Imbalance in lipid metabolism and membrane lipid homeostasis has been observed in numerous diseases including heart failure and cardiotoxicity. Growing evidence links phospholipid alterations ...especially cardiolipins (CLs) to defects in mitochondrial function and energy metabolism in heart failure. We have shown recently that doxorubicin cardiotoxicity is more severe in male than female Wistar rats. We aimed to study whether this sex specificity is linked to differences in cardiac phospholipid profiles.
Adult male and female rats were injected 2 mg/kg doxorubicin weekly for 7 weeks. Cardiac phospholipid molecular species were determined by liquid chromatography coupled with mass spectrometry fragmentation (LC)/MS(n). Sex difference in phosphatidylethanolamine and phosphatidylcholine species containing docosahexaenoic and docosapentaenoic acyl chains was observed, females having more than males. In both sexes, doxorubicin induced an important loss of the main CL(18:2)4, while the level of monolysocardiolipin MLCL(18:2)3 remained stable. However, a severe remodelling appeared in treated rats with the longest CL acyl chains in doxorubicin-treated females, which might compensate for the loss of tetra-linoleoyl CL. The level of oxidized cardiolipin was not particularly increased after doxorubicin treatment. Finally, expression of genes involved in the biosynthesis of fatty acid appeared to be decreased in doxorubicin-treated males.
These results emphasize for the first time the cardiac remodelling in the phospholipid classes after doxorubicin treatment. These observations suggest that doxorubicin has a sex-specific impact on the heart phospholipidome especially on cardiolipin, an essential mitochondrial lipid. Further studies are needed to better understand the roles of lipids in the anthracycline cardiotoxicity and sex differences, but phospholipid cardioprotection seems a valuable new additive therapeutic strategy for anthracycline cardiotoxicity.
Gondwana breakup: Messages from the North Natal Valley Moulin, Maryline; Aslanian, Daniel; Evain, Mikael ...
Terra nova (Oxford, England),
June 2020, 2020-06-00, 20200601, 2020-06, Letnik:
32, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The Natal Valley, offshore Mozambique, is a key area for understanding the evolution of East Gondwana. Within the scope of the integrated multidisciplinary PAMELA project, we present new wide‐angle ...seismic data and interpretations, which considerably alter Geoscience paradigms. These data reveal the presence of a 30‐km‐thick crust that we argue to be of continental nature. This falsifies all the most recent palaeo‐reconstructions of the Gondwana. This 30‐km‐thick continental crust 1,000 m below sea level implies a complex history with probable intrusions of mantle‐derived melts in the lower crust, connected to several occurrences of magmatism, which seems to evidence the crucial role of the lower continental crust in passive margin genesis.
RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 ...activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1−/− cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities (1, 2). To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1−/− cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1−/− cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIPL, and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.
The structure of the North-East equatorial Brazilian margin was investigated during the MAGIC (Margins of brAzil, Ghana and Ivory Coast) seismic wide-angle experiment. This study focuses on the MC5 ...profile, that spans NW-SE 720 km in length, from the São Paulo Double Fracture Zone to the Barreirinhas margin and continental Borborema province. Its main objective is to understand the fundamental processes which lead to the thinning and finally to the breakup of the continental crust in a specific context of a divergent pull-apart system with two strike-slip borders. The experiment was devised to obtain the 2D structure along this profiles from joint pre-stack depth migration of streamer data and travel-time inversion by forward modeling of 43 Ocean Bottom Seismometers and 21 Land Seismic Stations records. Along the MC5 wide-angle transect, 4 major sectors are identified: 1) the São Paulo Double Fracture Zone presenting a 4.5 km thick volcano-sedimentary Basin on top of a 5.5 km thick basement; 2) a volcanic alignment and intermediate domain SE-ward, formed by the 4.5 km thick Basin III; 3) the 7.5 km thick Basin II, and the 5.5 km thick Basin I composing the continental slope and shelf. While all the offshore basement remains about 6 km thick in the deep-sea domains, acoustic velocity evolves from two-layer 4.8–6 km/s and 6.1–6.8 km/s beneath Basin III to two-layer high velocity 6.1–6.8 km/s and 7.2–7.4 km/s beneath Basin II and I, The necking zone, forming the Parnaiba Platform and associated Piaui-Camocim and Ceará Basins, is 50 km wide; 4) the Médio Coreaú and Ceará Central thrust belt, where the un-thinned continental crust thickness reaches 32 km. Finally, a schematic kinematic reconstruction that satisfies these observation is argumented.
•The MAGIC (Margins of brAzil, Ghana and Ivory Coast) wide-angle experiment.•The North-East equatorial Brazilian margin.•A 50 km wide necking zone.•The exhumed lower continental crust.•A trapped piece of African exhumed lower continental crust.
Abstract PGC-1α, a key regulator of energy metabolism, seems to be a relevant therapeutic target to rectify the energy deficit observed in heart failure (HF). Since our previous work has shown ...positive effects of cobalamin (Cb) on PGC-1α cascade, we investigate the protective role of Cb in pressure overload-induced myocardial dysfunction. Mice were fed with normal diet (ND) or with Cb and folate supplemented diet (SD) 3 weeks before and 4 weeks after transverse aortic constriction (TAC). At the end, left ventricle hypertrophy and drop of ejection fraction were significantly lower in SD mice than in ND mice. Alterations in mitochondrial oxidative capacity, fatty acid oxidation and mitochondrial biogenesis transcription cascade were markedly improved by SD. In SD-TAC mice, lower expression level of the acetyltransferase GCN5 and upregulation of the methyltransferase PRMT1 were associated with a lower protein acetylation and a higher protein methylation levels. This was accompanied by a sustained expression of genes involved in mitochondrial biogenesis transcription cascade ( Tfam , Nrf2 , Cox1 and Cox4 ) after TAC in SD mice, suggesting a preserved activation of PGC-1α; this could be at least partly due to corrected acetylation/methylation status of this co-activator. The beneficial effect of the treatment would not be due to an effect of Cb and folate on oxidative stress or on homocysteinemia, which were unchanged by SD. These results showed that Cb and folate could protect the failing heart by preserving energy status through maintenance of mitochondrial biogenesis. It reinforces the concept of a metabolic therapy of HF.
During the SALSA experiment, in 2014, twelve combined wide-angle refraction and coincident multi-channel seismic profiles were acquired in the Jequitinhonha-Almada-Camamu, Jacuípe, and ...Sergipe-Alagoas basins, NE Brazil. Profile SL09 images the Almada-Camamu basin and the São Francisco craton, with 18 four-channel ocean-bottom seismometers and 22 land stations. The datasets were forward modelled and combined with pre-stack depth migration to increase the horizontal resolution of the velocity models.
Our results show that sediment thickness varies between 3.8 km in the oceanward part of the profile, 4.3 km in the Almada basin and 6.5 km in the Camamu basin. Crustal thickness at the north-western edge of the profile is of around 40 km, with velocity gradients indicating a continental origin.
The Camamu basin, which corresponds to the triple junction between the aborted N–S oriented Tucano rift, the SW-NE oriented Jacuipe-Sergipe-Alagoas branch, and the N–S Jequitinhonha-Almada branch, presents two crustal layers: a very thin upper layer, about 1.5 km thick, which increases seawards to 3 km in the Almada basin, and an higher velocity (HV) layer (6.8–7.2 km/s) about 4 km thick. This lower layer gradually disappears in the Almada basin. At the south-eastern edge of the profile, the resolution is lower but the thickness of the crust seems to increase up to 5 km. Deep wide-angle reflections indicate upper mantle stratification.
Crustal organisation and P-wave propagation velocities in the Almada and Camamu basins indicate a transitional crust domain of exhumed continental crust affinity. In the Camamu triple junction and beneath this thin exhumed continental crust, the HV layer may probably reflect intruded materials. No exhumed upper mantle is observed along the entire profile. The easternmost part of the profile may correspond to a proto-oceanic crust. Typical oceanic crust is never imaged along the 260 km-long offshore profile.
•The transitional domain in the Almada and Camamu basins has exhumed continental crust affinity.•The distal basin may correspond to a proto-oceanic domain.•Typical oceanic crust in not imaged on profile SL09.•Necking occurs within 60 km.
Deep Earth dynamics impact so strongly on surface geological processes that we can use sediment palaeo‐markers as a window into the deeper Earth. Derived from climatic and tectonic erosive actions on ...the continents, and related to eustasy, subsidence and isostasy, the sediment in a deep basin is the main recorder of these processes. Nevertheless, defining and quantifying the relative roles of parameters that interact to give the final sedimentary architecture is not a simple task. Using a 3D‐grid of seismic and wide‐angle data, boreholes and numerical stratigraphic modelling, we propose here a quantification of post‐rift vertical movements in the Provençal Basin (West Mediterranean) involving three domains of subsidence: seaward tilting on the platform and the slope and purely vertical subsidence in the deep basin. These domains fit the deeper crustal domains highlighted by previous geophysical data. Post‐break‐up sedimentary markers may therefore be used to identify the initial hinge lines of the rifting phase and the subsidence laws.
Coincident wide-angle and multi-channel seismic data acquired within the scope of the PAMELA Moz3-5 project allow us to reconsider the formation mechanism of East African margins offshore of southern ...Mozambique. This study specifically focuses on the sedimentary and deep-crustal architecture of the Limpopo margin (LM) that fringes the eastern edge of the Mozambique’s Coastal Plain (MCP) and its offshore southern prolongation the North Natal Valley (NNV). It relies primarily on the MZ3 profile that runs obliquely from the northeastern NNV towards the Mozambique basin (MB) with additional inputs from a tectonostratigraphy analysis of industrial onshore–offshore seismic lines and nearby or crossing velocity models from companion studies. Over its entire N–S extension the LM appears segmented into (1) a western domain that shows the progressive eastward crustal thinning and termination of the MCP/NNV continental crust and its overlying pre-Neocomian volcano-sedimentary basement and (2) a central corridor of anomalous crust bounded to the east by the Mozambique fracture zone (MFZ) and the oceanic crust of the MB. A prominent basement high marks the boundary between these two domains. Its development was most probably controlled by a steep and deeply rooted fault, i.e., the Limpopo fault. We infer that strike-slip or slightly transtensional rifting occurred along the LM and was accommodated along this Limpopo fault. At depth we propose that ductile shearing was responsible for the thinning of the continental crust and an oceanward flow of lower crustal material. This process was accompanied by intense magmatism that extruded to form the volcanic basement and gave the corridor its peculiar structure and mixed nature. The whole region remained at a relative high level during the rifting period and a shallow marine environment dominated the pre-Neocomian period during the early phase of continent–ocean interaction. It is only some time after break-up in the MB and the initiation of the MFZ that decoupling occurred between the MCP/NNV and the corridor, allowing for the latter to subside and become covered by deep marine sediments. A scenario for the early evolution and formation of the LM is proposed taking into account both recent kinematic and geological constraints. It implies that no or little change in extensional direction occurred between the intra-continental rifting and subsequent phase of continent–ocean interaction.
Overactivation of the transforming growth factor-β (TGFβ) signaling in Duchenne muscular dystrophy (DMD) is a major hallmark of disease progression, leading to fibrosis and muscle dysfunction. Here, ...we investigated the role of SETDB1 (SET domain, bifurcated 1), a histone lysine methyltransferase involved in muscle differentiation. Our data show that, following TGFβ induction, SETDB1 accumulates in the nuclei of healthy myotubes while being already present in the nuclei of DMD myotubes where TGFβ signaling is constitutively activated. Transcriptomics revealed that depletion of SETDB1 in DMD myotubes leads to down-regulation of TGFβ target genes coding for secreted factors involved in extracellular matrix remodeling and inflammation. Consequently, SETDB1 silencing in DMD myotubes abrogates the deleterious effect of their secretome on myoblast differentiation by impairing myoblast pro-fibrotic response. Our findings indicate that SETDB1 potentiates the TGFβ-driven fibrotic response in DMD muscles, providing an additional axis for therapeutic intervention.
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