1,721,140 research outputs found
Repositioning Chromones for Early Anti-inflammatory Treatment of COVID-19
Full text linkThe COVID-19 pandemic is posing an unprecedented sanitary threat. In the absence of specific vaccines and anti-SARS-CoV-2 drugs, medicines that may assist in tackling the emergency and limiting the high number of fatalities are urgently needed. The repositioning of available drugs to treat COVID-19 is the only and rapid option in the face of the lack of direct antiviral agents and vaccines available. In this light it is important to focus on available drugs, which, based on their pharmacodynamics, could plausibly attenuate viral growth as well as COVID-19's worst complications. This is the case of chloroquine and tocilizumab which seem to limit virus replication and the severity of interstitial pneumonia, respectively. However, these treatments, particularly those aimed at containing inflammation, are still reserved for the most severe cases. This commentary elaborates on the pharmacological rationale of repositioning the mast cell stabilizer chromones as an adjunctive treatment for SARS-CoV-2 infection, and proposes their practical clinical testing as an early, safe, and cost-effective anti-inflammatory intervention in COVID-19 to limit the eventual secondary progression toward life-threatening respiratory complications
The fast-halo assay for the assessment of DNA damage at the single-cell level
No full textOver the past three decades the development of methods for visualizing at the cell level the extent of DNA breakage significantly contributed to genotoxicity testing: their availability greatly improved the knowledge in the field of genetic toxicology. These procedures are based on the separation and visualization of DNA fragments resulting from cleavage of nuclear DNA from intact DNA. The separation can be obtained either electrically (comet assay, linear migration of DNA fragments) or chemically (fast halo assay, radial diffusion of DNA fragments). Once separated and stained, intact and fragmented DNA can be observed at the fluorescence or light microscope. Appropriate computer-assisted image analysis allows quantitative determination of the extent of DNA breakage. These procedures have been proven to be sensitive, flexible and reliable and, as compared to former methods, they are more simple, less time and money consuming and have the unique capability of detecting DNA damage at the single cell level. This last feature has the additional advantage of allowing the identification of cellular subpopulations characterized by different sensitivity to the damaging agent. The fast halo assay is currently the simplest and quickest; recent modifications of FHA further implemented the assay and pave the way to a full exploitation of its analytical potential. In this chapter the development, the procedures, the applications and the limits of FHA will be illustrated
Delayed formation of hydrogen peroxide mediates the lethal response evoked by peroxynitrite in U937 cells
Full text linkThe toxicity paradigm used in the present study involves exposure of U937 cells to a concentration of authentic peroxynitrite, leading to a rapid necrotic response mediated by mitochondrial permeability transition. We found that addition of catalase after treatment with peroxynitrite specifically prevents the loss of mitochondrial membrane potential and the ensuing lethal response. The protective effects of catalase were mimicked by the cocktail glutathione peroxidase/reduced glutathione. A defensive role of intracellular catalase was implied by experiments showing that catalase-depleted cells are hypersensitive to peroxynitrite and that cells with an increased catalase content, selected for their resistance to H2O2, are cross-resistant to peroxynitrite. Further experiments demonstrated that H2O2 formation takes place after peroxynitrite exposure. Various approaches using inhibitors of the mitochondrial respiratory chain as well as respiration-deficient cells revealed that the oxidant is produced upon dismutation of superoxides generated at the level of complex III. Interestingly, respiration-deficient cells were found to be resistant to peroxynitrite toxicity, and all those treatments increasing formation of H2O2produced a parallel increase in toxicity. In conclusion, the results presented in this study indicate that peroxynitrite-induced impairment of electron transport from cytochrome b to cytochromec1 leads to delayed formation of hydrogen peroxide, which plays a pivotal role in the ensuing necrotic response
Effects of creatine in skeletal muscle cells and in myoblasts differentiating under normal or oxidatively stressing conditions
No full textCreatine (Cr) - along with the Cr kinase (CK) system - plays a fundamental role in muscle biochemistry and physiology not limited to its ergogenic role. Indeed Cr has been shown to exert pleiotropic effects, which promote protein accretion, muscle-specific protein synthesis, growth in cultured myogenic cells and favour the myogenic process either in normal or stressing conditions. This review focuses on the effects of Cr supplementation on cellular and mitochondrial biochemistry and function in the course of skeletal muscle differentiation, either in normal or oxidatively stressing conditions, and on the ensuing nutraceutical/therapeutic perspectives
Regulatory role of extracellular medium components in metal induced cyto- and geno-toxicity.
No full textPeroxynitrite promotes mitochondrial permeability transition-dependent rapid U937 cell necrosis: survivors proliferate with kinetics superimposable on those of untreated cells.
No full textReactive oxygen species in skeletal muscle signaling
Full text linkGeneration of reactive oxygen species (ROS) is a ubiquitous phenomenon in eukaryotic cells’ life. Up to the 1990s of the past
century, ROS have been solely considered as toxic species resulting in oxidative stress, pathogenesis and aging. However, there is
now clear evidence that ROS are not merely toxic species but also—within certain concentrations—useful signaling molecules
regulating physiological processes. During intense skeletal muscle contractile activity myotubes’ mitochondria generate high ROS
flows: this renders skeletal muscle a tissue where ROS hold a particular relevance. According to their hormetic nature, in muscles
ROS may trigger different signaling pathways leading to diverging responses, from adaptation to cell death. Whether a “positive”
or “negative” response will prevail depends on many variables such as, among others, the site of ROS production, the persistence
of ROS flow or target cells’ antioxidant status. In this light, a specific threshold of physiological ROS concentrations above which
ROS exert negative, toxic effects is hard to determine, and the concept of “physiologically compatible” levels of ROS would better
fit with such a dynamic scenario. In this review these concepts will be discussed along with the most relevant signaling pathways
triggered and/or affected by ROS in skeletal muscle
Cytotoxic and Antitumor Activity of Sulforaphane: The Role of Reactive Oxygen Species
Full text linkAccording to recent estimates, cancer continues to remain the second leading cause of death and is becoming the leading one in old age. Failure and high systemic toxicity of conventional cancer therapies have accelerated the identification and development of innovative preventive as well as therapeutic strategies to contrast cancer-associated morbidity and mortality. In recent years, increasing body of in vitro and in vivo studies has underscored the cancer preventive and therapeutic efficacy of the isothiocyanate sulforaphane. In this review article, we highlight that sulforaphane cytotoxicity derives from complex, concurring, and multiple mechanisms, among which the generation of reactive oxygen species has been identified as playing a central role in promoting apoptosis and autophagy of target cells. We also discuss the site and the mechanism of reactive oxygen species' formation by sulforaphane, the toxicological relevance of sulforaphane-formed reactive oxygen species, and the death pathways triggered by sulforaphane-derived reactive oxygen species
Detection of protein associated DNA breaks by the alkaline elution technique utilizing polycarbonate or polyvinylchloride membranes
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