Oxidative stress in DNA repeat expansion disorders: a focus on NRF2 signaling involvement

DNA repeat expansion disorders are a group of neuromuscular and neurodegenerative diseases that arise from the inheritance of long tracts of nucleotide repetitions, located in the regulatory region, introns, or inside the coding sequence of a gene. Although loss of protein expression and/or the gain of function of its transcribed mRNA or translated product represent the major pathogenic effect of these pathologies, mitochondrial dysfunction and imbalance in redox homeostasis are reported as common features in these disorders, deeply affecting their severity and progression. In this review, we examine the role that the redox imbalance plays in the pathological mechanisms of DNA expansion disorders and the recent advances on antioxidant treatments, particularly focusing on the expression and the activity of the transcription factor NRF2, the main cellular regulator of the antioxidant response

Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NRF2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed a modulation of relevant markers of the inflammatory response, such as heme oxygenase 1 and IL-6, suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human

Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NRF2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed a modulation of relevant markers of the inflammatory response, such as heme oxygenase 1 and IL-6, suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human

'Perciò è azzardo: perché non sai cosa trovi'. Il rapporto tra videogiochi e gioco d'azzardo nella prospettiva dei giovani gamer

'Perciò è azzardo: perché non sai cosa trovi'. Il rapporto tra videogiochi e gioco d'azzardo nella prospettiva dei giovani gamer- Indice #8- Capitolo 1. Introduzione #10- Capitolo 2. Metodologia e campione #12- Capitolo 3. Risultati #16- Capitolo 4. Riflessioni conclusive #5

Targeting NRF2 for the treatment of Friedreich's ataxia: a comparison among drugs

NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich's Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules

Ferroptosis in Friedreich’s ataxia: a metal-induced neurodegenerative disease

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress

Charmonium resonances with JPC=1−− and 3−− from D¯D scattering on the lattice

We present a lattice QCD study of charmonium resonances and bound states with JPC = 1(--) and 3(--) near the open-charm threshold, taking into account their strong transitions to (D) over barD. Vector charmonia are the most abundant in the experimentally established charmonium spectrum, while recently LHCb reported also the first discovery of a charmonium with likely spin three. The (D) over barD scattering amplitudes for partial waves l = 1 and l = 3 are extracted on the lattice by means of the Luscher formalism, using multiple volumes and inertial frames. Parametrizations of the scattering amplitudes provide masses and widths of the resonances, as well as the masses of bound states. CLS ensembles with 2 + 1 dynamical flavors of nonperturbatively O(a) improved Wilson quarks are employed with m(pi) similar or equal to 280 MeV, a single lattice spacing of a = 0.09 fm and two lattice spatial extents of L = 24 and 32. Two values of the charm quark mass are considered to examine the influence of the position of the (D) over barD threshold on the hadron masses. For the lighter charm quark mass we find the vector resonance psi(3770) with mass m = 3780(7) MeV and coupling g = 16.0((+2.1)(-0.2)) (related to the width by Gamma = g(2)p(3)/6 pi m(2)). Both quantities are consistent with their experimental values, m(exp) = 3773.13(35) MeV and g(exp) = 18.7(9). The vector psi(2S) appears as a bound state with m = 3666(10) MeV. The charmonium resonance with J(PC) = 3(--) is found at m = 3831((+10)(-16)) MeV, consistent with the Xo3842+ recently discovered by LHCb. At our heavier charm-quark mass the psi(2S) as well as the psi(3770) are bound states and the Xo3842+ remains a resonance. We stress that all quoted uncertainties are only statistical, while lattice spacing effects and the approach to the physical point (for the light and strange quarks) still need to be explored. This study of conventional charmonia sets the stage for more challenging future studies of unconventional charmoniumlike states

Detectors for the next-generation PET scanners

Next-generation PET scanners are expected to fulfill very high requirements in terms of spatial, energy and timing resolution. Modern scanner performances are inherently limited by the use of standard photomultiplier tubes. The use of Silicon Photomultiplier (SiPM) matrices is proposed for the construction of a small animal PET system with depth of interaction capabilities. Measurements showing that SiPM matrices are highly ideal for PET applications, have been reported