Studio delle implicazioni dell’omeostasi del rame in patologie neurodegenerative

Numerose patologie neurodegenerative sono caratterizzate da danni ossidativi, alterazioni dell’omeostasi di metalli di transizione ed infiammazione. Il sistema nervoso centrale, come altri distretti corporei, presenta una complessa rete proteica deputata allo stretto controllo della distribuzione e della reattività del rame, un metallo di transizione essenziale e potenzialmente tossico. Il rame e/o la sua alterata omeostasi sembrano implicati nell’eziologia di numerose patologie neurodegenerative; questo studio ha riguardato alcuni aspetti dell’implicazione dell’alterata omeostasi del rame nella malattia di Alzheimer (AD) e nella Sclerosi Laterale Amiotrofica di origine familiare (SLAf). Il coinvolgimento del rame nell’AD è ancora dibattuto, tuttavia i nostri risultati rafforzano la nozione di uno squilibrio sistemico dell’omeostasi del rame nei pazienti AD, evidenziando un aumento di rame in fibroblasti provenienti da espianti cutanei; inoltre, abbiamo rilevato una ridotta attività della ceruloplasmina nei liquidi cerebrospinali AD, proponendola quale marcatore diagnostico per questa patologia. Nella SLAf, invece, il coinvolgimento del rame è stato sempre correlato all’enzima a rame SOD1; il 20% dei casi di origine familiare sono associati a forme mutate della proteina. In questo lavoro abbiamo studiato le possibili implicazioni della carenza di rame nella SLAf, trattando cellule NSC-34, considerate il miglior modello sperimentale di neuroni motori, con un chelante specifico del rame, il Trien. I risultati ottenuti mostrano l’importanza del rame nell’accumulo delle SOD1 nel mitocondrio, fenomeno comune a numerose forme mutate della proteina, ma non è coinvolto nella tossicità ai danni della citocromo c ossidasi, bersaglio principale in questi organelli. Effettore di questa azione tossica sembra essere invece l’NO. Interessantissima è la scoperta che le SOD1 mutate sembrano influenzare i livelli intracellulari di rame, fenomeno che suggerisce nuove vie di investigazione ai fini di una correlazione tra la SOD1, il rame e la SLAf.Several neurodegenerative diseases are characterized by oxidative damage, redox metals homeostasis impairment and inflammation. Central nervous system, like other districts, contains an protein apparatus to perform an accurate control of the distribution and reactivity of the transition metal copper, a janus-faced element, which combines essentiality and potential toxicity. Copper itself and/or the disturbances of copper homeostasis are considered implicated in the aetiology of many neurodegenerative diseases. We focused our investigation on Alzheimer’s disease (AD) and familial amiotrophic lateral sclerosis (fALS). In AD the role of copper is still debated, but our results reinforce the knowledge on the implication of altered copper homeostasis in AD, both in central nervous system and in peripheral districts: Indeed, in the present study we found that the intracellular copper levels are increased in AD skin fibroblasts and that the activity of the cuproenzyme ceruloplasmin is sensibly decreased in AD cerebrospinal fluid, so that to propose the evaluation of ceruloplasmin enzyme activity as a possible in vivo diagnostic marker for this pathology. Until today, the copper-fALS connection was justified by Cu, Zn superoxide dismutase (SOD1), a relevant intracellular antioxidant enzyme. 20% of fALS cases are linked to mutated forms of this protein. Here, we investigated the possible implication of copper deficiency in fALS treating NSC-34 cells, the best motor-neuron model, with a specific copper chelator (triethylene tetramine). Our results indicate that copper is important to SOD1s accumulation in mitochondria, a common pathological mechanisms of the mutated proteins, but it is not implicated in the toxic effect. Our results suggest that the NO formed as a consequence of mutated SOD1s expression is a putative mediator of the imparment of cytochrome c oxidase activity. We also observed that fALS-linked SOD1s are implicated in the regulation of intracellular copper content, thus suggesting novel possible correlations between copper and fALS

Studio delle implicazioni dell’omeostasi del rame in patologie neurodegenerative

Numerose patologie neurodegenerative sono caratterizzate da danni ossidativi, alterazioni dell’omeostasi di metalli di transizione ed infiammazione. Il sistema nervoso centrale, come altri distretti corporei, presenta una complessa rete proteica deputata allo stretto controllo della distribuzione e della reattività del rame, un metallo di transizione essenziale e potenzialmente tossico. Il rame e/o la sua alterata omeostasi sembrano implicati nell’eziologia di numerose patologie neurodegenerative; questo studio ha riguardato alcuni aspetti dell’implicazione dell’alterata omeostasi del rame nella malattia di Alzheimer (AD) e nella Sclerosi Laterale Amiotrofica di origine familiare (SLAf). Il coinvolgimento del rame nell’AD è ancora dibattuto, tuttavia i nostri risultati rafforzano la nozione di uno squilibrio sistemico dell’omeostasi del rame nei pazienti AD, evidenziando un aumento di rame in fibroblasti provenienti da espianti cutanei; inoltre, abbiamo rilevato una ridotta attività della ceruloplasmina nei liquidi cerebrospinali AD, proponendola quale marcatore diagnostico per questa patologia. Nella SLAf, invece, il coinvolgimento del rame è stato sempre correlato all’enzima a rame SOD1; il 20% dei casi di origine familiare sono associati a forme mutate della proteina. In questo lavoro abbiamo studiato le possibili implicazioni della carenza di rame nella SLAf, trattando cellule NSC-34, considerate il miglior modello sperimentale di neuroni motori, con un chelante specifico del rame, il Trien. I risultati ottenuti mostrano l’importanza del rame nell’accumulo delle SOD1 nel mitocondrio, fenomeno comune a numerose forme mutate della proteina, ma non è coinvolto nella tossicità ai danni della citocromo c ossidasi, bersaglio principale in questi organelli. Effettore di questa azione tossica sembra essere invece l’NO. Interessantissima è la scoperta che le SOD1 mutate sembrano influenzare i livelli intracellulari di rame, fenomeno che suggerisce nuove vie di investigazione ai fini di una correlazione tra la SOD1, il rame e la SLAf.Several neurodegenerative diseases are characterized by oxidative damage, redox metals homeostasis impairment and inflammation. Central nervous system, like other districts, contains an protein apparatus to perform an accurate control of the distribution and reactivity of the transition metal copper, a janus-faced element, which combines essentiality and potential toxicity. Copper itself and/or the disturbances of copper homeostasis are considered implicated in the aetiology of many neurodegenerative diseases. We focused our investigation on Alzheimer’s disease (AD) and familial amiotrophic lateral sclerosis (fALS). In AD the role of copper is still debated, but our results reinforce the knowledge on the implication of altered copper homeostasis in AD, both in central nervous system and in peripheral districts: Indeed, in the present study we found that the intracellular copper levels are increased in AD skin fibroblasts and that the activity of the cuproenzyme ceruloplasmin is sensibly decreased in AD cerebrospinal fluid, so that to propose the evaluation of ceruloplasmin enzyme activity as a possible in vivo diagnostic marker for this pathology. Until today, the copper-fALS connection was justified by Cu, Zn superoxide dismutase (SOD1), a relevant intracellular antioxidant enzyme. 20% of fALS cases are linked to mutated forms of this protein. Here, we investigated the possible implication of copper deficiency in fALS treating NSC-34 cells, the best motor-neuron model, with a specific copper chelator (triethylene tetramine). Our results indicate that copper is important to SOD1s accumulation in mitochondria, a common pathological mechanisms of the mutated proteins, but it is not implicated in the toxic effect. Our results suggest that the NO formed as a consequence of mutated SOD1s expression is a putative mediator of the imparment of cytochrome c oxidase activity. We also observed that fALS-linked SOD1s are implicated in the regulation of intracellular copper content, thus suggesting novel possible correlations between copper and fALS

MicroRNAs in Nonalcoholic Fatty Liver Disease: Novel Biomarkers and Prognostic Tools during the Transition from Steatosis to Hepatocarcinoma

Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). The influence of NAFLD on HCC development has drawn attention in recent years. HCC is one of the most common malignant tumors and the third highest cause of cancer-related death. HCC is frequently diagnosed late in the disease course, and patient’s prognosis is usually poor. Early diagnosis and identification of the correct stage of liver damage during NAFLD progression can contribute to more effective therapeutic interventions, improving patient outcomes. Therefore, scientists are always searching for new sensitive and reliable markers that could be analysed through minimally invasive tests. MicroRNAs are short noncoding RNAs that act as posttranscriptional regulators of gene expression. Several studies identified specific miRNA expression profiles associated to different histological features of NAFLD. Thus, miRNAs are receiving growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets. This review focuses on the current knowledge of the miRNAs involved in NAFLD and related HCC development, highlighting their diagnostic and prognostic value for the screening of NAFLD patients

Mitochondrial Dysfunctions and Altered Metals Homeostasis: New Weapons to Counteract HCV-Related Oxidative Stress

The hepatitis C virus (HCV) infection produces several pathological effects in host organism through a wide number of molecular/metabolic pathways. Today it is worldwide accepted that oxidative stress actively participates in HCV pathology, even if the antioxidant therapies adopted until now were scarcely effective. HCV causes oxidative stress by a variety of processes, such as activation of prooxidant enzymes, weakening of antioxidant defenses, organelle damage, and metals unbalance. A focal point, in HCV-related oxidative stress onset, is the mitochondrial failure. These organelles, known to be the “power plants” of cells, have a central role in energy production, metabolism, and metals homeostasis, mainly copper and iron. Furthermore, mitochondria are direct viral targets, because many HCV proteins associate with them. They are the main intracellular free radicals producers and targets. Mitochondrial dysfunctions play a key role in the metal imbalance. This event, today overlooked, is involved in oxidative stress exacerbation and may play a role in HCV life cycle. In this review, we summarize the role of mitochondria and metals in HCV-related oxidative stress, highlighting the need to consider their deregulation in the HCV-related liver damage and in the antiviral management of patients

Prediction of carotid intima-media thickness in obese patients with low prevalence of comorbidities by serum copper bioavailability.

BACKGROUND AND AIM: Western societies, with growing prevalence, suffer from various metabolic diseases like obesity and hepatic steatosis, better defined as non-alcoholic fatty liver disease, or cardiovascular (CV) diseases that are strictly linked to each other. The association of their occurrence with the altered homeostasis of metals is an intriguing issue. Copper in particular was identified as key player in various metabolic derangements. On these bases, we aimed at investigating the possible association of serum copper levels with an indicator of early CV risk as the intima-media thickness (IMT) of carotid artery and its predictive value in a selected population of obese patients. METHODS: We performed a cross-sectional study recruiting 100 obese patients characterized by a low prevalence of comorbidities. Ultrasound investigation for hepatic steatosis and IMT evaluation were performed. Serum samples were collected and then analyzed through atomic absorption spectrometry to evaluate their copper content. Possible correlations between copper bioavailability and biochemical, clinical, and anthropometric characteristics of patients were sought. RESULTS: Age negatively predicted copper serum levels of patients (P = 0.009). However, the most interesting finding is the negative prediction of IMT by the copper serum levels (t = -2.23, P = 0.028, least absolute deviations regression). Factor analysis confirmed the aforementioned inverse correlation and highlighted the strong inverse correlation between smoking and copper serum levels. CONCLUSION: Our data show that an altered copper bioavailability predicts early atherosclerosis as main CV risk in obese patients with hepatic steatosis detected by ultrasound, shedding some light in this pathological scenario