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Background Human adipose-derived mesenchymal stem cells (hADSCs) are promising cells that may promote hepatocyte differentiation (Hep-Dif) and improve liver function, but the involvement of Cdc42, a key small RhoGTPase which plays a crucial role in aging, is still not well established. We hypothesized that the inhibition of Cdc42 may rescue the hepatogenic potential of hADSCs derived from aged donors. Methods hADSCs isolated from 61 women of different ages were cultured for evaluation of the proliferation of cells, adherence, apoptosis, immunomodulation, immunophenotyping, multipotency, gene expression, and cell function during Hep-Dif. Inhibition of Cdc42 by ML141 was realized during two phases: initiation (days –2 to 14 (D–2/14)) from undifferentiated to hepatoblast-like cells, or maturation (days 14 to 28 (D14/28)) from undifferentiated to hepatocyte-like cells. Mechanistic insights of the Wnt(s)/MAPK/PI3K/miR-122 pathways were studied. Results Cdc42 activity in undifferentiated hADSCs showed an age-dependent significant increase in Cdc42-GTP correlated to a decrease in Cdc42GAP; the low potentials of cell proliferation, doubling, adherence, and immunomodulatory ability (proinflammatory over anti-inflammatory) contrary to the apoptotic index of the aged group were significantly reversed by ML141. Aged donor cells showed a decreased potential for Hep-Dif which was rescued by ML141 treatment, giving rise to mature and functional hepatocyte-like cells as assessed by hepatic gene expression, cytochrome activity, urea and albumin production, low-density lipoprotein (LDL) uptake, and glycogen storage. ML141-induced Hep-Dif showed an improvement in mesenchymal-epithelial transition, a switch from Wtn-3a/β-catenin to Wnt5a signaling, involvement of PI3K/PKB but not the MAPK (ERK/JNK/p38) pathway, induction of miR-122 expression, reinforcing the exosomes release and the production of albumin, and epigenetic changes. Inhibition of PI3K and miR-122 abolished completely the effects of ML141 indicating that inhibition of Cdc42 promotes the Hep-Dif through a Wnt5a/PI3K/miR-122/HNF4α/albumin/E-cadherin-positive action. The ML141(D–2/14) protocol had more pronounced effects when compared with ML141(D14/28); inhibition of DNA methylation in combination with ML141(D–2/14) showed more efficacy in rescuing the Hep-Dif of aged hADSCs. In addition to Hep-Dif, the multipotency of aged hADSC-treated ML141 was observed by rescuing the adipocyte and neural differentiation by inducing PPARγ/FABP4 and NeuN/O4 but inhibiting Pref-1 and GFAP, respectively. Conclusion ML141 has the potential to reverse the age-related aberrations in aged stem cells and promotes their hepatogenic differentiation. Selective inhibition of Cdc42 could be a potential target of drug therapy for aging and may give new insights on the improvement of Hep-Dif.

Background Chronic heart failure (CHF) is one of the most common causes of mortality in industrialized countries despite regular therapeutic advances. Numerous factors influence mortality in CHF patients, including nutritional status. It is known that malnutrition is a risk factor for mortality, whereas obesity may play a protective role, a phenomenon dubbed the “obesity paradox”. However, the effect of the obesity-malnutrition association on mortality has not been previously studied for CHF. Our aim was to study the effect of nutritional status on overall mortality in CHF patients. Methods This retrospective, multicenter study was based on a French nationwide database (PMSI). We included all CHF patients aged ≥18 years admitted to all public and private hospitals between 2012 and 2016 and performed a survival analysis over 1 to 4 years of follow-up. Results Malnutrition led to a significant decrease in life expectancy in CHF patients when compared with normal nutritional status (aHR=1.16 [1.14-1.18] at one year and aHR=1.04 [1.004-1.08] at four years), obese, and obese-malnutrition groups. In contrast, obesity led to a significant increase in life expectancy compared with normal nutritional status (aHR=0.75 [0.73-0.78] at one year and aHR=0.85 [0.81-0.90] at four years), malnutrition, and obese-malnutrition groups. The mortality rate was similar in patients presenting both malnutrition and obesity and patients with normal nutritional status. Conclusions Our results indicate that the protective effect on mortality observed in obese CHF patients seems to be linked to fat massincrease. Furthermore, malnourished obese and normal nutritional status patients had similar mortality rates. Further studies should be conducted to confirm our results and to explore the physiopathological mechanisms behind these effects.

The nutritional sequelae of COVID-19 have not been explored in a large cohort study.ObjectivesTo identify factors associated with the change in nutritional status between discharge and 30 days post-discharge (D30). Secondary objectives were to determine the prevalence of subjective functional loss and severe disability at D30 and their associated factors.MethodsCollected data included symptoms, nutritional status, self-evaluation of food intake, Performance Status (PS) Scale, Asthenia Scale, self-evaluation of strength (SES) for arms and legs at discharge and at D30. An SES <7 was used to determine subjective functional loss. A composite criteria for severe disability was elaborated combining malnutrition, subjective functional loss and PS >2. Patients were classified into three groups according to change in nutritional status between discharge and D30 (persistent malnutrition, correction of malnutrition and the absence of malnutrition).ResultsOf 549 consecutive patients hospitalised for COVID-19 between 1 March and 29 April 2020, 130 died including 17 after discharge (23.7%). At D30, 312 patients were at home, 288 (92.3%) of whom were interviewed. Of the latter, 33.3% were malnourished at discharge and still malnourished at D30, while 23.2% were malnourished at discharge but no longer malnourished at D30. The highest predictive factors of persistent malnutrition were intensive care unit (ICU) stay (OR=3.42, 95% CI: 2.04 to 5.75), subjective functional loss at discharge (OR=3.26, 95% CI: 1.75 to 6.08) and male sex (OR=2.39, 95% CI: 1.44 to 3.97). Subjective functional loss at discharge (76.8%) was the main predictive factor of subjective functional loss at D30 (26.3%) (OR=32.6, 95% CI: 4.36 to 244.0). Lastly, 8.3% had a severe disability, with a higher risk in patients requiring an ICU stay (OR=3.39, 95% CI: 1.43 to 8.06).ConclusionPatients who survived a severe form of COVID-19 had a high risk of persistent malnutrition, functional loss and severe disability at D30. We believe that nutritional support and rehabilitation should be strengthened, particularly for male patients who were admitted in ICU and had subjective functional loss at discharge.Trial registration numberNCT04451694.

IntroductionThe objectives were to evaluate bone fragility on computed tomography (CT) in patients with obesity before and 2 years after bariatric surgery and to identify risk factors for a decrease in the scanographic bone attenuation coefficient of the first lumbar vertebra (SBAC-L1).Materials and MethodsPatients with obesity who underwent bariatric surgery and CT before and 2 years (± 6 months) after bariatric surgery were included. SBAC-L1 was measured on CT with a fracture threshold at 145 HU.Results78 patients were included, 85.9% women, mean age of 48.5 years (± 11.4); the mean BMI was 46.2 kg/m2 (± 7) before surgery and 29.8 kg/m2 (± 6.7) 2 years after surgery. There was a significant change in SBAC-L1 2 years after surgery (p = 0.037). In multivariate analysis, the risk factors for having an SBAC-L1 ≤ 145HU 2 years after bariatric surgery in those with an SBAC-L1 > 145HU before surgery were age and sex, with men and older patients having a higher risk (OR 32.6, CI 95% [1.86–568.77], and OR 0.85, CI 95% [0.74–0.98], respectively).ConclusionSBAC-L1 was significantly lower two years after bariatric surgery. Men sex and older patients were the risk factors for having an SBAC-L1 below the fracture threshold 2 years after surgery.

Sterol response element binding protein (SREBP) is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM) were related to peroxisome proliferator-activated receptor-γ (PPARγ), which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARγ/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths) or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK) but not JNK or p38 mitogen-activated protein kinase (MAPK). Ras/Raf-1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down-regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM-unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1-propanol (PPMP), where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM-enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARγ, reversed the effects of SM on SREBP-1, PPARγ and CREB. Taken together, these findings provide novel insights indicating that excess membrane SM might be critical for regulating SREBPs in adipocytes via a MAPK-dependent pathway.

BackgroundData about incidence and severity of reoperations up to 6 months after bariatric surgery are currently limited. The aim of this cohort study was to evaluate the incidence and severity of reoperations after initial bariatric surgical procedures and to compare this between the 3 most frequent current surgical procedures (sleeve, gastric bypass, gastric banding).Study DesignNationwide observational cohort study using data from French Hospital Information System (2013–2015) to evaluate incidence and severity of reoperations within 6 months after bariatric surgery. Hazard ratios (HR) of longitudinal comparison between historical propensity-matched cohorts were estimated from a Fine and Gray’s model using competing risk of death.ResultsCumulative reoperation rates increased from postoperative day-30 to day-180. Consequently, 31.1 to 90.0% of procedures would have been missed if the reoperation rate was based solely on a 30-day follow-up. Reoperation rate at 6 months was significantly higher after gastric bypass than after sleeve (HR 0.64; IC 95% [0.53–0.77]) and corresponded to moderate-risk reoperations (HR 0.65; IC 95% [0.53–0.78]). Reoperation rate at 6 months was significantly higher after gastric banding than after sleeve (HR 0.08; IC 95% [0.07–0.09]) and corresponded to moderate-risk reoperations (HR 0.08; IC 95% [0.07–0.10]).ConclusionCumulative incidence of reoperations increased from 30 days to 6 months after sleeve, gastric bypass, or gastric banding and corresponded to moderate-risk surgical procedures. Consequently, 30-day reoperation rate should no longer be considered when evaluating complications and surgical performance after bariatric surgery.

The aspartic protease cathepsin-D (cath-D) is overexpressed by human epithelial breast cancer cells and is closely correlated with poor prognosis in breast cancer. The adipocyte is one of the most prominent cell types in the tumor-microenvironment of breast cancer, and clinical studies have shown that obesity increases the incidence of breast cancer. Here, we provide the first evidence that cath-D expression is up-regulated in adipose tissue from obese human beings, as well as in adipocytes from the obese C57BI6/J mouse. Cath-D expression is also increased during human and mouse adipocyte differentiation. We show that cath-D silencing in 3T3-F442A murine preadipocytes leads to lipid-depleted cells after adipogenesis induction, and inhibits of the expression of PPARγ, HSL and aP2 adipocyte differentiation markers. Altogether, our findings demonstrate the key role of cath-D in the control of adipogenesis, and suggest that cath-D may be a novel target in obesity.

The cell surface low-density lipoprotein receptor-related protein 1, LRP1, plays a major role in lipid metabolism. The question that remains open concerns the function of LRP1 in adipogenesis. Here, we show that LRP1 is highly expressed in murine preadipocytes as well as in primary culture of human adipocytes. Moreover, LRP1 remains abundantly synthesised during mouse and human adipocyte differentiation. We demonstrate that LRP1 silencing in 3T3F442A murine preadipocytes significantly inhibits the expression of PPARgamma, HSL and aP2 adipocyte differentiation markers after adipogenesis induction, and leads to lipid-depleted cells. We further show that the absence of lipids in LRP1-silenced preadipocytes is not caused by lipolysis induction. In addition, we provide the first evidences that LRP1 is significantly up-regulated in obese C57BI6/J mouse adipocytes and obese human adipose tissues. Interestingly, silencing of LRP1 in fully-differentiated adipocytes also reduces cellular lipid level and is associated with an increase of basal lipolysis. However, the ability of mature adipocytes to induce lipolysis is independent of LRP1 expression. Altogether, our findings highlight the dual role of LRP1 in the control of adipogenesis and lipid homeostasis, and suggest that LRP1 may be an important therapeutic target in obesity.

Background The subcellular distribution of prorenin receptor and adaptor protein ATP6AP2 may affect neurogenesis. In this study, we hypothesized that ATP6AP2 expression and subcellular relocalization from caveolae/lipid raft microdomains (CLR-Ms) to intracellular sites may correlate with neuronal differentiation (Neu- Dif ) of adipose-derived mesenchymal stem cells (ADSCs). Methods Human ADSCs isolated from 24 healthy donors and 24 patients with neurological disorders (ND) were cultured and induced for Neu- Dif . The mechanism of action of ATP6AP2 and the impact of its localization within the plasma membrane (particularly CLR-Ms) and intracellular sites on several pathways (mitogen-activated protein kinase, Wnt(s) signaling and others) and intracellular calcium and exosome release were evaluated. The impact of CLR-Ms on ATP6AP2 or vice versa was determined by pharmacological disruption of CLR-Ms or siATP6AP2 assays. Results In patients with ND, loss of ATP6AP2 from CLR-Ms correlated with an inhibition of Neu- Dif and signaling. However, its relocalization in CLR-Ms was positively correlated to induction of Neu- Dif in healthy subjects . An apparent switch from canonical to noncanonical Wnt signaling as well as from caveolin to flotillin occurs concurrently with the increases of ATP6AP2 expression during neurogenesis. Stimulation by renin activates ERK/JNK/CREB/c-Jun but failed to induce β-catenin. Wnt5a enhanced the renin-induced JNK responsiveness. Gα proteins crosslink ATP6AP2 to caveolin where a switch from Gαi to Gαq is necessary for Neu- Dif . In ATP6AP2-enriched CLR-Ms, the release of exosomes was induced dependently from the intracellular Ca 2+ and Gαq. Pharmacological disruption of CLR-M formation/stability impairs both ATP6AP2 localization and Neu- Dif in addition to reducing exosome release, indicating an essential role of ATP6AP2 enrichment in CLR-Ms for the induction of Neu- Dif . The mechanism is dependent on CLR-M dynamics, particularly the membrane fluidity. Knockdown of ATP6AP2 inhibited Neu- Dif but increased astrocytic- Dif , depleted ATP6AP2/flotillin/Gαq but accumulated caveolin/Gαi in CLR-Ms, and blocked the activation of JNK/ERK/c-Jun/CREB/exosome release. siATP6AP2 cells treated with sphingomyelinase/methyl-β-cyclodextrin reversed the levels of caveolin/flotillin in CLR-Ms but did not induce Neu- Dif , indicating the crucial relocalization of ATP6AP2 in CLR-Ms for neurogenesis. Treatment of ND-derived cells with nSMase showed reversibility in ATP6AP2 abundance in CLR-Ms and enhanced Neu- Dif. Conclusions This study gives evidence of the determinant role of CLR-M ATP6AP2 localization for neuronal and oligodendrocyte differentiation involving mechanisms of switches from Gαi/caveolin/canonical to Gαq/flotillin/PCP, the ERK/JNK pathway and Ca 2+ -dependent release of exosomes and as a potential target of drug therapy for neurodegenerative disorders.