4,378 research outputs found
Counteraction of HCV-induced oxidative stress concurs to establish chronic infection in liver cell cultures
Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically
infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with
chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of
infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it
is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and
oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is
still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that
reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of
HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of
NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic
cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS
production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment
with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a
prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results
suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a
promising option for contrasting HCV infection
Antiviral and antioxidant activity of a hydroalcoholic extract from Humulus lupulus L.
A hydroalcoholic extract from female inflorescences of Humulus lupulus L. (HOP extract) was evaluated for its anti-influenza activity. The ability of the extract to interfere with different phases of viral replication was assessed, as well as its effect on the intracellular redox state, being unbalanced versus the oxidative state in infected cells. The radical scavenging power, inhibition of lipoperoxidation, and ferric reducing activity were assayed as antioxidant mechanisms. A phytochemical characterization of the extract was also performed. We found that HOP extract significantly inhibited replication of various viral strains, at different time from infection. Viral replication was partly inhibited when virus was incubated with extract before infection, suggesting a direct effect on the virions. Since HOP extract was able to restore the reducing conditions of infected cells, by increasing glutathione content, its antiviral activity might be also due to an interference with redox-sensitive pathways required for viral replication. Accordingly, the extract exerted radical scavenging and reducing effects and inhibited lipoperoxidation and the tBOOH-induced cytotoxicity. At phytochemical analysis, different phenolics were identified, which altogether might contribute to HOP antiviral effect. In conclusion, our results highlighted anti-influenza and antioxidant properties of HOP extract, which encourage further in vivo studies to evaluate its possible application
Suggestive evidence of a multi-cytokine resistin pathway in humans and its role on cardiovascular events in high-risk individuals
In cells and tissues resistin affects IL-1β, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMA IR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE
Modulating metabolism to improve cancer-induced muscle wasting
Muscle wasting is one of the main features of cancer cachexia, a multifactorial syndrome frequently occurring in oncologic patients. The onset of cachexia is associated with reduced tolerance and response to antineoplastic treatments, eventually leading to clinical conditions that are not compatible with survival. Among the mechanisms underlying cachexia, protein and energy dysmetabolism play a major role. In this regard, several potential treatments have been proposed, mainly on the basis of promising results obtained in preclinical models. However, at present, no treatment yet reached validation to be used in the clinical practice, although several drugs are currently tested in clinical trials for their ability to improve muscle metabolism in cancer patients. Along this line, the results obtained in both experimental and clinical studies clearly show that cachexia can be effectively approached by a multidirectional strategy targeting nutrition, inflammation, catabolism, and inactivity at the same time. In the present study, approaches aimed to modulate muscle metabolism in cachexia will be reviewed
Structured Light Profilometry on m-PTC
In concentrating solar systems, it is essential to study the optical losses of the collectors. A fundamental parameter is the intercept factor, namely, the fraction of sunrays reflected by the concentrator that reaches the receiver. Optical profilometry studies the relationship between the collector profile and the intercept factor, which influences the collection efficiency. Profilometric analyses were performed on a micro-parabolic trough collector (m-PTC), with reduced sizes and greater mirror curvature than a usual PTC. The proposed technique projects a luminous pattern (structured light) both on the collector with an opaque covering and on a flat reference plane. Measurement set-up and calibration technique were developed for m-PTC. A program coded in Python analyzed the images and reconstructs the mirror profile. The tilted reference plane was reconstructed using an original geometric model and a calibration procedure. The focal length of each parabolic section was calculated, providing information on surface defects in the mirror. An important parameter obtained was the displacement of the focus of the parabola with respect to the ideal position. Using this value, the intercept factor was estimated to be 0.89. The proposed technique was validated by comparing the results with an independent profilometric study applied to the same m-PTC
Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold
Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling
COVID-19 susceptibility and vaccination coverage for measles, rubella and mumps in students and healthcare workers in Trieste hospitals (NE Italy)
Background: Measles, mumps, and rubella (MMR) vaccines have been suggested as preventive measures to protect subjects from the worst sequelae of COVID-19 infection because neutralizing antibodies can cross-react with other viruses.
Aim: To verify COVID-19 infection in MMR vaccinated and non-vaccinated healthcare workers and medical students in Trieste Hospitals.
Results: Nurse aids resulted in significantly more infections than structured physicians (OR 1.80; 95% CI 1.14-2.80) while students resulted in less infections (OR, 0.66; 95% CI 0.43-1.01). The presence of an MMR vaccination was inversely associated with COVID-19 (OR, 0.77; 95% CI 0.61-0.96) but only in univariate analysis. In the multivariable logistic regression analysis, MMR vaccination lost statistical significance (OR, 0.86; 95%CI 0.62-1.20). On 13 HCWs hospitalized for COVID-19, 11 resulted not vaccinated for MMR. Discussion: Our study found a mild, non-significant reduction in SARS-CoV-2 infections in workers vaccinated with MMR
The Many Manifestations of Downsizing: Hierarchical Galaxy Formation Models confront Observations
[abridged] It has been widely claimed that several lines of observational
evidence point towards a "downsizing" (DS) of the process of galaxy formation
over cosmic time. This behavior is sometimes termed "anti-hierarchical", and
contrasted with the "bottom-up" assembly of the dark matter structures in Cold
Dark Matter models. In this paper we address three different kinds of
observational evidence that have been described as DS: the stellar mass
assembly, star formation rate and the ages of the stellar populations in local
galaxies. We compare a broad compilation of available data-sets with the
predictions of three different semi-analytic models of galaxy formation within
the Lambda-CDM framework. In the data, we see only weak evidence at best of DS
in stellar mass and in star formation rate. We find that, when observational
errors on stellar mass and SFR are taken into account, the models acceptably
reproduce the evolution of massive galaxies, over the entire redshift range
that we consider. However, lower mass galaxies are formed too early in the
models and are too passive at late times. Thus, the models do not correctly
reproduce the DS trend in stellar mass or the archaeological DS, while they
qualitatively reproduce the mass-dependent evolution of the SFR. We demonstrate
that these discrepancies are not solely due to a poor treatment of satellite
galaxies but are mainly connected to the excessively efficient formation of
central galaxies in high-redshift haloes with circular velocities ~100-200
km/s. [abridged]Comment: MNRAS accepted, 16 pages, 10 figure
Differential redox state contributes to sex disparities in the response to influenza virus infection in male and female mice
Influenza virus replicates intracellularly exploiting several pathways involved in the
regulation of host responses. The outcome and the severity of the infection are thus
strongly conditioned by multiple host factors, including age, sex, metabolic, and redox
conditions of the target cells. Hormones are also important determinants of host immune
responses to influenza and are recently proposed in the prophylaxis and treatment. This
study shows that female mice are less susceptible than males to mouse-adapted influenza
virus (A/PR8/H1N1). Compared with males, PR8-infected females display higher
survival rate (+36%), milder clinical disease, and less weight loss. They also have milder
histopathological signs, especially free alveolar area is higher than that in males, even
if pro-inflammatory cytokine production shows slight differences between sexes; hormone
levels, moreover, do not vary significantly with infection in our model. Importantly,
viral loads (both in terms of viral M1 RNA copies and tissue culture infectious dose
50%) are lower in PR8-infected females. An analysis of the mechanisms contributing
to sex disparities observed during infection reveals that the female animals have higher
total antioxidant power in serum and their lungs are characterized by increase in (i) the
content and biosynthesis of glutathione, (ii) the expression and activity of antioxidant
enzymes (peroxiredoxin 1, catalase, and glutathione peroxidase), and (iii) the expression
of the anti-apoptotic protein Bcl-2. By contrast, infected males are characterized by
high expression of NADPH oxidase 4 oxidase and phosphorylation of p38 MAPK, both
enzymes promoting viral replication. All these factors are critical for cell homeostasis and
susceptibility to infection. Reappraisal of the importance of the host cell redox state and
sex-related effects may be useful in the attempt to develop more tailored therapeutic
interventions in the fight against influenza
The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint
Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species.Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling.Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors
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