241 research outputs found
Mitochondrial ROS cause motor deficits induced by synaptic inactivity:implications for synapse pruning
Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles. We resolved whether: (1) synaptic inactivity increases mitochondrial ROS; and (2) antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bugarotoxin), nerve (α-latrotoxin) targeted neurotoxins or an endogenous pruning cue (SPARC), synaptic inactivity increased mitochondrial ROS in vivo. The manganese porphyrins MnTE-2-PyP5+ and/or MnTnBuOE-2-PyP5+ blocked mitochondrial ROS to significantly reduce neurotoxin and endogenous pruning cue induced motor deficits. Selectively inducing mitochondrial ROSâusing mitochondria-targeted Paraquat (MitoPQ)ârecapitulated synaptic inactivity induced motor deficits; which were significantly reduced by blocking mitochondrial ROS with MnTnBuOE-2-PyP5+. We unveil mitochondrial ROS as synaptic activity sentinels that regulate the phenotypical consequences of forced synaptic inactivity at the NMJ. Our novel results are relevant to pruning because synaptic inactivity is one of its defining features
Supraspinal inactivation of mitochondrial superoxide dismutase is a source of peroxynitrite in the development of morphine antinociceptive tolerance.
Effective treatment of chronic pain with morphine is limited by decreases in the drugâs analgesic action with chronic administration (antinociceptive tolerance). Because opioids are mainstays of pain management, restoring their efficacy has great clinical importance. We have recently reported that formation of peroxynitrite (ONOO(â), PN) in the dorsal horn of the spinal cord plays a critical role in the development of morphine antinociceptive tolerance and have further documented that nitration and enzymatic inactivation of mitochondrial superoxide dismutase (MnSOD) at that site provides a source for this nitroxidative species. We now report for the first time that antinociceptive tolerance is also associated with the inactivation of MnSOD at supraspinal sites. Inactivation of MnSOD led to nitroxidative stress as evidenced by increased levels of products of oxidative DNA damage and activation of the nuclear factor poly (ADP-ribose) polymerase in whole brain homogenates. Co-administration of morphine with potent Mn porphyrin-based peroxynitrite scavengers, (MnTE-2-PyP(5+) and MnTnHex-2-PyP(5+)) (1) restored the enzymatic activity of MnSOD, (2) attenuated PN derived nitroxidative stress, and (3) blocked the development of morphine induced antinociceptive tolerance. The more lipophilic analogue, MnTnHex-2-PyP(5+) was able to cross the blood brain barrier at higher levels than its lipophylic counterpart MnTE-2-PyP(5+) and was about 30 fold more efficacious. Collectively, these data suggest that peroxynitrite mediated enzymatic inactivation of supraspinal MnSOD provides a source of nitroxidative stress, which in turn contributes to central sensitization associated with the development of morphine antinociceptive tolerance. These results support our general contention that PN-targeted therapeutics may have potential as adjuncts to opiates in pain management
The importance of the nucleon-nucleon correlations for the eta alpha S-wave scattering length, and the pi-eta mixing angle in the low-energy eta alpha scattering length model
Using the new set of dd --> eta alpha near threshold experimental data, the
estimate of the importance of the nucleon-nucleon correlations for the eta
alpha S-wave scattering length in the multiple scattering theory is obtained
using the low-energy scattering length model. The contribution turns out to be
much bigger then previously believed. The pi-eta mixing angle is extracted
using the experimental data on the dd --> eta alpha and dd --> pi alpha
processes. The model is dominated by the subthreshold extrapolation recipe for
the eta alpha scattering amplitudes. When the recipe is chosen the model is
completely insensitive to the eta alpha parameters for the subthreshold value
of the eta cm momentum of p_{eta}^2 = -(0.46)^2 fm^{-2}. Provided that the
subthreshold extrapolation recipe is correct, a good estimate of the pi-eta
mixing angle is obtained, if the experimental cross sections for the dd --> pi
alpha reaction at the corresponding deuteron input energy are taken from the
literature.Comment: 8 pages, 2 figure
The nucleon-nucleon interaction
We review the major progress of the past decade concerning our understanding
of the nucleon-nucleon interaction. The focus is on the low-energy region
(below pion production threshold), but a brief outlook towards higher energies
is also given. The items discussed include charge-dependence, the precise value
of the coupling constant, phase shift analysis and high-precision NN
data and potentials. We also address the issue of a proper theory of nuclear
forces. Finally, we summarize the essential open questions that future research
should be devoted to.Comment: 42 pages, 12 figures, iopart.cls style; Topical Review prepared for
J. Phys. G: Nucl. Part. Phy
Level crossing of particle-hole and mesonic modes in eta mesic nuclei
We study eta meson properties in the infinite nuclear matter and in atomic
nuclei with an emphasis on effects of the eta coupling to
N*(1535)--nucleon-hole modes. The N*(1535) resonance, which dominates the
low-energy eta-nucleon scattering, can be seen as a chiral partner of the
nucleon. The change of the chiral mass gap between the N* and the nucleon in a
nuclear medium has an impact on the properties of the eta-nucleus system. If
the N*-nucleon mass gap decreases with a density increase (chiral symmetry
restoration) the calculations show the existence of the resonance state at the
energy about 60 MeV and two bound eta-nucleus states with the binding energies
about -80 MeV. These states can have strong effect on predicted cross sections
of the ^12C (gamma,p) ^11B reaction with eta-meson production.Comment: 22 pages, 12 figure
Redox Proteomic Identification of HNE-Bound Mitochondrial Proteins in Cardiac Tissues Reveals a Systemic Effect on Energy Metabolism After Doxorubicin Treatment
Doxorubicin (DOX), one of the most effective anticancer drugs, is known to generate progressive cardiac damage, which is due, in part, to DOX-induced reactive oxygen species (ROS). The elevated ROS often induce oxidative protein modifications that result in alteration of protein functions. This study demonstrates that the level of proteins adducted by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, is significantly increased in mouse heart mitochondria after DOX treatment. A redox proteomics method involving two-dimensional electrophoresis followed by mass spectrometry and investigation of protein databases identified several HNE-modified mitochondrial proteins, which were verified by HNE-specific immunoprecipitation in cardiac mitochondria from the DOX-treated mice. The majority of the identified proteins are related to mitochondrial energy metabolism. These include proteins in the citric acid cycle and electron transport chain. The enzymatic activities of the HNE-adducted proteins were significantly reduced in DOX-treated mice. Consistent with the decline in the function of the HNE-adducted proteins, the respiratory function of cardiac mitochondria as determined by oxygen consumption rate was also significantly reduced after DOX treatment. Treatment with Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, an SOD mimic, averted the doxorubicin-induced mitochondrial dysfunctions as well as the HNEâprotein adductions. Together, the results demonstrate that free radical-mediated alteration of energy metabolism is an important mechanism mediating DOX-induced cardiac injury, suggesting that metabolic intervention may represent a novel approach to preventing cardiac injury after chemotherapy
Exotic Anti-Decuplet of Baryons: Prediction from Chiral Solitons
We predict an exotic Z^+ baryon (having spin 1/2, isospin 0 and strangeness
+1) with a relatively low mass of about 1530 MeV and total width of less than
15 MeV. It seems that this region of masses has avoided thorough searches in
the past.Comment: Revised version, to appear in Z. fuer Phys. A. The importance of 1/Nc
corrections to antidecuplet widths is demonstrated. 21 pages, 1 LaTeX figur
Electromagnetic Meson Production in the Nucleon Resonance Region
Recent experimental and theoretical advances in investigating electromagnetic
meson production reactions in the nucleon resonance region are reviewed.Comment: 75 pages, 42 figure
Intermediate mass excess of dilepton production in heavy ion collisions at BEVALAC energies
Dielectron mass spectra are examined for various nuclear reactions recently
measured by the DLS collaboration. A detailed description is given of all
dilepton channels included in the transport model UrQMD 1.0, i.e. Dalitz decays
of mesons and of the resonance, direct
decays of vector mesons and bremsstrahlung. The microscopic calculations
reproduce data for light systems fairly well, but tend to underestimate the
data in at high energies and in at low energies. These conventional
sources, however, cannot explain the recently reported enhancement for
nucleus-nucleus collisions in the mass region 0.15 GeV<<0.6 GeV. Chiral
scaling and meson broadening in the medium are investigated as a
source of this mass excess. They also cannot explain the recent DLS data.Comment: 26 pages, 9 figures, references update
- âŠ