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Expression of concern for 'Heat-based transdermal delivery of a ramipril loaded cream for treating hypertension' by Anna Voronova et al. , Nanoscale , 2022, 14 , 12247-12256, https://doi.org/10.1039/D2NR02295H.

Background: Cardiac surgery triggers sterile innate immune responses leading to postoperative complications. Clonal hematopoiesis (CH) is associated with short-term inflammation-mediated outcomes after cardiac surgery. The impact of CH on long-term postoperative outcomes remains unknown., Methods and Results: In this cohort study, patients undergoing elective cardiac surgery were included from January 2017 to September 2019. Patients were screened for CH using a predefined gene panel of 19 genes. Recorded clinical events were all-cause death, major adverse cardiac and cerebral events including cardiovascular death, myocardial infarction or nonscheduled coronary revascularization, stroke, and hospitalization for acute heart failure. The primary study outcome was time to a composite criterion including all-cause mortality and major adverse cardiac and cerebral events. Among 314 genotyped patients (median age: 67 years; interquartile range 59-74 years), 139 (44%) presented with CH, based on a variant allelic frequency ≥1%. Carriers of CH had a higher proportion of patients with a history of atrial fibrillation (26% for CH versus 17% for non-CH carriers, P =0.022). The most frequently mutated genes were DNMT3A , TET2 , and ASXL1 . After a median follow-up of 1203 [813-1435] days, the primary outcome occurred in 50 patients. After multivariable adjustment, CH was independently associated with a higher risk for the primary outcome (hazard ratio, 1.88 [95% CI, 1.05-3.41], P =0.035). Most adverse events occurred in patients carrying TET2 variants., Conclusions: In patients undergoing cardiac surgery, CH is frequent and associated with a 2-fold increased long-term risk for major adverse clinical outcomes. CH is a novel risk factor for long-term postcardiac surgery complications and might be useful to personalize management decisions., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03376165.

Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr 455 and Ser 490 and of TEAD4 at Ser 69 and Ser 99 . Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes., (© 2024. The Author(s).)

Background: Severe aortic stenosis (AS) has been associated with bleeding. However, there is a lack of prospective assessment of bleeding events and their clinical significance in a large population of outpatients with variable degree of AS severity., Objectives: To assess the incidence, source, determinants, and prognostic impact of major bleeding in patients with variable degree of AS severity., Methods: Between May 2016 and December 2017, consecutive outpatients were included. Major bleeding was defined as type ≥3 bleed using the Bleeding Academic Research Consortium definition. Cumulative incidence was calculated with death as the competing event. Data was censored at time of aortic valve replacement., Results: Among 2,830 patients, 46 major bleeding events occurred (0.7%/year) during a median follow-up of 2.1 years (interquartile range: 1.4-2.7). Most frequent sites of bleeding were gastrointestinal (50%) and intracranial (30.4%). Major bleeding was significantly associated with all-cause mortality (hazard ratio: 5.93 (95% confidence interval 3.64-9.65); P < .001). AS severity was associated with major bleedings (P = .041). By multivariable analysis, severe AS was an independent determinant of major bleeding (hazard ratio vs mild AS: 3.59 [95% confidence interval 1.56-8.29]; P = .003). The increased risk of bleeding associated with severe AS was significantly exacerbated in patients using oral anticoagulation., Conclusion: In AS patients, major bleeding is rare but a strong independent predictor of death. AS severity is a determinant of bleeding events. Severe AS and oral anticoagulation should be identified as an association at very high risk of major bleeding., Competing Interests: Disclosures None reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype., Objectives: The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery., Methods: Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes., Results: The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64 + CD14 + CD16 - circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium., Conclusions: HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte-derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants from Fédération Française de Cardiologie, Fondation Leducq convention 16CVD01 (“Defining and Targeting Epigenetic Pathways in Monocytes and Macrophages That Contribute to Cardiovascular Disease”), the European Genomic Institute for Diabetes (ANR-10-LABX-0046), Fondation Pour la Recherche Médicale (REFERENCE PROJET EQU202203014650), and Agence Nationale de la Recherche (TOMIS leukocytes: ANR-CE14-0003-01). Dr Staels is a recipient of an Advanced European Research Council Grant (694717). Dr Vicario was supported by the 2018 American Association for Cancer Research–Bristol Myers Squibb Fellowship for Young Investigators in Translational Immuno-Oncology. Work at the Memorial Sloan Kettering Cancer Center (MSKCC) is supported by an MSKCC core grant (P30 CA008748), National Institutes of Health grants 1R01NS115715-01, 1 R01 HL138090-01, and 1 R01 AI130345-01, Basic and Translational Immunology Grants from the Ludwig Center for Cancer Immunotherapy to Dr Geissmann. Dr de Winther is funded by grants from the Netherlands Heart Foundation (CVON: GENIUS2) and the Netherlands Heart Foundation and Spark-Holding (2019B016). Dr Neele is a Dekker fellow of the Netherlands Heart Foundation (2020T029). Dr White is founder and owner of Resphera Biosciences. Dr Geissmann has performed consulting for Third Rock Ventures. Dr Fragkogianni is employed by Tempus Labs. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis., Approach and Results: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F ( APOF ) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo , and reduced hepatocyte VLDL uptake by ~15% in vitro . Transcriptomic analysis of APOF -overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1 , among others., Conclusion: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Since the SARS-CoV-2 pandemic, the potential of exhaled breath (EB) to provide valuable information and insight into the health status of a person has been revisited. Mass spectrometry (MS) has gained increasing attention as a powerful analytical tool for clinical diagnostics of exhaled breath aerosols (EBA) and exhaled breath condensates (EBC) due to its high sensitivity and specificity. Although MS will continue to play an important role in biomarker discovery in EB, its use in clinical setting is rather limited. EB analysis is moving toward online sampling with portable, room temperature operable, and inexpensive point-of-care devices capable of real-time measurements. This transition is happening due to the availability of highly performing biosensors and the use of wearable EB collection tools, mostly in the form of face masks. This feature article will outline the last developments in the field, notably the novel ways of EBA and EBC collection and the analytical aspects of the collected samples. The inherit non-invasive character of the sample collection approach might open new doors for efficient ways for a fast, non-invasive, and better diagnosis., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Current data regarding the impact of diabetes mellitus (DM) on cardiovascular mortality in patients with aortic stenosis (AS) are restricted to severe AS or aortic valve replacement (AVR) trials. We aimed to investigate cardiovascular mortality according to DM across the entire spectrum of outpatients with AS., Methods: Between May 2016 and December 2017, patients with mild (peak aortic velocity=2.5-2.9 m/s), moderate (3-3.9 m/s) and severe (≥4 m/s) AS graded by echocardiography were included during outpatient cardiology visits in the Nord-Pas-de-Calais region in France and followed-up for modes of death between May 2018 and August 2020., Results: Among 2703 patients, 820 (30.3%) had DM, mean age was 76±10.8 years with 46.6% of women and a relatively high prevalence of underlying cardiovascular diseases. There were 200 cardiovascular deaths prior to AVR during the 2.1 years (IQR 1.4-2.7) follow-up period. In adjusted analyses, DM was significantly associated with cardiovascular mortality (HR=1.40, 95% CI 1.04 to 1.89; p=0.029). In mild or moderate AS, the cardiovascular mortality of patients with diabetes was similar to that of patients without diabetes. In severe AS, DM was associated with higher cardiovascular mortality (HR=2.65, 95% CI 1.50 to 4.68; p=0.001). This was almost exclusively related to a higher risk of death from heart failure (HR=2.61, 95% CI 1.15 to 5.92; p=0.022) and sudden death (HR=3.33, 95% CI 1.28 to 8.67; p=0.014)., Conclusion: The effect of DM on cardiovascular mortality varied across AS severity. Despite no association between DM and outcomes in patients with mild/moderate AS, DM was strongly associated with death from heart failure and sudden death in patients with severe AS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS.

Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that BNC2 expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that BNC2 transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFβ and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence, Bnc2 deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis., (© 2022. The Author(s).)

Angiotensin-converting enzyme (ACE) inhibitors play an important role in the development of anti-hypertension approaches, with ramipril being one of the most widely used ACE inhibitor prodrugs orally administered once or twice a day. Due to its low bioavailability, large amounts have to be administered to obtain a therapeutic effect. In this work, we propose a ramipril loaded pharmaceutical formulation in contact with an electrothermal actuator based on a gold nanohole array as an efficient approach to increase the transdermal ramipril flux. Using rats as an in vivo model, the effect on the systolic and diastolic blood pressure is evaluated, showing that under optimized conditions the blood pressure could be regulated. Heat activation resulted in total drug delivery out of a bandage loaded with 1 mg ramipril, revealing a flux of 50.9 ± 2.8 μg cm -2 h -1 . Importantly, heat-based transdermal dispensing allowed efficient and rapid delivery of ramipril in spontaneously hypertensive rats, with its active form (ramiprilat) detected in blood as early as 5 minutes after delivery onset, accompanied by significant decrease in blood pressure.

Background: A number of epidemiological studies have suggested an association between metabolic dysfunction-associated fatty liver disease (MAFLD) and the incidence of atrial fibrillation (AF). However, the pathogenesis leading to AF in the context of MAFLD remains unclear. We therefore aimed at assessing the impact of MAFLD and liver fibrosis status on left atrium (LA) structure and function., Methods: Patients with a Fatty Liver Index (FLI) >60 and the presence of metabolic comorbidities were classified as MAFLD+. In MAFLD+ patients, liver fibrosis severity was defined using the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS), as follows: MAFLD w/o fibrosis (NFS ≦ -1.455), MAFLD w/indeterminate fibrosis (-1.455 < NFS < 0.675), and MAFLD w/fibrosis (NFS ≧ 0.675). In the first cohort of patients undergoing AF ablation, the structural and functional impact on LA of MAFLD was assessed by LA strain analysis and endocardial voltage mapping. Histopathological assessment of atrial fibrosis was performed in the second cohort of patients undergoing cardiac surgery. Finally, the impact of MAFLD on AF recurrence following catheter ablation was assessed., Results: In the AF ablation cohort (NoMAFLD n = 123; MAFLD w/o fibrosis n = 37; MAFLD indeterm. fibrosis n = 75; MAFLD w/severe fibrosis n = 10), MAFLD patients with high risk of F3-F4 liver fibrosis presented more LA low-voltage areas as compared to patients without MAFLD (16.5 [10.25; 28] vs 5.0 [1; 11] low-voltage areas p = 0.0115), impaired LA reservoir function assessed by peak left atrial longitudinal strain (19.7% ± 8% vs 8.9% ± 0.89% p = 0.0268), and increased LA volume (52.9 ± 11.7 vs 43.5 ± 18.0 ml/m 2 p = 0.0168). Accordingly, among the MAFLD patients, those with a high risk of F3-F4 liver fibrosis presented a higher rate of AF recurrence during follow-up (p = 0.0179). In the cardiac surgery cohort (NoMAFLD n = 12; MAFLD w/o fibrosis n = 5; MAFLD w/fibrosis n = 3), an increase in histopathological atrial fibrosis was observed in MAFLD patients with a high risk of F3-F4 liver fibrosis (p = 0.0206 vs NoMAFLD; p = 0.0595 vs MAFLD w/o fibrosis)., Conclusion: In conclusion, we found that liver fibrosis scoring in MAFLD patients is associated with adverse atrial remodeling and AF recurrences following catheter ablation. The impact of the management of MAFLD on LA remodeling and AF ablation outcomes should be assessed in dedicated studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Decoin, Butruille, Defrancq, Robert, Destrait, Coisne, Aghezzaf, Woitrain, Gouda, Schino, Klein, Maboudou, Brigadeau, Klug, Vincentelli, Dombrowicz, Staels, Montaigne and Ninni.)

Sensitive and selective detection of biomarkers in serum in a short time has a significant impact on health. The enormous clinical importance of developing reliable methods and devices for testing serum levels of cardiac troponin I (cTnI), which are directly correlated to acute myocardial infarction (AMI), has spurred an unmatched race among researchers for the development of highly sensitive and cost-effective sensing formats to be able to differentiate patients with early onset of cardiac injury from healthy individuals with a mean cTnI level of 26 pg mL -1 . Electronic- and electrochemical-based detection schemes allow for fast and quantitative detection not otherwise possible at the point of care. Such approaches rely largely on voltammetric and field-effect-based readouts. Here, we systematically investigate electric and electrochemical point-of-care sensors for the detection of cTnI in serum samples by using the same surface receptors, cTnI aptamer-functionalized CVD graphene-coated interdigated gold electrodes. The analytical performances of both sensors are comparable with a limit of detection (LoD) of 5.7 ± 0.6 pg mL -1 (electrochemical) and 3.3 ± 1.2 pg mL -1 (electric). However, both sensors exhibit different equilibrium dissociation constant (K D ) values between the aptamer-linked surface receptor and the cTnI analyte, being 160 pg mL -1 for the electrochemical and about three times lower for the electrical approach with K D  = 51.4 pg mL -1 . This difference is believed to be related to the use of a redox mediator in the electrochemical sensor for readout. The ability of the redox mediator to diffuse from the solution to the surface via the cTnI/aptamer interface is hindered, correlating to higher K D values. In contrast, the electric readout has the advantage of being label-free with a sensing limitation due to ionic strength effects, which can be limited using poly(ethylene) glycol surface ligands., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for studying long-term immunity and vaccine strategies. We quantified IFNγ-secreting T cells reactive against the main viral SARS-CoV-2 antigens using a standardised enzyme-linked immunospot assay (ELISpot)., Methods: Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T-CoV-Spot assay, we assessed T-cell and antibody responses in mild, moderate and severe SARS-CoV-2 patients and in control samples collected before the outbreak., Results: Specific T cells were assessed in 60 consecutive patients (mild, n  = 26; moderate, n  = 10; and severe patients, n  = 24) during their follow-up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in n  = 60 (100%), n  = 56 (93.3%), n  = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T-CoV-Spot assay showed a specificity of 96.7% (95% CI, 88.5-99.6%) and a specificity of 90.3% (75.2-98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti-S1 and anti-RBD serum antibodies., Conclusion: IFNγ T-CoV-Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long-lived memory T-cell response after vaccination. Our study demonstrates that SARS-CoV-2 patients developing a severe disease achieve a higher adaptive immune response., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients., (©2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intra-hepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy., Competing Interests: Competing interests: BS and SF are consultants for Genfit S.A. SF and LV are consultants for Inventiva. All other authors have nothing to declare.

Adipocyte differentiation and function relies on a network of transcription factors, which is disrupted in obesity-associated low grade, chronic inflammation leading to adipose tissue dysfunction. In this context, there is a need for a thorough understanding of the transcriptional regulatory network involved in adipose tissue pathophysiology. Recent advances in the functional annotation of the genome has highlighted the role of non-coding RNAs in cellular differentiation processes in coordination with transcription factors. Using an unbiased genome-wide approach, we identified and characterized a novel long intergenic non-coding RNA (lincRNA) strongly induced during adipocyte differentiation. This lincRNA favors adipocyte differentiation and coactivates the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPARγ) through interaction with the paraspeckle component and hnRNP-like RNA binding protein 14 (RBM14/NCoAA), and was therefore called PPARγ-activator RBM14-associated lncRNA (Paral1). Paral1 expression is restricted to adipocytes and decreased in humans with increasing body mass index. A decreased expression was also observed in diet-induced or genetic mouse models of obesity and this down-regulation was mimicked in vitro by TNF treatment. In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.

Nonalcoholic fatty liver disease prevalence is soaring with the obesity pandemic, but the pathogenic mechanisms leading to the progression toward active nonalcoholic steatohepatitis (NASH) and fibrosis, major causes of liver-related death, are poorly defined. To identify key components during the progression toward NASH and fibrosis, we investigated the liver transcriptome in a human cohort of NASH patients. The transition from histologically proven fatty liver to NASH and fibrosis was characterized by gene expression patterns that successively reflected altered functions in metabolism, inflammation, and epithelial-mesenchymal transition. A meta-analysis combining our and public human transcriptomic datasets with murine models of NASH and fibrosis defined a molecular signature characterizing NASH and fibrosis and evidencing abnormal inflammation and extracellular matrix (ECM) homeostasis. Dermatopontin expression was found increased in fibrosis, and reversal of fibrosis after gastric bypass correlated with decreased dermatopontin expression. Functional studies in mice identified an active role for dermatopontin in collagen deposition and fibrosis. PPARα activation lowered dermatopontin expression through a transrepressive mechanism affecting the Klf6/TGFβ1 pathway. Liver fibrotic histological damages are thus characterized by the deregulated expression of a restricted set of inflammation- and ECM-related genes. Among them, dermatopontin may be a valuable target to reverse the hepatic fibrotic process.

Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation., Objective: To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice., Approach and Results: Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice., Conclusions: These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.