Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.

International audienceNumerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis)

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

Mitochondrial Dysfunction and Diseases (H Jaeschke, Section Editor)International audienceDrug-induced inhibition of mitochondrial fatty acid β-oxidation (mtFAO) is a key mechanism whereby drugs can induce steatosis. The type and severity of this liver lesion is dependent on the residual mtFAO flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure, which can be favored by genetic predispositions. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is by itself a benign lesion. In the long-term, however, macrovacuolar steatosis can progress with some drugs to steatohepatitis. Interestingly, drugs that are more likely to cause steatohepatitis are those impairing the mitochondrial respiratory chain (MRC) activity. Indeed, MRC impairment favors not only hepatic fat accretion but also oxidative stress and lipid peroxidation. Drugs inhibiting mtFAO could be more toxic in obese patients with preexisting nonalcoholic fatty liver disease (NAFLD) since higher mtFAO is a key metabolic adaptation to curb fat accretion during NAFLD

Effect of spatial concentration fluctuations on effective kinetics in diffusion-reaction systems

International audienceThe effect of spatial concentration fluctuations on the reaction of two solutes, A þ B* C, is considered. In the absence of fluctuations, the concentration of solutes decays as Adet ¼ Bdet t 1. Contrary to this, experimental and numerical studies suggest that concentrations decay significantly slower. Existing theory suggests a t d/4 scaling in the asymptotic regime (d is the dimensionality of the problem). Here we study the effect of fluctuations using the classical diffusion-reaction equation with random initial conditions. Initial concentrations of the reactants are treated as correlated random fields.We use the method of moment equations to solve the resulting stochastic diffusion-reaction equation and obtain a solution for the average concentrations that deviates from t 1 to t d/4 behavior at characteristic transition time t . We also derive analytical expressions for t as a function of Damköhler number and the coefficient of variation of the initial concentration

Temporal and spatial scaling of hydraulic response to recharge in fractured aquifers: Insights from a frequency domain analysis

International audienceQuantification of the recharge in fractured aquifers is particularly challenging because of the multiscale heterogeneity and the range of temporal scales involved. Here we investigate the hydraulic response to recharge of a fractured aquifer, using a frequency domain approach. Transfer functions are calculated in a range of temporal scales from 1 day up to a few years, for a fractured crystalline-rock aquifer located in Ploemeur (S Brittany, France), using recharge and groundwater level fluctuations as input and output respectively. The spatial variability of the response to recharge (characteristic response time, amplitude, temporal scaling) is analyzed for 10 wells sampling the different compartments of the aquifer. Some of the transfer functions follow the linear reservoir model behavior. On the contrary, others display a temporal scaling at high frequency that cannot be represented by classic models. Large-scale hydraulic parameters, estimated from the low-frequency response, are compared with those estimated from hydraulic tests at different scales. The variability of transmissivity and storage coefficient tends to decrease with scale, and the average estimates converge toward the highest values at large scale. The small-scale variability of diffusivities, which implies the existence of a range of characteristic temporal scales associated with different pathways, is suggested to be at the origin of the unconventional temporal scaling of the hydraulic response to recharge at high frequenc

Use of Human Cancer Cell Lines Mitochondria to Explore the Mechanisms of BH3 Peptides and ABT-737-Induced Mitochondrial Membrane Permeabilization

Current limitations of chemotherapy include toxicity on healthy tissues and multidrug resistance of malignant cells. A number of recent anti-cancer strategies aim at targeting the mitochondrial apoptotic machinery to induce tumor cell death. In this study, we set up protocols to purify functional mitochondria from various human cell lines to analyze the effect of peptidic and xenobiotic compounds described to harbour either Bcl-2 inhibition properties or toxic effects related to mitochondria. Mitochondrial inner and outer membrane permeabilization were systematically investigated in cancer cell mitochondria versus non-cancerous mitochondria. The truncated (t-) Bid protein, synthetic BH3 peptides from Bim and Bak, and the small molecule ABT-737 induced a tumor-specific and OMP-restricted mitochondrio-toxicity, while compounds like HA-14.1, YC-137, Chelerythrine, Gossypol, TW-37 or EM20-25 did not. We found that ABT-737 can induce the Bax-dependent release of apoptotic proteins (cytochrome c, Smac/Diablo and Omi/HtrA2 but not AIF) from various but not all cancer cell mitochondria. Furthermore, ABT-737 addition to isolated cancer cell mitochondria induced oligomerization of Bax and/or Bak monomers already inserted in the mitochondrial membrane. Finally immunoprecipatations indicated that ABT-737 induces Bax, Bak and Bim desequestration from Bcl-2 and Bcl-xL but not from Mcl-1L. This study investigates for the first time the mechanism of action of ABT-737 as a single agent on isolated cancer cell mitochondria. Hence, this method based on MOMP (mitochondrial outer membrane permeabilization) is an interesting screening tool, tailored for identifying Bcl-2 antagonists with selective toxicity profile against cancer cell mitochondria but devoid of toxicity against healthy mitochondria

An ISOCAM survey through gravitationally lensing galaxy clusters

ISOCAM was used to perform a deep survey through three gravitationally lensing clusters of galaxies. Nearly seventy sq. arcmin were covered over the clusters A370, A2218 and A2390. We present maps and photometry at 6.7 & 14.3 microns, showing a total of 145 mid-IR sources and the associated source counts. The 15 micron counts reach the faintest level yet recorded. All sources have counterparts in the optical or near-IR. Models of the clusters were used to correct for the effects of lensing, which increases the sensitivity of the survey. Seven of fifteen SCUBA sources were detected at 15 microns. Five have redshift between 0.23 & 2.8, with a median of 0.9. The field sources were counted to a lensing-corrected sensitivity of 30 microJy at 15 microns, and 14 microJy at 7 microns. The counts, corrected for completeness, contamination by cluster sources and lensing, confirm and extend findings of an excess by a factor of ten in the 15 micron population with respect to source models with no evolution. Source redshifts are mostly between 0.4 and 1.5. For the counts at 7 microns, integrating from 14 microJy to 460 microJy, we resolve 0.49+/-0.2 nW.m^(-2).sr^(-1) of the infrared background light (IBL) into discrete sources. At 15 microns we include the counts from other ISOCAM surveys to integrate from 30 microJy to 50 mJy, two to three times deeper than unlensed surveys, to resolve 2.7+/-0.62 nW.m^(-2).sr^(-1) of the IBL. These values are 10% and 55%, respectively, of the upper limit to the IBL, derived from photon-photon pair production of the TeV gamma rays from BL-Lac sources on the IBL photons. However, recent detections of TeV gamma rays from the z=0.129 BL Lac H1426+428 suggest that the 15 micron background reported implies substantial absorption of TeV photons from that source.Comment: 35 pages, 17 figures, to appear in Astronomy and Astrophysics, full paper with high-resolution figures available at http://www.iso.vilspa.esa.es/science/pub/2003

PEP: first Herschel probe of dusty galaxy evolution up to z~3

We exploit the deepest existing far-infrared (FIR) data obtained so far by Herschel at 100 and 160 um in the GOODS-N, as part of the PACS Evolutionary Probe (PEP) survey, to derive for the first time the evolution of the rest-frame 60-um, 90-um, and total IR luminosity functions (LFs) of galaxies and AGNs from z=0 to unprecedented high redshifts (z~2-3). The PEP LFs were computed using the 1/Vmax method. The FIR sources were classified by means of a detailed broad- band SED-fitting analysis and spectral characterisation. Based on the best-fit model results, k-correction and total IR (8-1000 um) luminosity were obtained for each source. LFs (monochromatic and total) were then derived for various IR populations separately in different redshift bins and compared to backward evolution model predictions. We detect strong evolution in the LF to at least z~2. Objects with SEDs similar to local spiral galaxies are the major contributors to the star formation density (SFD) at z< 0.3, then, as redshift increases, moderate SF galaxies - most likely containing a low-luminosity AGN - start dominating up to z ~= 1.5. At >1.5 the SFD is dominated by the contributions of starburst galaxies. In agreement with previous findings, the comoving IR LD derived from our data evolves approximately as (1 + z)^(3.8+/-0.3) up to z~1, there being some evidence of flattening up to z~2.Comment: Accepted for publication in the A&A Herschel first results Special Issu

Anomalous transport in disordered fracture networks: Spatial Markov model for dispersion with variable injection modes

We investigate tracer transport on random discrete fracture networks that are characterized by the statistics of the fracture geometry and hydraulic conductivity. While it is well known that tracer transport through fractured media can be anomalous and particle injection modes can have major impact on dispersion, the incorporation of injection modes into effective transport modeling has remained an open issue. The fundamental reason behind this challenge is that-even if the Eulerian fluid velocity is steady-the Lagrangian velocity distribution experienced by tracer particles evolves with time from its initial distribution, which is dictated by the injection mode, to a stationary velocity distribution. We quantify this evolution by a Markov model for particle velocities that are equidistantly sampled along trajectories. This stochastic approach allows for the systematic incorporation of the initial velocity distribution and quantifies the interplay between velocity distribution and spatial and temporal correlation. The proposed spatial Markov model is characterized by the initial velocity distribution, which is determined by the particle injection mode, the stationary Lagrangian velocity distribution, which is derived from the Eulerian velocity distribution, and the spatial velocity correlation length, which is related to the characteristic fracture length. This effective model leads to a time-domain random walk for the evolution of particle positions and velocities, whose joint distribution follows a Boltzmann equation. Finally, we demonstrate that the proposed model can successfully predict anomalous transport through discrete fracture networks with different levels of heterogeneity and arbitrary tracer injection modes. © 2017 Elsevier Ltd.PKK and SL acknowledge a grant (16AWMP- B066761-04) from the AWMP Program funded by the Ministry of Land, Infrastructure and Transport of the Korean government and the support from Future Research Program (2E27030) funded by the Korea Institute of Science and Technology (KIST). PKK and RJ acknowledge a MISTI Global Seed Funds award. MD acknowledges the support of the European Research Council (ERC) through the project MHetScale (617511). TLB acknowledges the support of European Research Council (ERC) through the project Re- activeFronts (648377). RJ acknowledges the support of the US Department of Energy through a DOE Early Career Award (grant DE-SC0009286). The data to reproduce the work can be obtained from the corresponding author.N

Notch ligand activity is modulated by glycosphingolipid membrane composition in Drosophila melanogaster

A specific glycosphingolipid regulates the E3 ubiquitin ligase Mindbomb1, which promotes the ligand endocytosis necessary for Notch activation

A comparison of Eulerian and Lagrangian transport and non-linear reaction algorithms

When laboratory-measured chemical reaction rates are used in simulations at the field-scale, the models typically overpredict the apparent reaction rates. The discrepancy is primarily due to poorer mixing of chemically distinct waters at the larger scale. As a result, realistic field-scale predictions require accurate simulation of the degree of mixing between fluids. The Lagrangian particle-tracking (PT) method is a now-standard way to simulate the transport of conservative or sorbing solutes. The method’s main advantage is the absence of numerical dispersion (and its artificial mixing) when simulating advection. New algorithms allow particles of different species to interact in nonlinear (e.g., bimolecular) reactions. Therefore, the PT methods hold a promise of more accurate field-scale simulation of reactive transport because they eliminate the masking effects of spurious mixing due to advection errors inherent in grid-based methods. A hypothetical field-scale reaction scenario is constructed and run in PT and Eulerian (finite-volume/finite-difference) simulators. Grid-based advection schemes considered here include 1st- to 3rd-order spatially accurate total-variation-diminishing flux-limiting schemes, both of which are widely used in current transport/reaction codes. A homogeneous velocity field in which the Courant number is everywhere unity, so that the chosen Eulerian methods incur no error when simulating advection, shows that both the Eulerian and PT methods can achieve convergence in the L1 (integrated concentration) norm, but neither shows stricter pointwise convergence. In this specific case with a constant dispersion coefficient and bimolecular reaction A+B¿P, the correct total amount of product is 0.221MA0, where MA0 is the original mass of reactant A. When the Courant number drops, the grid-based simulations can show remarkable errors due to spurious over- and under-mixing. In a heterogeneous velocity field (keeping the same constant and isotropic dispersion), the PT simulations show an increased reaction total from 0.221MA0 to 0.372MA0 due to fluid deformation, while the 1st-order Eulerian simulations using ˜ 106 cells (with a classical grid Peclet number ¿x/aL of 10) have total product of 0.53MA0, or approximately twice as much additional reaction due to advection error. The 3rd-order TVD algorithm fares better, with total product of 0.394MA0, or about 1.14 times the increased reaction total. A very strict requirement on grid Peclet numbers for Eulerian simulations will be required for realistic reactions because of their nonlinear nature. We analytically estimate the magnitude of the effect for the end-member cases of very fast and very slow reactions and show that in either case, the mass produced is proportional to View the MathML source where Pe is the Peclet number. Therefore, extra mass is produced according to View the MathML source where the dispersion includes any numerical dispersion error. We test two PT methods, one that kills particles upon reaction and another that decrements a particle’s mass. For the bimolecular reaction studied here, the computational demands of the particle-killing methods are much smaller than, and the particle-number-preserving algorithm are on par with, the fastest Eulerian methods.Peer ReviewedPostprint (author's final draft