DMARD's, infliximab was started to control the arthritis. After achieving clinical remission of the disease, infliximab was discontinued and a 75 g- oral glucose tolerance test (OGTT) was performed. After the test, we observed a conversion from IFG/IGT glucose tolerance status to type 2 diabetes. No diet, lifestyle or therapy modifications were made during the observation period. Autoimmune diabetes was ruled out by serum antibodies determination and body weight remained constant, sustaining a protective role in infliximab in the worsening of glucose tolerance.

[The HPA axis in the pathogenesis of chronic fatigue syndrome]. / L'asse ipotalamo-ipofi si-surrene nella patogenesi della Sindrome da Stanchezza Cronica.

Chronic fatigue syndrome (CFS) is a clinical syndrome characterized by profound disabling chronic fatigue associated with a wide array of other physical symptoms. Its etiology is currently unknown. Among the various hypotheses, considerable interest has been placed in the hypothalamus-pituitary-adrenal axis as a possible target of the pathogenesis of CFS. This article reviews the available scientific evidence about a role of hypothalamic-pituitary-adrenal axis in the pathogenesis of chronic fatigue syndrome.

[TNF-alpha and insulin-resistance: metabolic effects of in vivo therapeutic blockade]. / TNF-alfa e insulino-resistenza: effetti metabolici del blocco terapeutico in vivo.

Insulin resistance is a key pathophysiologic feature of obesity, type 2 diabetes mellitus and prediabetic states (impaired fasting glucose, impaired glucose tolerance). TNF-alpha, a proinflammatory cytokine, plays an important role in the pathogenesis of insulin resistance associated with inflammation during the course of rheumatic diseases. Therapies aimed at neutralizing TNF-alpha, such as the monoclonal antibody infliximab, represent a relatively new approach in the treatment of rheumatic diseases and allow to obtain significant results in terms of control of the inflammatory process. In this article we reviewed the scientific evidence published in the literature about a potential role of TNF-alpha blockade in improving insulin resistance in rheumatic patients without diabetes.

The nuclear form of phospholipid hydroperoxide glutathione peroxidase is a protein thiol peroxidase contributing to sperm chromatin stability.

The selenoenzyme phospholipid hydroperoxide glutathione peroxidase (PHGPx) is regarded as the major molecular target of selenodeficiency in rodents, accounting for most of the histopathological and structural abnormalities of testicular tissue and male germ cells. PHGPx exists as a cytosolic form, mitochondrial form, and nuclear form (nPHGPx) predominantly expressed in late spermatids and spermatozoa. Here, we demonstrate that mice with a targeted deletion of the nPHGPx gene were, unlike mice with the full knockout (KO) of PHGPx, not only viable but also, surprisingly, fully fertile. While both morphological analysis of testis and epididymis and sperm parameter measurements did not show any apparent abnormality, toluidine blue and acridine orange stainings of spermatozoa indicated defective chromatin condensation in the KO sperm isolated from the caput epididymis. Furthermore, upon drying and hydrating, KO sperm exhibited a significant proportion of morphologically abnormal heads. Monobromobimane labeling and protein-free thiol titration revealed significantly less extensive oxidation in the cauda epididymis when compared to that in the wild type. We conclude that nPHGPx, by acting as a protein thiol peroxidase in vivo, contributes to the structural stability of sperm chromatin.

PHGPx and spermatogenesis.

PHGPx of rat sperm mitochondrial capsule is cross-linked and inactive. The enzyme is in part released in an active form by mercaptoethanol. Treatment with H(2)O(2) of reduced and solubilised capsule proteins, in the absence of any added reductant, results in: i) H(2)O(2) consumption which depends on the presence of both, PHGPx activity and protein thiols; ii) protein thiol oxidation with a stoichiometry of 2 equivalents of thiol per mole of hydroperoxide and, iii) PHGPx inactivation and cross-linking. SDS-PAGE analysis of monobromobimane-labeled proteins, following incubation with H(2)O(2), shows that the oxidation takes place in specific bands in the area of 20~kDa. It is concluded that the protein thiol peroxidase activity of PHGPx is responsible for cross-linking proteins in the mammalian sperm capsule and accounts for the selenium dependency of spermatogenesis.

Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL(-).

A subpopulation of low-density lipoproteins (LDL) is present in human plasma that contains lipid hydroperoxides and is more negatively charged (LDL(-)) than normal native LDL. By circular dichroism and tryptophan lifetime measurements we found that apoB-100 secondary structure is markedly decreased and its conformation is severely altered in LDL(-). The low tryptophan fluorescence intensity confirms the oxidative degradation of the lipoprotein, and the very long lifetime value of one of its decay components indicates a low polarity environment for the remaining unbleached residues. Either a peculiar folding or, most likely, a sinking of the apoB-100 into the lipid core can account for the observed long lifetime component. Oxidation in vitro produces a similar unfolding of the apolipoprotein but the lifetime of tryptophan fluorescence is shifted to lower values, indicating that the denatured apoprotein remains at the hydrophilic surface of the lipoprotein particle. A disordering and an increased polarity of the LDL(-) surface lipids was demonstrated by measuring the generalized polarization of 2-dimethylamino-6-lauroylnaphthalene (Laurdan). The looser monolayer packing apparently favors the new conformation of apoB-100 and its sinking into a more hydrophobic environment, possibly accounting for it reduced receptor binding properties.

Red wine mitigates the postprandial increase of LDL susceptibility to oxidation.

The aim of the present study was to verify the extent of oxidative stress induced by a meal at plasma and LDL level, and to investigate the capacity of red wine to counteract this action. In two different sessions, six healthy men ate the same test meal consisting of "Milanese" meat and fried potatoes. The meal was taken either with 400 ml red wine or with an isocaloric hydroalcoholic solution. Oxidative stress at plasma level was estimated through the measure of ascorbic acid, alpha-tocopherol, protein SH groups, uric acid, and antioxidant capacity, measured before and 1 and 3 h after the meal. The change in the resistance of LDL to oxidative modification was taken as an index of exposure to pro-oxidants. The susceptibility to Cu(II)-catalyzed oxidation of baseline and postprandial LDL was measured as conjugated dienes formation, tryptophan residues, and relative electrophoretic mobility. The experimental meal taken with wine provoked a significant increase in the total plasma antioxidant capacity and in the plasma concentration of alpha-tocopherol and SH groups. Postprandial LDL was more susceptible to metal-catalyzed oxidation than the homologous baseline LDL after the ethanol meal. On the contrary, postprandial LDL obtained after the wine meal was as resistant or more resistant to lipid peroxidation than fasting LDL.

Lipid peroxidation in human proteinuric disease.

BACKGROUND: While metabolically generated oxidants are produced locally in experimental glomerular diseases, little is still known of their significance and the respective scavenger systems in human glomerular diseases. METHODS: Here we studied kidneys from patients with congenital nephrotic syndrome of the Finnish type (CNF), a human model disease of isolated proteinuria. Expression of specific mRNAs for a major antioxidant system against lipoperoxidation [phospholipid hydroperoxide glutathione peroxidase (PHGPx)] and for mitochondrial proteins were studied in Northern blotting together with analysis of PHGPx in semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). The respective proteins and lipoperoxide (LPO) adducts malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were analyzed in immunohistochemistry. RESULTS: PHGPx and the mitochondrially encoded subunits of cytochrome-c-oxidase were distinctly down-regulated within the glomeruli of CNF kidneys. These changes were confirmed in semiquantitative RT-PCR. Increases of lipoperoxidation products MDA and 4-HNE were constantly found in the glomeruli of CNF. In agreement with findings in CNF, similar results were obtained in biopsies from other human glomerular diseases. CONCLUSIONS: These findings suggest that local mitochondrial damage initiates LPO, which then causes deposition of the cytotoxic LPO products in glomeruli, as seen especially in CNF kidneys. Together with down-regulation of the local antioxidant protection, these may be important pathophysiologic mechanisms in human glomerular disease.

Estradiol enhances the resistance of LDL to oxidation by stabilizing apoB-100 conformation.

Among different proposed mechanisms to account for the protection exerted by estrogens against cardiovascular diseases, the antioxidant effect has attracted considerable attention. We confirmed that 17-beta-estradiol (E2), when added to human LDL at a 6:1 ratio to apoB-100, markedly delays the phase of massive LDL lipid peroxidation induced by Cu(2+). We also observed an increased oxidative resistance of E2-treated LDL by monitoring the early phase of oxidative degradation on the basis of increased LDL surface polarity by the generalized polarization of the lipophilic fluorescent probe 2-(dimethylamino)-6-lauroylnaphthalene (Laurdan). A scavenging of free radicals by E2 is ruled out since, consistent with its structure, its rate constant for the reduction of peroxy radicals is extremely low, i.e., 0.02% of that of vitamin E. Tryptophan fluorescence lifetime and circular dichroism measurements revealed that (i) apoB-100 undergoes a conformational modification and a progressive loss of secondary structure during lipid peroxidation; (ii) E2 increases apoB-100 secondary structure and modifies its conformation; and (iii) the apoB-100 conformational change induced by E2 makes this protein resistant to modifications brought about by lipid peroxidation. We propose that E2, by affecting apoB-100 secondary structure and conformation, modifies the interaction of this protein with the outer layer of the LDL particle thus increasing its overall oxidative resistance.

Inhibition of LDL oxidation and oxidized LDL-induced cytotoxicity by dihydropyridine calcium antagonists.

PURPOSE: The antioxidant activity of dihydropyridine calcium channel antagonists was evaluated based on LDL oxidation kinetics, oxidative cell injury associated with reactive species generation, and increases in free intracellular calcium (Ca2+) levels. Interactions with ascorbic acid were studied under conditions representative of LDL oxidation in plasma and tissue. METHODS: Analysis of antioxidant activity utilized measurements of one-electron oxidation potentials and scavenging of peroxy radical-mediated oxidation. LDL antioxidant potency was determined spectrophotometrically using copper-mediated oxidation kinetics in the absence and presence of 100 microM ascorbic acid. Prevention of oxidant-induced endothelial cell injury was determined from the formation of reactive oxygen species generation and increases in intracellular free calcium concentrations following addition of oxidized LDL or linoleic acid hydroperoxide. RESULTS: Felodipine and amlodipine effectively inhibit peroxyl radical-mediated oxidation in lipoproteins and cells that is markedly enhanced in the presence of ascorbic acid. In the presence of ascorbic acid, inhibition of LDL oxidation is over four times greater than in LDL treated without antioxidants, and oxidized LDL and linoleic acid hydroperoxide-induced reactive oxygen species formation is effectively suppressed in cells. Inhibition of intracellular calcium increases was achieved using nM concentrations of felodipine or amlodipine. CONCLUSIONS: The additive effect for ascorbic acid and the calcium channel antagonist is postulated to involve a combination of peroxide-degrading and peroxyl radical scavenging reactions, demonstrating the importance of lipid peroxides during LDL oxidation and oxidized LDL-induced cytotoxicity. Cytoprotection is associated with inhibition of oxidant-induced increases in intracellular free calcium. Both the cytoprotective and LDL antioxidant activity for these compounds is manifested at concentrations approaching the therapeutic levels found in plasma.