Search

Growing epidemiological studies highlight a bi-directional relationship between depressive symptoms and diabetes mellitus. However, the detrimental impact of their co-existence on mental health suggests the need to treat this comorbidity as a separate entity rather than the two different pathologies. Herein, we characterized the peculiar mechanisms activated in mouse hippocampus from the concurrent development of hyperglycaemia, characterizing the different diabetes subtypes, and chronic stress, recognized as a possible factor predisposing to major depression. Our work demonstrates that kynurenine overproduction, leading to apoptosis in the hippocampus, is triggered in a different way depending on hyperglycaemia or chronic stress. Indeed, in the former, kynurenine appears produced by infiltered macrophages whereas, in the latter, peripheral kynurenine preferentially promotes resident microglia activation. In this scenario, QA, derived from kynurenine catabolism, appears a key mediator causing glutamatergic synapse dysfunction and apoptosis, thus contributing to brain atrophy. We demonstrated that the coexistence of hyperglycaemia and chronic stress worsened hippocampal damage through alternative mechanisms, such as GLUT-4 and BDNF down-expression, denoting mitochondrial dysfunction and apoptosis on one hand and evoking the compromission of neurogenesis on the other. Overall, in the degeneration of neurovascular unit, hyperglycaemia and chronic stress interacted each other as the partners of a "West Coast Swing" in which the leading role can be assumed alternatively by each partner of the dance. The comprehension of these mechanisms can open novel perspectives in the management of diabetic/depressed patients, but also in the understanding the pathogenesis of other neurodegenerative disease characterized by the compromission of hippocampal function. [Display omitted] [ABSTRACT FROM AUTHOR]

There is a need for continued drug development for nonalcoholic steatohepatitis (NASH). Bergamot is a plant whose fruit juice is enriched with flavonoids and phenolic compounds which improves dyslipidemia and markers of systemic inflammation in patients with Metabolic Syndrome. The aim of this study was to perform a preclinical "proof of concept" study of Bergamot polyphenolic formulation (BPF99) for the treatment of NASH. A disease reversal study was performed in the diet-induced animal model of NAFLD (DIAMOND). Groups of 8 weeks old mice were randomly assigned to receive chow diet, high fat diet with sugar in drinking water (Western diet- WD). Mice on WD were further randomized to continue on WD gavaged with vehicle or continue on WD with additional gavage of BPF99 (50 mg/kg) after 16 weeks of diet. Mice were euthanized after 11 additional weeks. The primary endpoint was resolution of NASH. Secondary endpoints included changes in individual histological features, body weight, liver enzymes, dyslipidemia, markers of oxidative stress and molecular markers of disease activity and fibrosis. The results showed that BPF99 reduced ALT (mean 71.6 vs 44.6 IU/l, p < 0.01), triglycerides (38.8 vs 28.1 mg/dl, p < 0.05), LDL-C (39.2 vs 23.7 mg/dl, p < 0.001). It significantly improved NASH resolution (p < 0.001) and the SAF scores (p < 0.05) while the NAS improvement approached significance. BPF99 reduced markers of oxidative stress, along with reduced JNK and p38 MAP kinase activity. BPF99 did not reduce the number of mice with fibrosis but improved collagen proportional area (p < 0.04) and procollagen I and III expression. Collectively our results showed that BPF99 resolves NASH and ameliorates key histological and pathophysiological features of NASH along with improvement in ALT and dyslipidemia in the DIAMOND mice. [ABSTRACT FROM AUTHOR]

Background: Experimental and epidemiological studies show that bergamot polyphenolic fraction (BPF) ameliorates the serum lipemic profile, normalizes blood pressure and improves non alcoholic fatty liver disease in patients suffering from metabolic syndrome. Despite this evidence, the molecular mechanisms responsible for these beneficial effects remain unclear. The aim of our study is to clarify the effects of BPF on the lipoprotein assembly and to identify oxidative stress biomarkers correlating hyperlipidaemia and BPF-induced metabolic changes. Methods: Male Wistar rats (180–200 g) were randomly assigned to receive a standard diet, a hypercholesterolemic diet or a hypercholesterolemic diet+BPF (20 mg/Kg/rat daily, gavage), respectively, for 90 days. Total cholesterol (tChol), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and fasting plasma glucose were evaluated at the baseline as well as at the end of the treatment. To assess the effect of BPF on the Lipid Transfer Protein System, detection of ACAT, LCAT, CETP, PON1, Apo A1 and Apo B have also been carried out. Finally, the lipid peroxidation biomarker (TBARS) and oxyLDL were also measured. Results: BPF prevented tChol, LDL-C, TG and fasting plasma glucose enhancement and improved HDL-C. Treatment of hyperlipæmic rats with BPF significantly restored altered the serum concentration of lipemic biomarkers and the activity of ACAT, LCAT, CETP and PON1, an effect accompanied by the concomitant normalization of Apo A1 and APO B levels. In addition, TBARS levels were reduced significantly by the treatment with BPF. Conclusions: BPF prevents diet-induced alteration of the lipid profile in rats, counteracting oxidative stress and improving the dysregulation of the Lipid Transfer Protein System. These data add new insights into the molecular mechanisms underlying the beneficial role of BPF in the therapy of hyperlipidaemia, thus suggesting a novel approach in the prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

The use of renin–angiotensin–aldosterone system (RAAS) inhibitors in the treatment of chronic heart failure (HF) and arterial hypertension is recommended by the European Society of Cardiology Guidelines on the basis of consolidated evidence supporting their efficacy in the development of such a disease. However, the high incidence of re-hospitalization and mortality in patients undergoing chronic HF, leads to the need for the development of novel RAAS inhibitors possessing a better pharmacokinetic/pharmacodynamics profile in approaching hemodynamic imbalance and myocardial dysfunction associated with the development of chronic HF. Here we summarize some of the recent advances in the area of RAAS-modulators, including novel renin inhibitors, mineralcorticoid receptor antagonists and novel AT1 and AT2-receptor modulators. In addition, the pharmacology of a new class of compounds which display both AT1-receptor blocking properties combined with inhibition of neprilysin, the vasopeptidase enzyme degradating natriuretic peptide (ARNi), will be reviewed, alongside with their impact in the pathophysiology of chronic HF. [ABSTRACT FROM AUTHOR]

Hyperuricemia has long been established as the major etiologic factor in gout. Alongside with an inflammatory state triggered by urate crystal deposition in the joints, hyperuricemia displayed additional pathophysiological consequences leading to tissue inflammation mainly in the vascular wall. Thus, therapeutic strategies used to treat hyperuricemia in the past decades have often been focused on limiting acute episodes. Recently, evidence has been accumulated suggesting that chronic urate deposition requires a correct treatment not limited to acute episodes based on the modulation of the activity of key enzymes involved in metabolism and excretion of urate including xanthine oxidoreductase (XO) and URAT1. The present review article will try to summarize the most recent evidences on the efficacy of XO inhibitors and uricosuric compounds in lowering uric acid levels in both the bloodstream and peripheral tissues. In particular, we will focus on the effect of novel XO inhibitors in counteracting uric acid overproduction. On the other hand, the effect of lowering uric acid levels via XO inhibition will be correlated with attenuation oxidative stress which leads to endothelial dysfunction thereby contributing to the pathophysiology of diabetes, hypertension, arteriosclerosis, and chronic heart failure. Hence, scavenging and prevention of the XO generated oxygen radical accumulation emerge as an intriguing novel treatment option to counteract uric acid-induced tissue damages. [ABSTRACT FROM AUTHOR]

Background Overproduction of oxidized-low density lipoproteins (oxyLDLs) has been found to contribute in endothelial cell (EC) dysfunction thereby leading to atherosclerosis development and progression. In particular, oxyLDLs lead to apoptotic cell death of EC via oxidative stress production, mostly subsequent to the overexpression of the scavenger receptor LOX-1. Here, we hypothesize that LOX-1 expression in EC represents a crucial event which attenuates protective autophagic response, thereby enhancing programmed endothelial cell death. Methods and results Bovine aortic endothelial cells (BAECs) in culture were exposed to oxyLDL (1-100 μM). After 48 h incubation, oxyLDL produced pronounced malondialdehyde (MDA) elevation and apoptotic cell death of BAEC as detected by FACS analysis, an effect counteracted by antioxidant N-acetyl-cysteine (NAC) as well as by the NO-donor SNAP. OxyLDL-induced apoptotic cell death was also accompanied by reduced VEGF-dependent phosphorylation of constitutive NO synthase (cNOS) in BAEC and consistent attenuation of autophagic response as detected by the expression of Beclin-1 and LC3, two reliable biomarkers of autophagy. Moreover, silencing LOX-1 receptor significantly restored LC3 expression in oxyLDL-treated BAEC, thus suggesting a key role of LOX-1 overproduction in oxyLDL-induced endothelial dysfunction. Conclusions OxyLDL leads to impaired NO generation and apoptotic cell death in BAECs. This effect occurs via the overexpression of LOX-1 and subsequent attenuation of protective autophagic response thereby contributing to the pathophysiology of oxyLDL-induced endothelial dysfunction which characterizes early stages of atherosclerotic process. [ABSTRACT FROM AUTHOR]

Abstract: Background: Statins are the most commonly prescribed drugs to reduce cardiometabolic risk. Besides the well-known efficacy of such compounds in both preventing and treating cardiometabolic disorders, some patients experience statin-induced side effects. We hypothesize that the use of natural bergamot-derived polyphenols may allow patients undergoing statin treatment to reduce effective doses while achieving target lipid values. The aim of the present study is to investigate the occurrence of an enhanced effect of bergamot-derived polyphenolic fraction (BPF) on rosuvastatin-induced hypolipidemic and vasoprotective response in patients with mixed hyperlipidemia. Methods: A prospective, open-label, parallel group, placebo-controlled study on 77 patients with elevated serum LDL-C and triglycerides was designed. Patients were randomly assigned to a control group receiving placebo (n =15), two groups receiving orally administered rosuvastatin (10 and 20mg/daily for 30days; n =16 for each group), a group receiving BPF alone orally (1000mg/daily for 30days; n =15) and a group receiving BPF (1000mg/daily given orally) plus rosuvastatin (10mg/daily for 30days; n =15). Results: Both doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic patients, compared to control group. The cholesterol lowering effect was accompanied by reductions of malondialdehyde, oxyLDL receptor LOX-1 and phosphoPKB, which are all biomarkers of oxidative vascular damage, in peripheral polymorphonuclear cells. Conclusions: Addition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy. [Copyright &y& Elsevier]

Low-dose aspirin represents the best option in the secondary prevention of coronary artery disease, but its extensive use in primary prevention is limited by the occurrence of gastric mucosal lesions and increased risk of bleeding. We investigated the safety profile of a novel sublingual aspirin formulation in 200 healthy volunteers, randomly assigned to ten (n = 20 each) different 7-day once-daily treatment regimens. Gastric mucosal injury based on the modified Lanza score (MLS), the histopathology of gastric mucosa and the serum determination of thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 levels were evaluated at basal as well as after 7 days of each placebo or aspirin treatment regimen. In Groups A and B (placebo—oral and sublingual, respectively), no changes in MLS and in gastric mucosal micro-vessel diameter were found at day 7. In contrast, in Groups C and D (oral standard aspirin—100 and 50 mg daily, respectively), the median MLS was significantly increased. Very few changes were found in Groups E and F (standard sublingual aspirin—100 and 50 mg, respectively). Groups G and H (oral administration of micronized collagen-cogrinded aspirin) showed gastric protection compared to Groups C and D. Moreover, Groups I and L (sublingual collagen-cogrinded aspirin—100 and 50 mg, respectively) showed a significant reduction (Group I) or total abolition (Group L) of gastric mucosal lesions and no difference compared to the standard one in serum TXB2 and urinary 11-dehydro-TXB2 levels. In conclusion, our data show that the new formulation leads to a better safety profile compared to standard aspirin, representing a better therapeutic option for extended use in primary and secondary prevention of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads to a greater expression of proinflammatory adipokines, excessive lipid storage and adipogenesis. The purpose of this review is to clarify how inflammatory mediators act during adipose tissue dysfunction in the development of insulin resistance and all obesity-associated diseases. In particular, we focused our attention on the role of inflammatory signaling in brown adipose tissue (BAT) thermogenic activity and the browning of white adipose tissue (WAT), which represent a relevant component of adipose alterations during obesity. Furthermore, we reported the most recent evidence in the literature on nutraceutical supplementation in the management of the adipose inflammatory state, and in particular on their potential effect on common inflammatory mediators and pathways, responsible for WAT and BAT dysfunction. Although further research is needed to demonstrate that targeting pro-inflammatory mediators improves adipose tissue dysfunction and activates thermogenesis in BAT and WAT browning during obesity, polyphenols supplementation could represent an innovative therapeutic strategy to prevent progression of obesity and obesity-related metabolic diseases. [ABSTRACT FROM AUTHOR]

• Peripheral and CNS cholesterol metabolism are separated by the blood brain barrier (BBB) and are regulated independently. • Cholesterol homeostasis dysfunction leads to metabolic, cardiovascular and neurological diseases that can be interconnected. • Lipoproteins, miRNAs and oxysterols are involved in the cross talk between central and peripheral cholesterol metabolism. • The modulation of cholesterol mediators suggests new perspectives in the management of cholesterol-related diseases. Cholesterol homeostasis is a highly regulated process in human body because of its several functions underlying the biology of cell membranes, the synthesis of all steroid hormones and bile acids and the need of trafficking lipids destined to cell metabolism. In particular, it has been recognized that peripheral and central nervous system cholesterol metabolism are separated by the blood brain barrier and are regulated independently; indeed, peripherally, it depends on the balance between dietary intake and hepatic synthesis on one hand and its degradation on the other, whereas in central nervous system it is synthetized de novo to ensure brain physiology. In view of this complex metabolism and its relevant functions in mammalian, impaired levels of cholesterol can induce severe cellular dysfunction leading to metabolic, cardiovascular and neurodegenerative diseases. The aim of this review is to clarify the role of cholesterol homeostasis in health and disease highlighting new intriguing aspects of the cross talk between its central and peripheral metabolism. [ABSTRACT FROM AUTHOR]

The maintenance of the physiological values of blood pressure is closely related to unchangeable factors (genetic predisposition or pathological alterations) but also to modifiable factors (dietary fat and salt, sedentary lifestyle, overweight, inappropriate combinations of drugs, alcohol abuse, smoking and use of psychogenic substances). Hypertension is usually characterized by the presence of a chronic increase in systemic blood pressure above the threshold value and is an important risk factor for cardiovascular disease, including myocardial infarction, stroke, micro- and macro-vascular diseases. Hypertension is closely related to functional changes in the endothelium, such as an altered production of vasoconstrictive and vasodilator substances, which lead to an increase in vascular resistance. These alterations make the endothelial tissue unresponsive to autocrine and paracrine stimuli, initially determining an adaptive response, which over time lead to an increase in risk or disease. The gut microbiota is composed of a highly diverse bacterial population of approximately 1014 bacteria. A balanced intestinal microbiota preserves the digestive and absorbent functions of the intestine, protecting from pathogens and toxic metabolites in the circulation and reducing the onset of various diseases. The gut microbiota has been shown to produce unique metabolites potentially important in the generation of hypertension and endothelial dysfunction. This review highlights the close connection between hypertension, endothelial dysfunction and gut microbiota. [ABSTRACT FROM AUTHOR]

The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention. [ABSTRACT FROM AUTHOR]

The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve. [ABSTRACT FROM AUTHOR]

The main neurovascular unit of the Blood Brain Barrier (BBB) consists of a cellular component, which includes endothelial cells, astrocytes, pericytes, microglia, neurons, and oligodendrocytes as well as a non-cellular component resulting from the extracellular matrix. The endothelial cells are the major vital components of the BBB able to preserve the brain homeostasis. These cells are situated along the demarcation line between the bloodstream and the brain. Therefore, an alteration or the progressive disruption of the endothelial layer may clearly impair the brain homeostasis. The proper functioning of the brain endothelial cells is generally ensured by two elements: (1) the presence of junction proteins and (2) the preservation of a specific polarity involving an apical-luminal and a basolateral-abluminal membrane. This review intends to identify the molecular mechanisms underlying BBB function and their changes occurring in early stages of neurodegenerative processes in order to develop novel therapeutic strategies aimed to counteract neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Obesity is one of the world's most serious public health issues, with a high risk of developing a wide range of diseases. As a result, focusing on adipose tissue dysfunction may help to prevent the metabolic disturbances commonly associated with obesity. Nutraceutical supplementation may be a crucial strategy for improving WAT inflammation and obesity and accelerating the browning process. The aim of this study was to perform a preclinical "proof of concept" study on Bergacyn®, an innovative formulation originating from a combination of bergamot polyphenolic fraction (BPF) and Cynara cardunculus (CyC), for the treatment of adipose tissue dysfunction. In particular, Bergacyn® supplementation in WD/SW-fed mice at doses of 50 mg/kg given orally for 12 weeks, was able to reduce body weight and total fat mass in the WD/SW mice, in association with an improvement in plasma biochemical parameters, including glycemia, total cholesterol, and LDL levels. In addition, a significant reduction in serum ALT levels was highlighted. The decreased WAT levels corresponded to an increased weight of BAT tissue, which was associated with a downregulation of PPARγ as compared to the vehicle group. Bergacyn® was able to restore PPARγ levels and prevent NF-kB overexpression in the WAT of mice fed a WD/SW diet, suggesting an improved oxidative metabolism and inflammatory status. These results were associated with a significant potentiation of the total antioxidant status in WD/SW mice. Finally, our data show, for the first time, that Bergacyn® supplementation may be a valuable approach to counteract adipose tissue dysfunction and obesity-associated effects on cardiometabolic risk. [ABSTRACT FROM AUTHOR]

Evidence exists that the gut microbiota contributes to the alterations of lipid metabolism associated with high-fat diet (HFD). Moreover, the gut microbiota has been found to modulate the metabolism and absorption of dietary lipids, thereby affecting the formation of lipoproteins occurring at the intestinal level as well as systemically, though the pathophysiological implication of altered microbiota composition in HFD and its role in the development of atherosclerotic vascular disease (ATVD) remain to be better clarified. Recently, evidence has been collected indicating that supplementation with natural polyphenols and fibres accounts for an improvement of HFD-associated intestinal dysbiosis, thereby leading to improved lipidaemic profile. This study aimed to investigate the protective effect of a bergamot polyphenolic extract (BPE) containing 48% polyphenols enriched with albedo and pulp-derived micronized fibres (BMF) in the gut microbiota of HFD-induced dyslipidaemia. In particular, rats that received an HFD over a period of four consecutive weeks showed a significant increase in plasma cholesterol, triglycerides and plasma glucose compared to a normal-fat diet (NFD) group. This effect was accompanied by body weight increase and alteration of lipoprotein size and concentration, followed by high levels of MDA, a biomarker of lipid peroxidation. Treatment with a combination of BPE plus BMF (50/50%) resulted in a significant reduction in alterations of the metabolic parameters found in HFD-fed rats, an effect associated with increased size of lipoproteins. Furthermore, the effect of BPE plus BMF treatment on metabolic balance and lipoprotein size re-arrangement was associated with reduced gut-derived lipopolysaccharide (LPS) levels, an effect subsequent to improved gut microbiota as expressed by modulation of the Gram-negative bacteria Proteobacteria, as well as Firmicutes and Bacteroidetes. This study suggests that nutraceutical supplementation of HFD-fed rats with BPE and BMP or with their combination product leads to restored gut microbiota, an effect associated with lipoprotein size re-arrangement and better lipidaemic and metabolic profiles. [ABSTRACT FROM AUTHOR]

The clinical use of anthracycline Doxorubicin as an antineoplastic drug in cancer therapy is limited by cardiotoxic effects that can lead to congestive heart failure. Recent studies have shown several promising activities of different species of the genus Ferula belonging to the Apiaceae Family. Ferula communis is the main source of Ferutinin—a bioactive compound isolated from many species of Ferula—studied both in vitro and in vivo because of their different effects, such as estrogenic, antioxidant, anti-inflammatory, and also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. However, the potential protective role of Ferutinin in myocardium impairment, caused by chemotherapeutic drugs, still represents an unexplored field. The aim of this study was to test the effects of Ferutinin rich-Ferula communis L. root extract (FcFE) at different concentrations on H9C2 cells. Moreover, we evaluated its antioxidant properties in cardiomyocytes in order to explore new potential therapeutic activities never examined before in other experimental works. FcFE, at a concentration of 0.25 µM, in the H9C2 line, significantly reduced the ROS production induced by H2O2 (50 µM and 250 µM) and traced the cell mortality of the H9C2 co-treated with Ferutinin 0.25 µM and Doxorubicin (0.5 µM and 1 µM) to control levels. These results showed that FcFE could protect against Doxorubicin-induced cardiotoxicity. Further molecular characterization of this natural compound may open the way for testing FcFE at low concentrations in vivo and in clinical studies as an adjuvant in cancer therapy in association with anthracyclines to prevent side effects on heart cells. [ABSTRACT FROM AUTHOR]

Chronic ethanol (EtOH) consumption causes early detrimental consequences in many tissues including the myocardium, though the molecular mechanisms leading to the alcoholic cardiomyopathy (ACM) still remain to be elucidated. Here, we studied several biomolecular changes occurring in cardiomyoblasts after their exposure to sublethal concentrations of EtOH and the potential synergistic effect with methylmercury (MM) or doxorubicin (DOXO), which are known to produce direct myocardial dysfunction. In addition, the possible role of autophagic responses and Nuclear Factor kappa-B (NFkB) modulation in early post-alcoholic myocardial damage has been investigated. H9c2 rat cardiomyoblasts were incubated for fifteen days with a sub-lethal concentrations of EtOH (1–1000 μM). In particular, treatment of H9c2 cells with EtOH produced an increase of reactive oxygen species (ROS) and the activation of autophagy. Furthermore, chronic exposure to EtOH, was accompanied by a translocation of NFkB into the nucleus dose-dependently. Finally, co-incubation of EtOH (1–1000 μM) with sublethal concentrations of MM or DOXO showed a prominent apoptotic death of cardiomyoblasts accompanied by ROS overproduction, autophagy activation and by an increased nuclear translocation of NFkB as compared to untreated cells. Thus, EtOH produces early changes in cardiomyoblasts characterized by oxidative stress, reactive autophagy and NFkB modulation at concentrations unable to produce direct cell death. Combination of EtOH with cardiotoxic pollutants or drugs makes the cardiomyocyte vulnerable to exogenous insults leading to apoptosis. These data contribute to better identify molecular mechanisms underlying early stages of alcoholic cardiomyopathy and suggest novel strategies to counteract integrated risk of cardiotoxicity in chronic alcohol consumption. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOXO) is one of the most widely used antineoplastic drugs. Despite its highly beneficial effects against several malignancies, the clinical use of DOXO is often associated to cardiomyopathy that leads to congestive heart failure. Here we investigated the antioxidant and cardioprotective effects of a polyphenol-rich fraction of citrus bergamot (BPF), in DOXO-induced cardiac damage in rats. Moreover, we evaluated the effect of BPF on cardiomyocyte survival and resident endogenous cardiac stem/progenitor cell (eCSC) activation. Adult male Wistar rats were i.p. injected with saline (serving as controls, CTRL, n = 10), BPF (20 mg/kg daily for 14 consecutive days, n = 10), DOXO (6 doses of 2,5 mg/Kg from day 1 to day 14, n = 10), and DOXO + BPF (n = 10). Animals were then sacrificed 7 days later (i.e., at 21 days). DOXO administration reduced cardiac function at 21 days, an adverse effect significantly attenuated in animals receiving DOXO + BPF. No changes were detected in rats receiving just saline or BPF alone. The cardioprotective effect of BPF on DOXO acute toxicity was also associated with a significant antioxidant effect coupled with protective autophagy restoration, and attenuation of cardiomyocyte apoptosis and reactive hypertrophy. Finally, treatment of rats with BPF prevented eCSCs attrition by DOXO which was followed by a limited but significant increase of newly-formed BrdU + cardiomyocytes. In conclusion, BPF reduces DOXO-induced cardiotoxicity by counteracting reactive oxygen species (ROS) overproduction, thereby restoring protective autophagy and attenuating cardiomyocyte apoptosis and pathologic remodeling. This beneficial effects on the early toxicity of DOXO is associated with enhanced CSCs survival and regenerative potential. Overall these data point to a potential clinical role by diet supplementation with polyphenol-rich fraction of citrus bergamot in counteracting antracycline-induced cardiomyopathy. [ABSTRACT FROM AUTHOR]

Ornamental plants often gain relevance not only for their decorative use, but also as a source of phytochemicals with interesting healing properties. Herein, spontaneous Centranthus ruber (L.) DC. and Tropaeolum majus L., mainly used as ornamental species but also traditionally consumed and used in popular medicine, were investigated. The aerial parts were extracted with methanol trough maceration, and resultant crude extracts were partitioned using solvents with increasing polarity. As previous studies mostly dealt with the phenolic content of these species, the phytochemical investigation mainly focused on nonpolar constituents, detected with GC-MS. The total phenolic and flavonoid content was also verified, and HPTLC analyses were performed. In order to explore the potential antiarthritic and anti-obesity properties, extracts and their fractions were evaluated for their anti-denaturation effects, with the use of the BSA assay, and for their ability to inhibit pancreatic lipase. The antioxidant properties and the inhibitory activity on the NO production were verified, as well. Almost all the extracts and fractions demonstrated good inhibitory effects on NO production. The n-hexane and dichloromethane fractions from T. majus, as well as the n-hexane fraction from C. ruber, were effective in protecting the protein from heat-induced denaturation (IC50 = 154.0 ± 1.9, 270.8 ± 2.3 and 450.1 ± 15.5 μg/mL, respectively). The dichloromethane fractions from both raw extracts were also effective in inhibiting pancreatic lipase, with IC50 values equal to 2.23 ± 0.02 mg/mL (for C. ruber sample), and 2.05 ± 0.02 mg/mL (T. majus). Obtained results support the traditional use of these species for their beneficial health properties and suggest that investigated plant species could be potential sources of novel antiarthritic and anti-obesity agents. [ABSTRACT FROM AUTHOR]

Eye health is crucial, and the onset of diseases can reduce vision and affect the quality of life of patients. The main causes of progressive and irreversible vision loss include various pathologies, such as cataracts, ocular atrophy, corneal opacity, age-related macular degeneration, uncorrected refractive error, posterior capsular opacification, uveitis, glaucoma, diabetic retinopathy, retinal detachment, undetermined disease and other disorders involving oxidative stress and inflammation. The eyes are constantly exposed to the external environment and, for this reason, must be protected from damage from the outside. Many drugs, including cortisonics and antinflammatory drugs have widely been used to counteract eye disorders. However, recent advances have been obtained via supplementation with natural antioxidants and nutraceuticals for patients. In particular, evidence has accumulated that polyphenols (mostly deriving from Citrus Bergamia) represent a reliable source of antioxidants able to counteract oxidative stress accompanying early stages of eye diseases. Luteolin in particular has been found to protect photoreceptors, thereby improving vision in many disease states. Moreover, a consistent anti-inflammatory response was found to occur when curcumin is used alone or in combination with other nutraceuticals. Additionally, Coenzyme Q10 has been demonstrated to produce a consistent effect in reducing ocular pressure, thereby leading to protection in patients undergoing glaucoma. Finally, both grape seed extract, rich in anthocyanosides, and polynsatured fatty acids seem to contribute to the prevention of retinal disorders. Thus, a combination of nutraceuticals and antioxidants may represent the right solution for a multi-action activity in eye protection, in association with current drug therapies, and this will be of potential interest in early stages of eye disorders. [ABSTRACT FROM AUTHOR]

Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as "nitrate tolerance", which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2. [ABSTRACT FROM AUTHOR]

Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p < 0.05 vs NC NW). Our results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance, that is quantifiable by 1H-MRS in vivo, might cause structural damage to brain cells and dysfunctions of neurotransmitter release. [ABSTRACT FROM AUTHOR]

To date, the complex pathological interactions between renal and cardiovascular systems represent a real global epidemic in both developed and developing countries. In this context, renovascular hypertension (RVH) remains among the most prevalent, but also potentially reversible, risk factor for numerous reno-cardiac diseases in humans and pets. Here, we investigated the anti-inflammatory and reno-cardiac protective effects of a polyphenol-rich fraction of bergamot (BPF) in an experimental model of hypertension induced by unilateral renal artery ligation. Adult male Wistar rats underwent unilateral renal artery ligation and treatment with deoxycorticosterone acetate (DOCA) (20 mg/kg, s.c.), twice a week for a period of 4 weeks, and 1% sodium chloride (NaCl) water (n = 10). A subgroup of hypertensive rats received BPF (100 mg/kg/day for 28 consecutive days, n = 10) by gavage. Another group of animals was treated with a sub-cutaneous injection of vehicle (that served as control, n = 8). Unilateral renal artery ligation followed by treatment with DOCA and 1% NaCl water resulted in a significant increase in mean arterial blood pressure (MAP; p< 0.05. vs CTRL) which strongly increased the resistive index (RI; p<0.05 vs CTRL) of contralateral renal artery flow and kidney volume after 4 weeks (p<0.001 vs CTRL). Renal dysfunction also led to a dysfunction of cardiac tissue strain associated with overt dyssynchrony in cardiac wall motion when compared to CTRL group, as shown by the increased time-to-peak (T2P; p<0.05) and the decreased whole peak capacity (Pk; p<0.01) in displacement and strain rate (p<0.05, respectively) in longitudinal motion. Consequently, the hearts of RAL DOCA-Salt rats showed a larger time delay between the fastest and the lowest region (Maximum Opposite Wall Delay-MOWD) when compared to CTRL group (p<0.05 in displacement and p <0.01 in strain rate). Furthermore, a significant increase in the levels of the circulating pro-inflammatory cytokines and chemokines (p< 0.05 for IL-12(40), p< 0.01 for GM-CSF, KC, IL-13, and TNF- α) and in the NGAL expression of the ligated kidney (p< 0.001) was observed compared to CTRL group. Interestingly, this pathological condition is prevented by BPF treatment. In particular, BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats (p< 0.05) and exerts a protective effect on the volume of the contralateral kidney (p <0.01). Moreover, BPF ameliorates cardiac tissue strain dysfunction by increasing Pk in displacement (p <0.01) and reducing the T2P in strain rate motion (p<0.05). These latter effects significantly improve MOWD (p <0.05) preventing the overt dyssynchrony in cardiac wall motion. Finally, the reno-cardiac protective effect of BPF was associated with a significant reduction in serum level of some pro-inflammatory cytokines and chemokines (p<0.05 for KC and IL-12(40), p<0.01 for GM-CSF, IL-13, and TNF- α) restoring physiological levels of renal neutrophil gelatinase-associated lipocalin (NGAL, p<0.05) protein of the tethered kidney. In conclusion, the present results show, for the first time, that BPF promotes an efficient renovascular protection preventing the progression of inflammation and reno-cardiac damage. Overall, these data point to a potential clinical and veterinary role of dietary supplementation with the polyphenol-rich fraction of citrus bergamot in counteracting hypertension-induced reno-cardiac syndrome. • BPF treatment prevents the increase of blood pressure in RAL DOCA-Salt rats. • The treatment promotes a renovascular protection preventing inflammation. • MRI showed the protective effect of BPF on the volume of the contralateral kidney. • The speckle-tracking analysis showedthat BPF improves cardiac tissue strain dysfunction. • Further molecular studies could suggest BPF as a supplementation for the treatment of hypertension associated with renal or cardiovascular events. [ABSTRACT FROM AUTHOR]

Metabolic associated fatty liver disease (MAFLD), commonly known as non-alcoholic fatty liver disease, represents a continuum of events characterized by excessive hepatic fat accumulation which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and in some severe cases hepatocellular carcinoma. MAFLD might be considered as a multisystem disease that affects not only the liver but involves wider implications, relating to several organs and systems, the brain included. The present study aims to investigate changes associated with MAFLD-induced alteration of thalamic metabolism in vivo. DIAMOND (Diet-induced animal model of non-alcoholic fatty liver disease) mice were fed a chow diet and tap water (NC NW) or fat Western Diet (WD SW) for up to 28 weeks. At the baseline and weeks 4, 8, 20, 28 the thalamic neurochemical profile and total cerebral brain volume were evaluated longitudinally in both diet groups using 1H-MRS. To confirm the disease progression, at each time point, a subgroup of animals was sacrificed, the livers excised and placed in formalin. Liver histology was assessed and reviewed by an expert liver pathologist. MAFLD development significantly increases the thalamic levels of total N-acetylaspartate, total creatine, total choline, and taurine. Furthermore, in the WD SW group a reduction in total cerebral brain volume has been observed (p < 0.05 vs NC NW). Our results suggest that thalamic energy metabolism is affected by MAFLD progression. This metabolic imbalance, that is quantifiable by 1H-MRS in vivo, might cause structural damage to brain cells and dysfunctions of neurotransmitter release. [ABSTRACT FROM AUTHOR]

[Display omitted] Skeletal muscles and bone tissue form the musculoskeletal apparatus, a complex system essential for the voluntary movement. The loss of muscle mass and muscle strength is often associated with a loss of bone mass, in a "hazardous duet" which implies the co-existence of sarcopenia-osteoporosis and exposes patients to a deterioration in quality of life and increased mortality. From the mechanostat theory to the recent definition of the osteosarcopenia syndrome, many aspects of muscle-bone interaction have been investigated in recent decades. The mechanical interaction is now accepted, considering the close anatomical relationship between the two tissues, however, much remains to be discovered regarding the biochemical muscle-bone interaction. Skeletal muscle has been defined as an endocrine organ capable of exerting an action on other tissues. Myokines, bioactive polypeptides released by the muscle, could represent the encrypted message in the communication between muscle and bone. These two tissues have a reciprocal influence on their metabolisms and respond in a similar way to the multiple external factors. The aim of this review is to stimulate the understanding of the encrypted language between muscle and bone, highlighting the role of catabolic pathways and oxidative stress in the musculoskeletal apparatus to elucidate the shared mechanisms and the similarity of response to the same stimuli by different tissues. Our understanding of muscle-bone interactions it could be useful to identify and develop new strategies to treat musculoskeletal diseases, together with pharmacological, nutritional and exercise-based approaches, which are already in use for the treatment of these pathologies. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease that affects about 1% of the global population, with a female–male ratio of 3:1. RA preferably affects the joints, with consequent joint swelling and deformities followed by ankylosis. However, evidence has accumulated showing that patients suffering from RA can also develop extra-articular manifestations, including cardiovascular disease states, neuropathies, and multiorgan dysfunction. In particular, peripheral nerve disorders showed a consistent impact in the course of the disease (prevalence about 20%) mostly associated to vasculitis of the nerve vessels leading to vascular ischemia, axonal degeneration, and neuronal demyelination. The pathophysiological basis of this RA-associated microvascular disease, which leads to impairment of assonal functionality, is still to be better clarified. However, endothelial dysfunction and alterations of the so-called brain-nerve barrier (BNB) seem to play a fundamental role. This review aims to assess the potential mechanisms underlying the impairment of endothelial cell functionality in the development of RA and to identify the role of dysfunctional endothelium as a causative mechanism of extra-articular manifestation of RA. On the other hand, the potential impact of lifestyle and nutritional interventions targeting the maintenance of endothelial cell integrity in patients with RA will be discussed as a potential option when approaching therapeutic solutions in the course of the disease. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients. [ABSTRACT FROM AUTHOR]

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug. [ABSTRACT FROM AUTHOR]

C-peptide therapy protects against diabetic micro- and macrovascular damages and neuropatic complications. However, to date, the role of C-peptide in preventing diabetes-related bone loss has not been investigated. Our aim was to evaluate if C-peptide infusion improves bone quality in diabetic rats. Twenty-three male Wistar rats were randomly divided into three groups: normal control group; sham diabetic control group; diabetic plus C-peptide group. Diabetes was induced by streptozotocin injection and C-peptide was delivered subcutaneously for 6 weeks. We performed micro-CT and histological testing to assess several trabecular microarchitectural parameters. At the end, diabetic plus C-peptide rats had a higher serum C-peptide (p = 0.02) and calcium (p = 0.04) levels and tibia weight (p = 0.02) than the diabetic control group. The diabetic plus C-peptide group showed a higher trabecular thickness and cross-sectional thickness than the diabetic control group (p = 0.01 and p = 0.03). Both the normal control and diabetic plus C-peptide groups had more Runx-2 and PLIN1 positive cells in comparison with the diabetic control group (p = 0.045 and p = 0.034). Diabetic rats receiving C-peptide had higher quality of trabecular bone than diabetic rats not receiving this treatment. If confirmed, C-peptide could have a role in improving bone quality in diabetes. [ABSTRACT FROM AUTHOR]

The neurodegenerative process is characterized by the progressive ultrastructural alterations of selected classes of neurons accompanied by imbalanced cellular homeostasis, a process which culminates, in the later stages, in cell death and the loss of specific neurological functions. Apart from the neuronal cell impairment in selected areas of the central nervous system which characterizes many neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, etc.), some alterations may be found in the early stages including gliosis and the misfolding or unfolding accumulation of proteins. On the other hand, several common pathophysiological mechanisms can be found early in the course of the disease including altered oxidative metabolism, the loss of cross-talk among the cellular organelles and increased neuroinflammation. Thus, antioxidant compounds have been suggested, in recent years, as a potential strategy for preventing or counteracting neuronal cell death and nutraceutical supplementation has been studied in approaching the early phases of neurodegenerative diseases. The present review will deal with the pathophysiological mechanisms underlying the early stages of the neurodegenerative process. In addition, the potential of nutraceutical supplementation in counteracting these diseases will be assessed. [ABSTRACT FROM AUTHOR]

Brain ischemia represents a leading cause of death and disability in industrialized countries. To date, therapeutic intervention is largely unsatisfactory and novel strategies are required for getting better protection of neurons injured by cerebral blood flow restriction. Recent evidence suggests that brain insulin leads to protection of neuronal population undergoing apoptotic cell death via modulation of oxidative stress and mitochondrial cytochrome c (CytC), an effect to be better clarified. In this work, we investigate on the effect of insulin given intracerebroventricular (ICV) before inducing a transient global ischemia by bilateral occlusion of the common carotid arteries (BCCO) in Mongolian gerbils (MG). The transient (3 min) global ischemia in MG is observed to produce neurodegenerative effect mainly into CA3 hippocampal region, 72 h after cerebral blood restriction. Intracerebroventricular microinfusion of insulin significantly prevents the apoptosis of CA3 hippocampal neurons. Histological observation, after hematoxylin and eosin staining, puts in evidence the neuroprotective role of insulin, but Raman microimaging provides a clearer insight in the CytC mechanism underlying the apoptotic process. Above all, CytC has been revealed to be an outstanding, innate Raman marker for monitoring the cells status, thanks to its resonant scattering at 530 nm of incident wavelength and to its crucial role in the early stages of cells apoptosis. These data support the hypothesis of an insulin-dependent neuroprotection and antiapoptotic mechanism occurring in the brain of MG undergoing transient brain ischemia. The observed effects occurred without any peripheral change on serum glucose levels, suggesting an alternative mechanism of insulin-induced neuroprotection. [ABSTRACT FROM AUTHOR]

Evidence exists that heart failure (HF) has an overall impact of 1–2 % in the global population being often associated with comorbidities that contribute to increased disease prevalence, hospitalization, and mortality. Recent advances in pharmacological approaches have significantly improved clinical outcomes for patients with vascular injury and HF. Nevertheless, there remains an unmet need to clarify the crucial role of nitric oxide/cyclic guanosine 3',5'-monophosphate (NO/cGMP) signalling in cardiac contraction and relaxation, to better identify the key mechanisms involved in the pathophysiology of myocardial dysfunction both with reduced (HFrEF) as well as preserved ejection fraction (HFpEF). Indeed, NO signalling plays a crucial role in cardiovascular homeostasis and its dysregulation induces a significant increase in oxidative and nitrosative stress, producing anatomical and physiological cardiac alterations that can lead to heart failure. The present review aims to examine the molecular mechanisms involved in the bioavailability of NO and its modulation of downstream pathways. In particular, we focus on the main therapeutic targets and emphasize the recent evidence of preclinical and clinical studies, describing the different emerging therapeutic strategies developed to counteract NO impaired signalling and cardiovascular disease (CVD) development. [Display omitted] [ABSTRACT FROM AUTHOR]

Considerable evidence demonstrated that the central role of reactive oxygen species and reactive nitrogen species (ROS and RNS) in the development of thermal hyperalgesia is associated to acute and chronic inflammation. Idebenone (IDE), a synthetic analogue of the endogenous cellular antioxidant coenzyme Q10 (CoQ10), is an active drug in the central nervous system which shows a protection in a variety of neurological disorders. Since it is lipophilic, poorly water soluble and highly bound to plasma proteins, different technological approaches have been explored to increase its solubility and new pharmaceutical properties. Therefore, it has been complexed with HP-β-cyclodextrins (HP) and its efficacy has been assessed in an animal model of carrageenan-induced thermal hyperalgesia. All male rats used for this study received a subplantar injection of carrageenan into the right hindpaw in the presence or absence of IDE alone and IDE/HP complex. We observed that IDE poorly reduced painful carrageenan effects whereas IDE/HP complex was able to prevent carrageenan-induced hyperalgesia and edema in a dose-dependent manner, reducing spinal MDA levels and protein nitration. Hence, our results demonstrated that when complexed with HP, idebenone exerts a potent analgesic and anti-inflammatory efficacy. [ABSTRACT FROM AUTHOR]

Widespread musculoskeletal pain characterizes fibromyalgia (FM), accompanied by sleep, fatigue, and mood problems. Chronic stress and depression play a crucial role in the etiology and pathophysiology of FM. They may contribute to a dysregulation of the central pain mechanisms together with the neuroendocrine and immune systems. Pharmacological treatments are the first-line therapy to reduce the symptoms of FM. The US Food and Drug Administration (FDA) indicated gabapentinoid, pregabalin, duloxetine, and milnacipran for adult patients. An alternative approach is widely used, based on therapies including interventions in patient education, behavioral therapy, exercise, pain management, and a healthy diet. A systematic search was performed on PubMed, MEDLINE, EMBASE, and Web of Science databases. The authors established the selection, inclusion, and exclusion criteria. We found a total of 908 articles. This systematic review will include ten articles selected after excluding duplicates and reading the abstracts and full texts. All studies related the effect of drugs to various symptoms caused by fibromyalgia patients with depression, such as insomnia/sleepiness, depression, suicide, difficulty walking/working, pain, fatigue, and nervousness. Although, we concluded that antidepressant drugs are effective in treating depression and pain in fibromyalgia, further studies are needed to understand the etiology of this disease and to find a combination of therapies to increase tolerability and adherence of the patient to the drug, decreasing the adverse effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Citrus Bergamia Risso, commonly known as Bergamot, is a fruit whose Essential Oil and Bergamot Polyphenolic Fraction have numerous medicinal properties. It is also an excellent antioxidant and in this study, for the first time, its potential effect on morphine induced tolerance in mice has been investigated. Our studies revealed that development of antinociceptive tolerance to repeated doses of morphine in mice is consistently associated with increased formation of superoxide, malondialdehyde and tyrosine-nitrated proteins in the dorsal horn of the spinal cord such as the enzyme glutamine synthase. Nitration of this protein is intimately linked to inactivation of its biological function and resulting increase of glutamate levels in the spinal cord. Administration of Bergamot Polyphenolic Fraction (5–50 mg/kg) attenuated tolerance development. This effect was accompanied by reduction of superoxide and malondialdehyde production, prevention of GS nitration, re-establishment of its activity and of glutamate levels. Our studies confirmed the main role of free radicals during the cascade of events induced by prolonged morphine treatment and the co-administration of natural derivatives antioxidant such as Bergamot Polyphenolic Fraction can be an important therapeutic approach to restore opioids analgesic efficacy. [ABSTRACT FROM AUTHOR]

Background: Amyloid β (Aβ)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer's disease (AD). Aβ is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO). Method: In this study, we investigated Aβ-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process. Results: Treatments of endothelial cells (EC) with Aβ promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, Aβ stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented Aβ effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation. Conclusions: The obtained data support the hypothesis that oxidative damage caused by Aβ results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to Aβ-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients. [ABSTRACT FROM AUTHOR]

Bioconversion of glyceryl trinitrate (GTN) into nitric oxide (NO) by aldehyde dehydrogenase-2 (ALDH-2) is a crucial mechanism which drives vasodilatory and antiplatelet effect of organic nitrates in vitro and in vivo . Oxidative stress generated by overproduction of free radical species, mostly superoxide anions and NO-derived peroxynitrite, has been suggested to play a pivotal role in the development of nitrate tolerance, though the mechanism still remains unclear. Here we studied the free radical-dependent impairment of ALDH-2 in platelets as well as vascular tissues undergoing organic nitrate ester tolerance and potential benefit when using the selective peroxynitrite decomposition catalyst Mn(III) tetrakis (4-Benzoic acid) porphyrin (MnTBAP). Washed human platelets were made tolerant to nitrates via incubation with GTN for 4 h. This was expressed by attenuation of platelet aggregation induced by thrombin (40 U/mL), an effect accompanied by GTN-related induction of cGMP levels in platelets undergoing thrombin-induced aggregation. Both effects were associated to attenuated GTN-induced nitrite formation in platelets supernatants and to prominent nitration of ALDH-2, the GTN to NO metabolizing enzyme, suggesting that GTN tolerance was associated to reduced NO formation via impairment of ALDH-2. These effects were all antagonized by co-incubation of platelets with MnTBAP, which restored GTN-induced responses in tolerant platelets. Comparable effect was found under in in vivo settings. Indeed, MnTBAP (10 mg/kg, i.p.) significantly restored the hypotensive effect of bolus injection of GTN in rats made tolerants to organic nitrates via chronic administration of isosorbide-5-mononitrate (IS-5-MN), thus confirming the role of peroxynitrite overproduction in the development of tolerance to vascular responses induced by organic nitrates. In conclusion, oxidative stress subsequent to prolonged use of organic nitrates, which occurs via nitration of ALDH-2, represents a key event in GTN tolerance, an effect counteracted both in vitro and in vivo by novel peroxynitrite decomposition catalyst. [ABSTRACT FROM AUTHOR]

Activation of the N-methyl-D-aspartate receptor (NMDAR) is fundamental in the development of hyperalgesia. Overactivation of this receptor releases superoxide and nitric oxide that, in turn, forms peroxynitrite (PN). All of these events have been linked to neurotoxicity. The receptors and enzymes involved in the handling of glutamate pathway--specifically NMDARs, glutamate transporter, and glutamine synthase (GS)--have key tyrosine residues which are targets of the nitration process causing subsequent function modification. Our results demonstrate that the thermal hyperalgesia induced by intrathecal administration of NMDA is associated with spinal nitration of GluN1 and GluN2B receptor subunits, GS, that normally convert glutamate into nontoxic glutamine, and glutamate transporter GLT1. Intrathecal injection of PN decomposition catalyst FeTM-4-PyP5+ prevents nitration and overall inhibits NMDA-mediated thermal hyperalgesia. Our study supports the hypothesis that nitration of key proteins involved in the regulation of glutamate transmission is a crucial pathway used by PN to mediate the development and maintenance of NMDA-mediated thermal hyperalgesia. The broader implication of our findings reinforces the notion that free radicals may contribute to various forms of pain events and the importance of the development of new pharmacological tool that can modulate the glutamate transmission without blocking its actions directly. [ABSTRACT FROM AUTHOR]

Paclitaxel is a chemotherapeutic drug used for cancer treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a common major dose-limiting side effect of many chemotherapeutic agents, including paclitaxel. CIPN is accompanied by mechanical and thermal hypersensitivity that resolves within weeks, months, or years after drug termination. To date, there is no available preventive strategy or effective treatment for CIPN due to the fact that its etiology has not been fully explained. It is clear that free radicals are implicated in many neurodegenerative diseases and recent studies have shown the important role of oxidative stress in development of CIPN. Here, we observed how, in rats, the administration of a natural antioxidant such as the bergamot polyphenolic extract (BPF), can play a crucial role in reducing CIPN. Paclitaxel administration induced mechanical allodynia and thermal hyperalgesia, which began to manifest on day seven, and reached its lowest levels on day fifteen. Paclitaxel-induced neuropathic pain was associated with nitration of proteins in the spinal cord including MnSOD, glutamine synthetase, and glutamate transporter GLT-1. This study showed that the use of BPF, probably by inhibiting the nitration of crucial proteins involved in oxidative stress, improved paclitaxel-induced pain behaviors relieving mechanical allodynia, thermal hyperalgesia, thus preventing the development of chemotherapy-induced neuropathic pain. [ABSTRACT FROM AUTHOR]

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 μg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 μg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena. [ABSTRACT FROM AUTHOR]

Oxidative stress induced post-translational protein modifications are associated with the development of inflammatory hypersensitivities. At least 90% of cellular reactive oxygen species (ROS) are produced in the mitochondria, where the mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), is located. MnSOD's ability to reduce ROS is enhanced by the mitochondrial NAD+-dependent deacetylase sirtuin (SIRT3). SIRT3 can reduce ROS levels by deacetylating MnSOD and enhancing its ability to neutralize ROS or by enhancing the transcription of MnSOD and other oxidative stress-responsive genes. SIRT3 can be post-translationally modified through carbonylation which results in loss of activity. The contribution of post-translational SIRT3 modifications in central sensitization is largely unexplored. Our results reveal that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with natural and synthetic antioxidants, prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD, and blocked the development of thermal hyperalgesia. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization. [ABSTRACT FROM AUTHOR]

Evidence has been accumulated demonstrating that heavy metals may accumulate in various organs, leading to tissue damage and toxic effects in mammals. In particular, the Central Nervous System (CNS) seems to be particularly vulnerable to cumulative concentrations of heavy metals, though the pathophysiological mechanisms is still to be clarified. In particular, the potential role of oligodendrocyte dysfunction and myelin production after exposure to subtoxic concentration I confirmed. It is ok of heavy metals is to be better assessed. Here we investigated on the effect of sub-toxic concentration of several essential (Cu2 +, Cr3 +, Ni2 +, Co2+) and non-essential (Pb2 +, Cd2+, Al3+) heavy metals on human oligodendrocyte MO3.13 and human neuronal SHSY5Y cell lines (grown individually or in co-culture). MO3.13 cells are an immortal human–human hybrid cell line with the phenotypic characteristics of primary oligodendrocytes but following the differentiation assume the morphological and biochemical features of mature oligodendrocytes. For this reason, we decided to use differentiated MO3.13 cell line. In particular, exposure of both cell lines to heavy metals produced a reduced cell viability of co-cultured cell lines compared to cells grown separately. This effect was more pronounced in neurons that were more sensitive to metals than oligodendrocytes when the cells were grown in co-culture. On the other hand, a significant reduction of lipid component in cells occurred after their exposure to heavy metals, an effect accompanied by substantial reduction of the main protein that makes up myelin (MBP) in co-cultured cells. Finally, the effect of heavy metals in oligodendrocytes were associated to imbalanced intracellular calcium ion concentration as measured through the fluorescent Rhod-2 probe, thus confirming that heavy metals, even used at subtoxic concentrations, lead to dysfunctional oligodendrocytes. In conclusion, our data show, for the first time, that sub-toxic concentrations of several heavy metals lead to dysfunctional oligodendrocytes, an effect highlighted when these cells are co-cultured with neurons. The pathophysiological mechanism(s) underlying this effect is to be better clarified. However, imbalanced intracellular calcium ion regulation, altered lipid formation and, finally, imbalanced myelin formation seem to play a major role in early stages of heavy metal-related oligodendrocyte dysfunction. [ABSTRACT FROM AUTHOR]

Background: Amyloid β (Aβ)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer's disease (AD). Aβ is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO).Method: In this study, we investigated Aβ-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process.Results: Treatments of endothelial cells (EC) with Aβ promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, Aβ stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented Aβ effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation.Conclusions: The obtained data support the hypothesis that oxidative damage caused by Aβ results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to Aβ-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients. [ABSTRACT FROM AUTHOR]