1,721,042 research outputs found
Editorial: Nutritional modulation of central nervous system development, maintenance, plasticity, and recovery
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A Nitric Oxide-Donor Furoxan Moiety Improves the Efficacy of Edaravone against Early Renal Dysfunction and Injury Evoked by Ischemia/Reperfusion
Full text linkEdaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, EDV) is a free-radical scavenger reduces organ ischemic injury. Here we investigated whether the protective effects of EDV in renal ischemia/reperfusion (I/R) injury may be enhanced by an EDV derivative bearing a nitric oxide- (NO-) donor furoxan moiety (NO-EDV). Male Wistar rats were subjected to renal ischemia (45 minutes), followed by reperfusion (6 hours). Administration of either EDV (1.2–6–30 µmol/kg, i.v.) or NO-EDV (0.3–1.2–6 µmol/kg, i.v.) dose-dependently attenuated markers of renal dysfunction (serum urea and creatinine, creatinine clearance, urine flow, urinary N-acetyl-β-D-glucosaminidase, and neutrophil gelatinase-associated lipocalin/lipocalin-2). NO-EDV exerted protective effects in the dose-range 1.2–6 µmol/kg, while a higher dose (30 µmol/kg) was needed to obtain protection by EDV. Both EDV and NO-EDV modulated tissue markers of oxidative stress and lipid peroxidation. NO-EDV, but not EDV, activated endothelial NO synthase (NOS) and blunted I/R-induced upregulation of inducible NOS, secondary to modulation of Akt and NF-κB activation, respectively. Besides NO-EDV administration inhibited I/R-induced IL-1β, IL-18, IL-6, and TNF-α overproduction. Overall, these findings demonstrate that the NO-donor moiety contributes to the protection against early renal I/R injury and suggest that NO-donor EDV codrugs are worthy of additional study as innovative pharmacological tools.Fil: Chiazza, Fausto. Universitã â Di Torino; ItaliaFil: Chegaev, Konstantin. Università  Di Torino; ItaliaFil: Rogazzo, Mara. Universitã â Di Torino; ItaliaFil: Cutrin, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); ArgentinaFil: Beneti, Elisa. Universita di Torino; ItaliaFil: Lazzarato, Loretta. Universita di Torino; ItaliaFil: Fruttero, Roberta. Universita di Torino; ItaliaFil: Collino, Massimo. Universita di Torino; Itali
Fructose-Derived Advanced Glycation End-Products Evoke Skeletal Muscle Damage in Mice by Multiple Interference with SCAP-SREBP Pathway
No full textNeuronal nitric oxide synthase is involved in vascular hyporeactivity and multiple organ dysfunction associated with hemorrhagic shock
Full text linkSevere hemorrhage can lead to global ischemia and hemorrhagic shock (HS), resulting in multiple organ failure (MOF) and death. Restoration of blood flow and re-oxygenation is associated with an exacerbation of tissue injury and inflammatory response. The neuronal nitric oxide synthase (nNOS) has been implicated in vascular collapse and systemic inflammation of septic shock; however, the role of nNOS in HS is poorly understood. The aim of this study was to evaluate the role of nNOS in the MOF associated with HS.Rats were subjected to HS under anesthesia. Mean arterial pressure was reduced to 30 mmHg for 90 min, followed by resuscitation with shed blood. Rats were randomly treated with two chemically distinct nNOS inhibitors [ARL 17477 (1 mg/kg) and 7-nitroindazol (5 mg/kg)] or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed.HS was associated with MOF development. Inhibition of nNOS activity at resuscitation protected rats against the MOF and vascular dysfunction. In addition, treatment of HS rats with nNOS inhibitors attenuated neutrophil infiltration into target organs and decreased the activation of NF-κB, iNOS expression, NO production, and nitrosylation of proteins. Furthermore, nNOS inhibition also reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 in HS rats.In conclusion, two distinct inhibitors of nNOS activity reduced the MOF, vascular dysfunction, and the systemic inflammation associated with HS. Thus, nNOS inhibitors may be useful as an adjunct therapy before fluids and blood administration in HS patients to avoid the MOF associated with reperfusion injury during resuscitation
Biological pathways and mechanisms linking COPD and cardiovascular disease
No full textCardiovascular disease (CVD) still poses a significant risk for morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). For a long time, among functional parameters, only the forced expiratory volume in 1 s (FEV1) has been considered as predictive of cardiovascular (CV) mortality especially in elderly patients in fact, there is evidence that reductions in lung function indices can increase the risk of ischaemic heart diseases and cerebrovascular diseases, independently from other risk factors. Now, there is considerable evidence suggesting that hypoxemia, systemic inflammation, oxidative stress and hyperinflation may lead to an early sub-clinical CV involvement in patients affected by COPD. Ageing in itself impacts specific aspects of the CV system, including reduced beta-adrenergic responsiveness, increased vagal tone and myocardial and vascular stiffness, endothelial dysfunction, diminished arterial baroreflex and compromised diastolic function. The complex involved interactions include ageing mechanisms as well as multiple known and unknown (e.g. genetic) risk factors. CVDs are leading causes of mortality in individuals with impaired lung function and the two entities commonly coexist with poor outcomes in patients experiencing both conditions. However, the precise mechanisms responsible for this association remain largely unknown. In this narrative review, we summarize current knowledge regarding the co-occurrence of COPD and CVD focusing on the shared biological pathways and biological mechanisms involved in these conditions
Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons
No full textType 2 diabetes (T2D) hampers stroke recovery though largely undetermined mechanisms. Few preclinical studies have investigated the effect of genetic/toxin-induced diabetes on long-term stroke recovery. However, the effects of obesity-induced T2D are mostly unknown. We aimed to investigate whether obesity-induced T2D worsens long-term stroke recovery through the impairment of brain's self-repair mechanisms - stroke-induced neurogenesis and parvalbumin (PV)+ interneurons-mediated neuroplasticity. To mimic obesity-induced T2D in the middle-age, C57bl/6j mice were fed 12 months with high-fat diet (HFD) and subjected to transient middle cerebral artery occlusion (tMCAO). We evaluated neurological recovery by upper-limb grip strength at 1 and 6 weeks after tMCAO. Gray and white matter damage, stroke-induced neurogenesis, and survival and potential atrophy of PV-interneurons were quantitated by immunohistochemistry (IHC) at 2 and 6 weeks after tMCAO. Obesity/T2D impaired neurological function without exacerbating brain damage. Moreover, obesity/T2D diminished stroke-induced neural stem cell (NSC) proliferation and neuroblast formation in striatum and hippocampus at 2 weeks after tMCAO and abolished stroke-induced neurogenesis in hippocampus at 6 weeks. Finally, stroke resulted in the atrophy of surviving PV-interneurons 2 weeks after stroke in both non-diabetic and obese/T2D mice. However, after 6 weeks, this effect selectively persisted in obese/T2D mice. We show in a preclinical setting of clinical relevance that obesity/T2D impairs neurological functions in the stroke recovery phase in correlation with reduced neurogenesis and persistent atrophy of PV-interneurons, suggesting impaired neuroplasticity. These findings shed light on the mechanisms behind impaired stroke recovery in T2D and could facilitate the development of new stroke rehabilitative strategies for obese/T2D patients
Prevalence of Urinary Tract Cancer in Patients with Obstructive Sleep Apnea: Data from the Vercelli Registry
No full textHigh-fructose intake as risk factor for neurodegeneration: Key role for carboxy methyllysine accumulation in mice hippocampal neurons
No full textSeveral studies indicate the involvement of advanced glycation end-products (AGEs) in neurodegenerative diseases. Moreover, the rising consumption of fructose in industrialized countries has been related to cognitive impairment, but the impact of fructose-derived AGEs on hippocampus has never been investigated. The present study aimed to evaluate in the hippocampus of C57Bl/6 mice fed a standard (SD) or a 60% fructose (HFRT) diet for 12weeks the production of the most studied AGEs, carboxy methyllysine (CML), focusing on the role of the glutathione-dependent enzyme glyoxalase (Glo-1), the main AGEs-detoxifying system, in relation to early signs of neuronal impairment. HFRT diet evoked CML accumulation in the cell body of pyramidal neurons, followed by RAGE/NFkB signaling activation. A widespread reactive gliosis and altered mitochondrial respiratory complexes activity have been evidenced in HFRT hippocampi, paralleled by oxidative stress increase due to impaired activity of Nrf2 signaling. In addition, a translocation of Glo-1 from axons toward cell body of pyramidal neurons has been observed in HFRT mice, in relation to CML accumulation. Despite increased expression of dimeric Glo-1, its enzymatic activity was not upregulated in HFRT hippocampi, due to reduced glutathione availability, thus failing to prevent CML accumulation. The prevention of CML production by administration of the specific inhibitor pyridoxamine was able to prevent all the fructose-induced hippocampal alterations. In conclusion, a high-fructose consumption, through CML accumulation and Glo-1 impairment, induces in the hippocampus the same molecular and metabolic alterations observed in early phases of neurodegenerative diseases, and can thus represent a risk factor for their onset
Maladaptive Modulations of NLRP3 Inflammasome and Cardioprotective Pathways Are Involved in Diet-Induced Exacerbation of Myocardial Ischemia/Reperfusion Injury in Mice
Full text linkExcessive fatty acids and sugars intake is known to affect the development of cardiovascular diseases, including myocardial infarction. However, the underlying mechanisms are ill defined. Here we investigated the balance between prosurvival and detrimental pathways within the heart of C57Bl/6 male mice fed a standard diet (SD) or a high-fat high-fructose diet (HFHF) for 12 weeks and exposed to cardiac ex vivo ischemia/reperfusion (IR) injury. Dietary manipulation evokes a maladaptive response in heart mice, as demonstrated by the shift of myosin heavy chain isoform content from α to β, the increased expression of the Nlrp3 inflammasome and markers of oxidative metabolism, and the downregulation of the hypoxia inducible factor- (HIF-)2α and members of the Reperfusion Injury Salvage Kinases (RISK) pathway. When exposed to IR, HFHF mice hearts showed greater infarct size and lactic dehydrogenase release in comparison with SD mice. These effects were associated with an exacerbated overexpression of Nlrp3 inflammasome, resulting in marked caspase-1 activation and a compromised activation of the cardioprotective RISK/HIF-2α pathways. The common mechanisms of damage here reported lead to a better understanding of the cross-talk among prosurvival and detrimental pathways leading to the development of cardiovascular disorders associated with metabolic diseases
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