The crucial role of vitamin C and its transporter (SVCT2) in bone marrow stromal cell autophagy and apoptosis

AbstractVitamin C is an antioxidant that plays a vital role in various biological processes including bone formation. Previously, we reported that vitamin C is transported into bone marrow stromal cells (BMSCs) through the sodium dependent Vitamin C Transporter 2 (SVCT2) and this transporter plays an important role in osteogenic differentiation. Furthermore, this transporter is regulated by oxidative stress. To date, however, the exact role of vitamin C and its transporter (SVCT2) in ROS regulated autophagy and apoptosis in BMSCs is poorly understood. In the present study, we observed that oxidative stress decreased survival of BMSCs in a dose-dependent manner and induced growth arrest in the G1 phase of the cell cycle. These effects were accompanied by the induction of autophagy, confirmed by P62 and LC3B protein level and punctate GFP-LC3B distribution. The supplementation of vitamin C significantly rescued the BMSCs from oxidative stress by regulating autophagy. Knockdown of the SVCT2 transporter in BMSCs synergistically decreased cell survival even under low oxidative stress conditions. Also, supplementing vitamin C failed to rescue cells from stress. Our results reveal that the SVCT2 transporter plays a vital role in the mechanism of BMSC survival under stress conditions. Altogether, this study has given new insight into the role of the SVCT2 transporter in oxidative stress related autophagy and apoptosis in BMSCs

Anxiety, depression and swallowing disorders in patients with Parkinson’s disease

Swallowing disturbances (SDs), anxiety and depression are commonly present in Parkinson’s disease (PD) patients. We hypothesized that there is an association between the presence of SDs and the PD affective state. Sixty nine PD patients were assessed for the presence of SDs by undergoing cognitive screening with the Mini Mental State Examination (MMSE), completing three inventories: a swallowing disturbance questionnaire (SDQ), the Spielberger manual for the trait anxiety and Beck depression inventories. All patients underwent clinical swallowing evaluations by a speech and language pathologist (SLP). Patients diagnosed with SDs were also assessed by fiberoptic endoscopic evaluation of swallowing (FEES) performed by an ENT and SLP. Thirty eight patients experienced SDs, the other 31 did not. The clinical characteristics of the two groups were matched. Patients with SDs experienced increased anxiety and depression compared to patients without SDs. Comparisons between patients who scored in the two opposite ends of the anxiety and depression ranges demonstrated that the most anxious and depressed patients reported more swallowing difficulties (SDQ scores) compared with the least anxious and depressed ones. In addition, the most anxious patients had significantly increased disease severity and decreased MMSE scores compared with the least anxious patients. Disease severity was also increased in the most depressed patients compared with the least depressed ones. Advanced disease emerged as being associated with high anxiety levels and greater numbers of SDs. The contribution of anxiety or depression to the development or worsening of SDs and their role in treatment strategy warrant further investigation

Mechanisms of exercise-induced improvements in the contractile apparatus of the mammalian myocardium

One of the main outcomes of aerobic endurance exercise training is the improved maximal oxygen uptake, and this is pivotal to the improved work capacity that follows the exercise training. Improved maximal oxygen uptake in turn is at least partly achieved because exercise training increases the ability of the myocardium to produce a greater cardiac output. In healthy subjects, this has been demonstrated repeatedly over many decades. It has recently emerged that this scenario may also be true under conditions of an initial myocardial dysfunction. For instance, myocardial improvements may still be observed after exercise training in post-myocardial infarction heart failure. In both health and disease, it is the changes that occur in the individual cardiomyocytes with respect to their ability to contract that by and large drive the exercise training-induced adaptation to the heart. Here, we review the evidence and the mechanisms by which exercise training induces beneficial changes in the mammalian myocardium, as obtained by means of experimental and clinical studies, and argue that these changes ultimately alter the function of the whole heart and contribute to the changes in whole-body function

Autoimmune Hepatitis Induced by Syngeneic Liver Cytosolic Proteins Biotransformed by Alcohol Metabolites

Aldehydes that are produced following the breakdown of ethanol (acetaldehyde) and lipid peroxidation of membranes (malondialdehyde) have been shown to bind (adduct) proteins. Additionally, these two aldehydes can combine (MAA) on non-syngeneic and syngeneic proteins to initiate numerous immune responses to the unmodified part of the protein in the absence of an adjuvant. Therefore, these studies provide a potential mechanism for the development of antigen-specific immune responses resulting in liver damage should syngeneic liver proteins be adducted with MAA

First AGILE Catalog of High Confidence Gamma-Ray Sources

We present the first catalog of high-confidence gamma-ray sources detected by the AGILE satellite during observations performed from July 9, 2007 to June 30, 2008. Catalogued sources are detected by merging all the available data over the entire time period. AGILE, launched in April 2007, is an ASI mission devoted to gamma-ray observations in the 30 MeV - 50 GeV energy range, with simultaneous X-ray imaging capability in the 18-60 keV band. This catalog is based on Gamma-Ray Imaging Detector (GRID) data for energies greater than 100 MeV. For the first AGILE catalog we adopted a conservative analysis, with a high-quality event filter optimized to select gamma-ray events within the central zone of the instrument Field of View (radius of 40 degrees). This is a significance-limited (4 sigma) catalog, and it is not a complete flux-limited sample due to the non-uniform first year AGILE sky coverage. The catalog includes 47 sources, 21 of which are associated with confirmed or candidate pulsars, 13 with Blazars (7 FSRQ, 4 BL Lacs, 2 unknown type), 2 with HMXRBs, 2 with SNRs, 1 with a colliding-wind binary system, 8 with unidentified sources.Comment: Revised version, 15 pages, 3 figures, 3 tables. To be published in Astronomy and Astrophysics. Text improved and clarified. Refined analysis of complex regions of the Galactic plane yields a new list of high-confidence sources including 47 sources (compared with the 40 sources appearing in the first version

Constraints on the Cosmic-Ray Density Gradient beyond the Solar Circle from Fermi gamma-ray Observations of the Third Galactic Quadrant

We report an analysis of the interstellar $\gamma$-ray emission in the third Galactic quadrant measured by the {Fermi} Large Area Telescope. The window encompassing the Galactic plane from longitude 210\arcdeg to 250\arcdeg has kinematically well-defined segments of the Local and the Perseus arms, suitable to study the cosmic-ray densities across the outer Galaxy. We measure no large gradient with Galactocentric distance of the $\gamma$-ray emissivities per interstellar H atom over the regions sampled in this study. The gradient depends, however, on the optical depth correction applied to derive the \HI\ column densities. No significant variations are found in the interstellar spectra in the outer Galaxy, indicating similar shapes of the cosmic-ray spectrum up to the Perseus arm for particles with GeV to tens of GeV energies. The emissivity as a function of Galactocentric radius does not show a large enhancement in the spiral arms with respect to the interarm region. The measured emissivity gradient is flatter than expectations based on a cosmic-ray propagation model using the radial distribution of supernova remnants and uniform diffusion properties. In this context, observations require a larger halo size and/or a flatter CR source distribution than usually assumed. The molecular mass calibrating ratio, $X_{\rm CO} = N({\rm H_{2}})/W_{\rm CO}$, is found to be $(2.08 \pm 0.11) \times 10^{20} {\rm cm^{-2} (K km s^{-1})^{-1}}$ in the Local-arm clouds and is not significantly sensitive to the choice of \HI\ spin temperature. No significant variations are found for clouds in the interarm region.Comment: Corresponding authors: I. A. Grenier ([email protected]); T. Mizuno ([email protected]); L. Tibaldo ([email protected]) accepted for publication in Ap

Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis

Detection of the Small Magellanic Cloud in gamma-rays with Fermi/LAT

The flux of gamma rays with energies >100MeV is dominated by diffuse emission from CRs illuminating the ISM of our Galaxy through the processes of Bremsstrahlung, pion production and decay, and inverse-Compton scattering. The study of this diffuse emission provides insight into the origin and transport of CRs. We searched for gamma-ray emission from the SMC in order to derive constraints on the CR population and transport in an external system with properties different from the Milky Way. We analysed the first 17 months of continuous all-sky observations by the Large Area Telescope of the Fermi mission to determine the spatial distribution, flux and spectrum of the gamma-ray emission from the SMC. We also used past radio synchrotron observations of the SMC to study the population of CR electrons specifically. We obtained the first detection of the SMC in high-energy gamma rays, with an integrated >100MeV flux of (3.7 +/-0.7) x10e-8 ph/cm2/s, with additional systematic uncertainty of <16%. The emission is steady and from an extended source ~3{\deg} in size. It is not clearly correlated with the distribution of massive stars or neutral gas, nor with known pulsars or SNRs, but a certain correlation with supergiant shells is observed. The observed flux implies an upper limit on the average CR nuclei density in the SMC of ~15% of the value measured locally in the Milky Way. The population of high-energy pulsars of the SMC may account for a substantial fraction of the gamma-ray flux, which would make the inferred CR nuclei density even lower. The average density of CR electrons derived from radio synchrotron observations is consistent with the same reduction factor but the uncertainties are large. From our current knowledge of the SMC, such a low CR density does not seem to be due to a lower rate of CR injection and rather indicates a smaller CR confinement volume characteristic size.Comment: 14 pages, 6 figures, accepted for publication in A&

Fermi LAT Observation of Diffuse Gamma-Rays Produced Through Interactions between Local Interstellar Matter and High Energy Cosmic Rays

Observations by the Large Area Telescope (LAT) on the \textit{Fermi} mission of diffuse $\gamma$-rays in a mid-latitude region in the third quadrant (Galactic longitude $l$ from 200\arcdeg to 260\arcdeg and latitude $| b |$ from 22\arcdeg to 60\arcdeg) are reported. The region contains no known large molecular cloud and most of the atomic hydrogen is within 1 kpc of the solar system. The contributions of $\gamma$-ray point sources and inverse Compton scattering are estimated and subtracted. The residual $\gamma$-ray intensity exhibits a linear correlation with the atomic gas column density in energy from 100 MeV to 10 GeV. The measured integrated $\gamma$-ray emissivity is (1.63 \pm 0.05) \times 10^{-26} {\rm photons s^{-1} sr^{-1} H\mathchar`-atom^{-1}} and (0.66 \pm 0.02) \times 10^{-26} {\rm photons s^{-1} sr^{-1} H\mathchar`-atom^{-1}} above 100 MeV and above 300 MeV, respectively, with additional systematic error of $\sim 10$. The differential emissivity in 100 MeV--10 GeV agrees with calculations based on cosmic ray spectra consistent with those directly measured, at the 10% level. The results obtained indicate that cosmic ray nuclei spectra within 1 kpc from the solar system in regions studied are close to the local interstellar spectra inferred from direct measurements at the Earth within $\sim 10$.Comment: accepted for publication in the Astrophysical Journal. Revised according to the author proof.(correction of typos and minor revisions