Human cachexia induces changes in mitochondria, autophagy and apoptosis in the skeletal muscle

Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients

Sulodexide counteracts endothelial dysfunction induced by metabolic or non-metabolic stresses through activation of the autophagic program

OBJECTIVE: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the “extension therapy” after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal de-oxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used. RESULTS: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited. CONCLUSIONS: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT

Immunometabolism: Molecular mechanisms, diseases, and therapies 2018

Immunometabolism: Molecular mechanisms, diseases, and therapies 201

On a modular property of N=2 superconformal theories in four dimensions

In this note we discuss several properties of the Schur index of N=2 superconformal theories in four dimensions. In particular, we study modular properties of this index under SL(2,Z) transformations of its parameters.Comment: 23 page, 2 figure

Weak Field Black Hole Formation in Asymptotically AdS Spacetimes

We use the AdS/CFT correspondence to study the thermalization of a strongly coupled conformal field theory that is forced out of its vacuum by a source that couples to a marginal operator. The source is taken to be of small amplitude and finite duration, but is otherwise an arbitrary function of time. When the field theory lives on $R^{d-1,1}$, the source sets up a translationally invariant wave in the dual gravitational description. This wave propagates radially inwards in $AdS_{d+1}$ space and collapses to form a black brane. Outside its horizon the bulk spacetime for this collapse process may systematically be constructed in an expansion in the amplitude of the source function, and takes the Vaidya form at leading order in the source amplitude. This solution is dual to a remarkably rapid and intriguingly scale dependent thermalization process in the field theory. When the field theory lives on a sphere the resultant wave either slowly scatters into a thermal gas (dual to a glueball type phase in the boundary theory) or rapidly collapses into a black hole (dual to a plasma type phase in the field theory) depending on the time scale and amplitude of the source function. The transition between these two behaviors is sharp and can be tuned to the Choptuik scaling solution in $R^{d,1}$.Comment: 50 pages + appendices, 6 figures, v2: Minor revisions, references adde

Exploring Curved Superspace

We systematically analyze Riemannian manifolds M that admit rigid supersymmetry, focusing on four-dimensional N=1 theories with a U(1)_R symmetry. We find that M admits a single supercharge, if and only if it is a Hermitian manifold. The supercharge transforms as a scalar on M. We then consider the restrictions imposed by the presence of additional supercharges. Two supercharges of opposite R-charge exist on certain fibrations of a two-torus over a Riemann surface. Upon dimensional reduction, these give rise to an interesting class of supersymmetric geometries in three dimensions. We further show that compact manifolds admitting two supercharges of equal R-charge must be hyperhermitian. Finally, four supercharges imply that M is locally isometric to M_3 x R, where M_3 is a maximally symmetric space.Comment: 39 pages; minor change

Gravitational quasinormal modes of AdS black branes in d spacetime dimensions

The AdS/CFT duality has established a mapping between quantities in the bulk AdS black-hole physics and observables in a boundary finite-temperature field theory. Such a relationship appears to be valid for an arbitrary number of spacetime dimensions, extrapolating the original formulations of Maldacena's correspondence. In the same sense properties like the hydrodynamic behavior of AdS black-hole fluctuations have been proved to be universal. We investigate in this work the complete quasinormal spectra of gravitational perturbations of $d$-dimensional plane-symmetric AdS black holes (black branes). Holographically the frequencies of the quasinormal modes correspond to the poles of two-point correlation functions of the field-theory stress-energy tensor. The important issue of the correct boundary condition to be imposed on the gauge-invariant perturbation fields at the AdS boundary is studied and elucidated in a fully $d$-dimensional context. We obtain the dispersion relations of the first few modes in the low-, intermediate- and high-wavenumber regimes. The sound-wave (shear-mode) behavior of scalar (vector)-type low-frequency quasinormal mode is analytically and numerically confirmed. These results are found employing both a power series method and a direct numerical integration scheme.Comment: added references, typos corrected, minor changes, final version for JHE

Supergravity for Effective Theories

Higher-derivative operators are central elements of any effective field theory. In supersymmetric theories, these operators include terms with derivatives in the K\"ahler potential. We develop a toolkit for coupling such supersymmetric effective field theories to supergravity. We explain how to write the action for minimal supergravity coupled to chiral superfields with arbitrary numbers of derivatives and curvature couplings. We discuss two examples in detail, showing how the component actions agree with the expectations from the linearized description in terms of a Ferrara-Zumino multiplet. In a companion paper, we apply the formalism to the effective theory of inflation.Comment: 26 page

de Sitter Supersymmetry Revisited

We present the basic $\mathcal{N} =1$ superconformal field theories in four-dimensional de Sitter space-time, namely the non-abelian super Yang-Mills theory and the chiral multiplet theory with gauge interactions or cubic superpotential. These theories have eight supercharges and are invariant under the full $SO(4,2)$ group of conformal symmetries, which includes the de Sitter isometry group $SO(4,1)$ as a subgroup. The theories are ghost-free and the anti-commutator $\sum_\alpha\{Q_\alpha, Q^{\alpha\dagger}\}$ is positive. SUSY Ward identities uniquely select the Bunch-Davies vacuum state. This vacuum state is invariant under superconformal transformations, despite the fact that de Sitter space has non-zero Hawking temperature. The $\mathcal{N}=1$ theories are classically invariant under the $SU(2,2|1)$ superconformal group, but this symmetry is broken by radiative corrections. However, no such difficulty is expected in the $\mathcal{N}=4$ theory, which is presented in appendix B.Comment: 21 pages, 2 figure