ORCID Profile
0000-0001-6539-5435
Current Organisations
Université Claude Bernard Lyon 1
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INSERM
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Laboratoire CarMeN
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Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.BBAMCR.2009.04.001
Abstract: Endothelial permeability is controlled by adhesive strengths which connect cells to each other through interendothelial junctions and by contractile forces associated with cytoskeleton reorganization. Phospholipase D (PLD) activation resulting in the generation of phosphatidic acid (PA) is increasingly recognized as a key event in the initiation of various cell responses. In human umbilical vein endothelial cells (HUV-EC), enhancement of intracellular PA by a variety of approaches increased the permeability of endothelial cell monolayers and induced stress fibre formation. Using adenovirus-mediated overexpression and siRNA silencing, we showed that PLD2 but not PLD1 was involved in the enhancement of basal permeability through cytoskeleton reorganization. Furthermore, PLD2 overexpression induced ERK1/2 activation and downregulated the expression of occludin, a major component of tight junctions. A substantial part of PLD2 protein was associated with the low-density caveolin-rich fractions isolated on sucrose gradients. The Raf-1 specific inhibitor GW-5074 drastically reduced hyperpermeability induced by PLD2 overexpression, and inhibited PA-mediated increase of endothelial permeability and ERK1/2 activation. On the whole, the present results demonstrate the selective role of PLD2 isoform in the control of endothelial permeability through a mechanism involving both stress fibre formation and contraction, and occludin downregulation, possibly resulting from PA-mediated activation of Raf-1.
Publisher: Wiley
Date: 29-06-2016
DOI: 10.1002/BIOF.1306
Abstract: Rather than being a passive barrier between circulating blood and smooth muscle cells and the underlying tissues, the endothelium is a fundamental functional component of the vasculature, and could be viewed as the largest human endocrine gland/organ, secreting multiple pro-/antiangiogenic factors, cytokines and low-molecular-weight mediators controlling the vascular tone. The location of endothelium, at the interface between the circulation and the tissues, makes this epithelial layer particularly exposed to physical and chemical cues coming from the bloodstream. In response to such stimuli, the endothelium modulates its morphology and functions to maintain vascular homeostasis. Dietary components significantly affect the proper functioning of the endothelium. High-calories and high-fat western diets, in the long term, cause endothelial dysfunction, which is a major contributor to the development of the metabolic syndrome and its pathological consequences, including atherosclerosis, diabetes, and hypertension. On the contrary, plant-derived antioxidant molecules and polyphenols have been shown to exert beneficial effects on endothelial function. Extensive research in the last decade has clearly shown the close relationship between food intake, dietary habits, and gene expression, which is driven by the action of macro- and micronutrients on chromatin regulation. Nutrient-induced chromatin epigenetic modifications via DNA methylation and histone post-translational modifications, especially in the context of the western diet, significantly contribute to the dysregulation of endothelial functioning. Here, we review the current understanding on how dietary components (macronutrients, antioxidants), acting on epigenetic mechanisms, regulate endothelial physiology, and physiopathology. © 2016 BioFactors, 43(1):5-16, 2017.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.JNUTBIO.2016.12.002
Abstract: Skeletal muscle is a plastic tissue during development with distinctive acute and chronic response to maternal protein restriction. This study evaluated gene and protein expression of key-enzymes of glycolytic pathway (HK2, PFK, PDK4 and CS), and fatty acid oxidation (CPT1 and β-HAD) of two different types of skeletal muscle [soleus and extensor digitorium longus (EDL)] from offspring rats at 30 and 90 days of age, exposed to maternal isoenergetic low protein diet throughout gestation and lactation. Pups from dams fed 17% protein diet (n=5, normal protein, Np), and low protein pups from dams fed 8% casein diet (low protein, Lp, n=5) were evaluated. Offspring were sacrificed either 30 or 90 days old. Soleus and EDL were analyzed for mRNA and protein expression by quantitative PCR and western blotting, respectively. Soleus was more affected by Lp maternal diet at 90 days by down-regulation of key enzymes of glycolytic pathway, in particular HK2 and PDK4 with a concomitant reduction of β-HAD mRNA. For EDL, the effects of Lp maternal diet were more pronounced at 30 days, as the transcriptional key enzymes of glycolytic pathway were down-regulated. One important finding was that the observed acute (30 days) transcriptional changes did not remain in adult Lp rats (90 days), except for PDK4. The robust PDK4 mRNA down-regulation, observed in both soleus and EDL, and at both ages, and the consequent down-regulation of the PDK4 protein expression can be responsible for a state of reduced metabolic flexibility of skeletal muscle in response to maternal low protein diet.
Publisher: Wiley
Date: 09-2010
DOI: 10.1002/BIOF.128
Publisher: Wiley
Date: 11-2000
DOI: 10.1096/FJ.00-0162
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0005-2760(98)00139-8
Abstract: Phosphoinositide kinases (PI3Ks) play an important role in mitogenic signaling and cell survival, cytoskeletal remodeling, metabolic control and vesicular trafficking. Here we summarize the structure-function relationships delineating the activation process of class I PI3Ks involving various domains of adapter subunits, Ras, and interacting proteins. The resulting product, PtdIns(3,4,5)P3, targets Akt rotein kinase B (PKB), Bruton's tyrosine kinase (Btk), phosphoinositide-dependent kinases (PDK), integrin-linked kinase (ILK), atypical protein kinases C (PKC), phospholipase Cgamma and more. Surface receptor-activated PI3Ks function in mammals, insects, nematodes and slime mold, but not yeast. While many members of the class II family have been identified and characterized biochemically, it is presently unknown how these C2-domain containing PI3Ks are activated, and which PI substrate they phosphorylate in vivo. PtdIns 3-P is produced by Vps34p/class III PI3Ks and operates via the PtdIns 3-P-binding proteins early endosomal antigen (EEA1), yeast Vac1p, Vps27p, Pip1p in lysosomal protein targeting. Besides the production of D3 phosphorylated lipids, PI3Ks have an intrinsic protein kinase activity. For trimeric GTP-binding protein-activated PI3Kgamma, protein kinase activity seems to be sufficient to trigger mitogen-activated protein kinase (MAPK). Recent disruption of PI3K genes in slime mold, Caenorhabditis elegans, Drosophila melanogaster and mice further underlines the importance of PI3K signaling systems and elucidates the role of PI3K signaling in multicellular organisms.
Publisher: Wiley
Date: 04-11-2004
DOI: 10.1016/J.FEBSLET.2004.10.066
Abstract: We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP-activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that this cycle requires both PI3K and AMPK signaling. This substrate cycling linking glucose and lipid metabolism to thermogenesis provides a novel thermogenic mechanism by which leptin protects skeletal muscle from excessive fat storage and lipotoxicity.
Publisher: Elsevier BV
Date: 06-2001
Publisher: Wiley
Date: 17-04-2008
DOI: 10.1002/IUB.47
Abstract: Resveratrol is one of the numerous polyphenolic compounds found in several vegetal sources. In recent years, the interest in this molecule has increased exponentially following the major findings that resveratrol (i) is shown to be chemopreventive in some cancer models, (ii) is cardioprotective, and (iii) has positive effects on several aspects of metabolism, leading to increased lifespan in all the metazoan models tested thus far, including small mammals. Such remarkable properties have elicited a vast interest towards the identification of target proteins of resveratrol and have led to the identification of enzymes inhibited by resveratrol and others whose activation is enhanced. In the vast majority of cases, resveratrol displays inhibitory/activatory effects in the micromolar range, which is potentially attainable pharmacologically, although targets with affinities in the nanomolar range have also been reported. Here, we provide an overview of the various classes of enzymes known to be inhibited (or activated) by resveratrol. It appears that resveratrol, as a pharmacological agent, has a wide spectrum of targets. The biological activities of resveratrol may thus be dependent on its simultaneous activity on multiple molecular targets.
Publisher: Cold Spring Harbor Laboratory
Date: 02-09-2011
Abstract: Emerging evidence suggests that poor glycemic control mediates post-translational modifications to the H3 histone tail. We are only beginning to understand the dynamic role of some of the erse epigenetic changes mediated by hyperglycemia at single loci, yet elevated glucose levels are thought to regulate genome-wide changes, and this still remains poorly understood. In this article we describe genome-wide histone H3K9/K14 hyperacetylation and DNA methylation maps conferred by hyperglycemia in primary human vascular cells. Chromatin immunoprecipitation (ChIP) as well as CpG methylation (CpG) assays, followed by massive parallel sequencing (ChIP-seq and CpG-seq) identified unique hyperacetylation and CpG methylation signatures with proximal and distal patterns of regionalization associative with gene expression. Ingenuity knowledge-based pathway and gene ontology analyses indicate that hyperglycemia significantly affects human vascular chromatin with the transcriptional up-regulation of genes involved in metabolic and cardiovascular disease. We have generated the first installment of a reference collection of hyperglycemia-induced chromatin modifications using robust and reproducible platforms that allow parallel sequencing-by-synthesis of immunopurified content. We uncover that hyperglycemia-mediated induction of genes and pathways associated with endothelial dysfunction occur through modulation of acetylated H3K9/K14 inversely correlated with methyl-CpG content.
Publisher: Portland Press Ltd.
Date: 08-1999
DOI: 10.1042/BST0270629
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.BCP.2016.09.013
Abstract: Posttranslational modifications of histone tails can alter chromatin structure and regulate gene transcription. While recent studies implicate the lysine/arginine protein methyltransferases in the regulation of genes for endothelial metabolism, the role of AMI-1 and AMI-5 compounds in angiogenesis remains unknown. Here, we show that global inhibition of arginine and lysine histone methyltransferases (HMTs) by AMI-5 induced an angiostatic profile in human microvascular endothelial cells and human umbilical vein endothelial cells. Based on FACS analysis, we found that inhibition of HMTs significantly affects proliferation of endothelial cells, by suppressing cell cycle progression in the G
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.PHRS.2017.10.014
Abstract: Epigenetic mechanisms, including histone post-translational modifications, are central regulators of cell cycle control. The euchromatic G9a histone methyltransferase (G9a HMT) is a key enzyme catalyzing histone H3 methylation on lysines 9 and 27, and its dysregulation has been linked to uncontrolled proliferation of tumor cells. Here, we have investigated the effect of G9a HMT silencing on cell proliferation of microvascular endothelial cells, a process necessary to sustain tumor growth through the formation of the vascular capillary network. Inhibition of G9a HMT activity in human microvascular endothelial cells (HMEC-1) was performed either pharmacologically, by treatment of cells with BIX-01294 or chaetocin, or transcriptionally, using shRNA. Cell viability and proliferation were examined using the resazurin reduction assay, flow cytometry and immunostaining of phosphorylated checkpoint kinase 1 (pSer317Chk1). Expression of cell cycle- and redox homeostasis-related genes was determined by quantitative PCR. Reactive oxygen species production was measured by oxidation of the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate and the cell's total antioxidant capacity by using the ABTS assay. Inhibition of G9a HMT activity by BIX-01294 treatment or by shRNA attenuated the proliferation of HMEC-1, nuclear localization of phosphorylated Chk1, and induced cell cycle arrest in G1 phase. Transcriptional analysis demonstrated increased gene expression of the cyclin-dependent kinase (CDK) inhibitor p21, and also of Rb1, in BIX-01294 treated cells. Decreased proliferation rate was accompanied by enhanced antioxidant potential of HMEC-1 cells, as demonstrated by reduced production of reactive oxygen species, increased total antioxidant capacity and expression of the antioxidant enzymes catalase and superoxide dismutase 1. Collectively, our results demonstrate of the central role of G9a HMT in the promotion of endothelial cells proliferation, and suggest that endothelial G9a HMT may be a target in the treatment of vascular proliferative disorders and tumor neovascularization.
Publisher: Baishideng Publishing Group Inc.
Date: 2015
Publisher: EDP Sciences
Date: 2016
Publisher: EDP Sciences
Date: 2016
Publisher: Elsevier BV
Date: 02-2004
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.MCE.2011.01.008
Abstract: The protein deacetylase SIRT1, and its activator resveratrol, exert beneficial effects on glucose metabolism. Different SIRT1 targets have been identified, including PTP1B, AMPK, FOXO, PGC-1α and IRS2. The latter may underscore a tight link between SIRT1 and insulin signaling components. However, whether SIRT1 has a direct effect on insulin resistance and whether resveratrol acts directly or indirectly in this context is still a matter of controversy and this question has not been addressed in muscle cells. Here, we show that SIRT1 protein expression is decreased in muscle biopsies and primary myotubes derived from type 2 diabetic patients, suggesting a contribution of diminished SIRT1 in the determination of muscle insulin resistance. To investigate the functional impact of SIRT1 on the insulin pathway, the activation of insulin downstream effector PKB was evaluated after SIRT1 inactivation by RNAi, SIRT1 overexpression, or resveratrol treatments. In muscle cells and HEK293 cells, downregulation of SIRT1 reduced, while overexpression increased, insulin-induced PKB activatory phosphorylation. Further molecular characterisation revealed that SIRT1 interacts in an insulin-independent manner with the PI3K adapter subunit p85. We then investigated whether resveratrol may improve insulin signaling in muscle cells via SIRT1, or alternative targets. Incubation of muscle cells with resveratrol reverted the insulin-resistant state induced by prolonged TNFα or insulin treatment. Resveratrol-dependent improvement of insulin-resistance occurred through inhibition of serine phosphorylation of IRS1/2, implicating resveratrol as a serine kinase inhibitor. Finally, a functional interaction between PI3K and SIRT1 was demonstrated in C. elegans, where constitutively active PI3K - mimicking increased IIS signaling - lead to shortened lifespan, while removal of sir-2.1 abolished PI3K-induced lifespan shortening. Our data identify SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K, and this mechanism appears to be conserved from C. elegans through humans.
Publisher: Elsevier BV
Date: 02-2004
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/583901
Publisher: Informa UK Limited
Date: 25-01-2016
Publisher: Springer Science and Business Media LLC
Date: 25-06-2014
DOI: 10.1038/NATURE13387
Abstract: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.BBADIS.2008.10.019
Abstract: A generally accepted view posits that insulin resistant condition in type 2 diabetes is caused by defects at one or several levels of the insulin-signaling cascade in skeletal muscles, adipose tissue and liver, that quantitatively constitute the bulk of the insulin-responsive tissues. Hence, the gradual uncovering of the biochemical events defining the intracellular signaling of insulin has been quickly followed by clinical studies on humans attempting to define the molecular defect(s) responsible for the establishment of the insulin resistant state. While the existence of molecular defects within the insulin signal transduction machinery is undisputed, contrasting data exist on what is the principal molecular alteration leading to insulin resistance. Such discrepancies in the literature may depend on: 1) different subject characteristics, 2) methodological differences 3) small cohorts of subjects, and - not least - 4) intrinsic limitations in studying every detail of the insulin signaling cascade. Here, we review the studies on humans exploring the defects of the insulin signaling cascade generated by insulin resistance and type 2 diabetes, focusing on muscle and adipose tissue - which account for most of the glucose disposal capacity of the body - with focus on the unresolved discrepancies present in the literature.
Publisher: Elsevier BV
Date: 06-2011
Publisher: MDPI AG
Date: 09-04-2020
DOI: 10.3390/IJMS21072606
Abstract: Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.MCE.2012.05.011
Abstract: Lysine acetylation is a protein post-translational modification (PTM) initially discovered in abundant proteins such as tubulin, whose acetylated form confers microtubule stability, and histones, where it promotes the transcriptionally active chromatin state. Other in idual reports identified lysine acetylation as a PTM regulating transcription factors and co-activators including p53, c-Myc, PGC1α and Ku70. The subsequent employment of proteomics-based approaches revealed that lysine acetylation is a widespread PTM, contributing to cellular regulation as much as protein-phosphorylation based mechanisms. In particular, most of the enzymes of central metabolic processes - glycolysis, tricarboxylic acid and urea cycles, fatty acid and glycogen metabolism - have been shown to be regulated by lysine acetylation, through the opposite actions of protein acetyltransferases and deacetylases, making protein acetylation a PTM that connects the cell's energetic state and its consequent metabolic response. In multicellular organisms, insulin/insulin-like signalling (IIS) is a major hormonal regulator of metabolism and cell growth, and very recent research indicates that most of the enzymes participating in IIS are likewise subjected to acetylation-based regulatory mechanisms, that integrate the classical phosphorylation mechanisms. Here, we review the current knowledge on acetylation/deacetylation regulatory phenomena within the IIS cascade, with emphasis on the enzymatic machinery linking the acetylation/deacetylation switch to the metabolic state. We cover this recent area of investigation because pharmacological modulation of protein acetylation/deacetylation has been shown to be a promising target for the amelioration of the metabolic abnormalities occurring in the metabolic syndrome.
Publisher: American Diabetes Association
Date: 12-03-2015
DOI: 10.2337/DB15-0162
Abstract: Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. While infiltration of adipose tissue (AT) with mononuclear cells (MNCs) is well established in obesity, the functional consequences of these interactions are less understood. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese in iduals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited γ-interferon and tumor necrosis factor α secretion by Th1 cells, and 3) increased monocyte-mediated IL-1β secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean in iduals. Th17 polarization mostly depended on physical contacts between ASCs and MNCs—with a contribution of intracellular adhesion molecule-1—and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. ASCs favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL-17A/F gene locus. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a novel proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.
Publisher: American Diabetes Association
Date: 12-04-2014
DOI: 10.2337/DB14-0238
Publisher: Springer Science and Business Media LLC
Date: 13-10-2017
Publisher: Informa UK Limited
Date: 04-1996
Abstract: Almond [
Publisher: Canadian Science Publishing
Date: 02-2014
Abstract: Besides its direct metabolic effects, insulin induces transcriptional alterations in its target tissues. However, whether such changes are accompanied by epigenetic changes on the chromatin template encompassing insulin responsive genes is unclear. Here, mRNA levels of insulin-responsive genes hexokinase 2 (Hk2), insulin receptor substrate (Irs2), and the PI3K subunit p85β (Pik3r2) were compared in control versus insulin-stimulated L6 myotubes. Chromatin immunoprecipitation (ChIP) was performed with antibodies directed to histone H2A, histone variant H2A.Z, acetylated histone H3 on lysines 9/14, and acetylated H2A.Z. Insulin induced a more than 2-fold Hk2 mRNA increase, while Irs2 and Pik3r2 were downregulated. ChIP to H2A and H2A.Z showed higher H2A.Z accumulation around the transcriptional start site (TSS) of these insulin-modulated genes, while H2A.Z accumulation was lower distally to the TSS in the Hk2 promoter. H2A.Z levels and H3K9/14 acetylation correlated on several loci along the Hk2 gene, and H3K9/14 as well as H2A.Z acetylation was enhanced by insulin treatment. On the contrary, reduced H3K9/14 acetylation was observed in insulin-repressed Irs2 and Pik3r2, and recovery of acetylation by treatment with the histone deacetylase inhibitor trichostatin A reverted insulin-induced Irs2 downregulation. The chromatin regions encompassing selected insulin-responsive genes are thus featured by accumulation of H2A.Z around the TSS. H2A.Z accumulation facilitates insulin-dependent modulation of pharmacologically treatable H3K9/14 and H2A.Z acetylations. Indeed, inhibition of histone deacetylases by TSA treatment reverted insulin induced Irs2 gene downregulation. Dysregulated histone acetylation may thus be potentially targeted with histone deacetylase inhibitors.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-10-1998
DOI: 10.1126/SCIENCE.282.5387.293
Abstract: Phosphoinositide 3-kinases (PI3Ks) activate protein kinase PKB (also termed Akt), and PI3Kγ activated by heterotrimeric guanosine triphosphate–binding protein can stimulate mitogen-activated protein kinase (MAPK). Exchange of a putative lipid substrate-binding site generated PI3Kγ proteins with altered or aborted lipid but retained protein kinase activity. Transiently expressed, PI3Kγ hybrids exhibited wortmannin-sensitive activation of MAPK, whereas a catalytically inactive PI3Kγ did not. Membrane-targeted PI3Kγ constitutively produced phosphatidylinositol 3,4,5-trisphosphate and activated PKB but not MAPK. Moreover, stimulation of MAPK in response to lysophosphatidic acid was blocked by catalytically inactive PI3Kγ but not by hybrid PI3Kγs. Thus, two major signals emerge from PI3Kγ: phosphoinositides that target PKB and protein phosphorylation that activates MAPK.
Publisher: MDPI AG
Date: 23-11-2022
Abstract: For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of carbohydrates and promoting the synthesis of ketone bodies imitating the metabolic effects of fasting, has been shown to provide a possible nutritional solution to alleviating diseases triggered by an inflammatory environment. The main ketone body, β-hydroxybutyrate (BHB), acts as an alternative fuel, and also as a substrate for a novel histone post-translational modification, β-hydroxybutyrylation. β-hydroxybutyrylation influences the state of chromatin architecture and promotes the transcription of multiple genes. BHB has also been shown to modulate inflammation in chronic diseases. In this review, we discuss, in the pathological context of cardiovascular risks, the current understanding of how ketone bodies, or a ketogenic diet, are able to modulate, trigger, or inhibit inflammation and how the epigenome and chromatin remodeling may be a key contributor.
Publisher: Wiley
Date: 21-11-2016
Abstract: Maternal protein restriction during pregnancy and lactation predisposes the adult offspring to sympathetic overactivity and arterial hypertension. Although the underlying mechanisms are poorly understood, dysregulation of the oxidative balance has been proposed as a putative trigger of neural-induced hypertension. The aim of the study was to evaluate the association between the oxidative status at transcriptional and functional levels in the medulla oblongata and maternal protein restriction induced-hypertension. Wistar rat dams were fed a control (normal protein 17% protein) or a low protein ((Lp) 8% protein) diet during pregnancy and lactation, and male offspring was studied at 90 days of age. Direct measurements of baseline arterial blood pressure (ABP) and heart rate (HR) were recorded in awakened offspring. In addition, quantitative RT-PCR was used to assess the mRNA expression of superoxide dismutase 1 (SOD1) and 2 (SOD2), catalase (CAT), glutathione peroxidase (GPx), Glutamatergic receptors (Grin1, Gria1 and Grm1) and GABA(A)-receptor-associated protein like 1 (Gabarapl1). Malondialdehyde (MDA) levels, CAT and SOD activities were examined in ventral and dorsal medulla. Lp rats exhibited higher ABP. The mRNA expression levels of SOD2, GPx and Gabarapl1 were down regulated in medullary tissue of Lp rats (P<.05, t test). In addition, we observed that higher MDA levels were associated to decreased SOD (approximately 45%) and CAT (approximately 50%) activities in ventral medulla. Taken together, our data suggest that maternal protein restriction induced-hypertension is associated with medullary oxidative dysfunction at transcriptional level and with impaired antioxidant capacity in the ventral medulla.
Publisher: Portland Press Ltd.
Date: 29-08-2007
DOI: 10.1042/BJ20070236
Abstract: Resveratrol, a polyphenol found in fruits, possesses chemopreventive and chemotherapeutic properties and has been shown to increase lifespan in yeast and metazoans, including mice. Genetic evidence and in vitro enzymatic measurements indicate that the deacetylase Sir2/SIRT1, an enzyme promoting stress resistance and aging, is the target of resveratrol. Similarly, down-regulation of insulin-like pathways, of which PI3K (phosphoinositide 3-kinase) is a key mediator, promotes longevity and is an attractive strategy to fight cancer. We show here that resveratrol inhibits, in vitro and in cultured muscle cell lines, class IA PI3K and its downstream signalling at the same concentration range at which it activates sirtuins. Our observations define class IA PI3K as a target of resveratrol that may contribute to the longevity-promoting and anticancer properties and identify resveratrol as a natural class-specific PI3K inhibitor.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2022
DOI: 10.1007/S00018-022-04126-3
Abstract: Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.
Publisher: Cambridge University Press (CUP)
Date: 17-08-2021
DOI: 10.1017/S2040174420000756
Abstract: Maternal protein restriction and physical activity can affect the interaction mother–placenta–fetus. This study quantified the gene expression of brain-derived neurotrophic factor (BDNF), neurothrophin 4, tyrosine kinase receptor B (TrkB/NTRK2), insulin-like growth factor (IGF-1), and insulin-like growth factor receptor (IGF-1r) in the different areas of mother’s brain (hypothalamus, hippoc us, and cortex), placenta, and fetus’ brain of rats. Female Wistar rats ( n = 20) were housed in cages containing a running wheel for 4 weeks before gestation. According to the distance spontaneously traveled daily, rats were classified as inactive or active. During gestation, on continued access to the running wheel, active and inactive groups were randomized to receive normoprotein diet (18% protein) or a low-protein (LP) diet (8% protein). At day 20 of gestation, gene expression of neurotrophic factors was analyzed by quantitative polymerase chain reaction in different brain areas and the placenta. Dams submitted to a LP diet during gestation showed upregulation of IGF-1r and BDNF messenger RNA in the hypothalamus, IGF-1r and NTRK2 in the hippoc us, and BDNF, NTRK2, IGF-1 and IGF-1r in the cortex. In the placenta, there was a downregulation of IGF-1. In the brain of pups from mothers on LP diet, IGF-1r and NTRK2 were downregulated. Voluntary physical activity attenuated the effects of LP diet on IGF-1r in the hypothalamus, IGF-1r and NTRK2 in the hippoc us, IGF-1 in the placenta, and NTRK2 in the fetus’ brain. In conclusion, both maternal protein restriction and spontaneous physical activity influence the gene expression of BDNF, NTRK2, IGF-1, and IGF-1r, with spontaneous physical activity being able to normalize in part the defects caused by protein restriction during pregnancy.
Publisher: FapUNIFESP (SciELO)
Date: 2022
DOI: 10.1590/1980-0037.2022V24E86719
Abstract: abstract Children with a deficit of growth because of perinatal malnutrition present specificities in the percentage of body fat (%BF) that could not be detected by previous fat mass-based equations. This study developed and validated predictive equations of the %BF derived from anthropometric variables in children aged 7 to 10 living in Northeast Brazil, using dual-energy x-ray absorptiometry (DXA) as a reference. Body composition data from 58 children were utilized. DXA was used as a reference. A stepwise (forward) multiple regression statistical model was used to develop the new equations. The Bland-Altman analysis (CI: 95%), paired Student's t-test, and the intraclass correlation coefficient (ICC) was used to validate and compare the developed equations. Two new equations were developed for either gender: boys: %BF: 13.642 + (1.527*BMI) + (-0.345*Height) + (0.875*Triceps) + (0.290* Waist Circumference) and girls: %BF: -13.445 + (2.061*Tight). The Bland-Altman analysis showed good agreement, with limits ranging from -1.33 to 1.24% for boys and -3.35 to 4.08% for girls. The paired Student’s t-test showed no difference between %BF-DXA and the two new equations (p 0.05), and the ICC was 0.948 and 0.915, respectively. DXA-based anthropometric equations provide an accurate and noninvasive method to measure changes in the %BF in children.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2008
DOI: 10.1007/S00125-007-0913-8
Abstract: The serine/threonine kinase Akt rotein kinase B (PKB) is required for the metabolic actions of insulin. Controversial data have been reported regarding Akt defective activation in the muscle of type 2 diabetic patients. Because three Akt isoforms exist, each having a distinct physiological role, we investigated the contribution of isoform-specific defects to insulin signalling in human muscle. The phosphorylation pattern and kinase activity of each Akt isoform were compared in primary myotubes from healthy control participants and type 2 diabetic patients. Phosphorylation of Ser(473) and of Thr(308) in each isoform was determined after immunoprecipitation in myotubes treated or not with insulin. Muscle cells from diabetic patients displayed defective insulin action and a drastic reduction of insulin-stimulated activity of all Akt isoforms. This was associated with specific defects of their phosphorylation pattern in response to insulin, with impaired Akt2- (and to a lower extent Akt3-) Ser(473) phosphorylation, and with altered Akt1-Thr(308) phosphorylation. These defects were not due to faulty phosphoinositide-dependent protein kinase 1 (PDK1) production or activation. Rather, we found higher levels of the Akt2-Ser(473)-specific protein phosphatase PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) in muscle from diabetic patients, which may contribute to the alteration of Akt2-Ser(473) phosphorylation. These results suggest that several mechanisms affecting Akt isoforms, including deregulated production of PHLPP1, could underlie the alterations of skeletal muscle insulin signalling in type 2 diabetes. Taking into account the recently described isoform-specific metabolic functions of Akt, our results provide mechanistic insight that may contribute to the defective regulation of glucose and lipid metabolisms in the muscle of diabetic patients.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2003
Publisher: Elsevier BV
Date: 05-2003
Publisher: MDPI AG
Date: 10-08-2018
Abstract: Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time display minimal toxic side effects to healthy tissues. Bevacizumab (Avastin)—a humanized monoclonal anti VEGF-A antibody—is now used as anti-angiogenic drug in several forms of cancers, yet with variable results. Recent years brought significant progresses in our understanding of the role of chromatin remodeling and epigenetic mechanisms in the regulation of angiogenesis and tumorigenesis. Many inhibitors of DNA methylation as well as of histone methylation, have been successfully tested in preclinical studies and some are currently undergoing evaluation in phase I, II or III clinical trials, either as cytostatic molecules—reducing the proliferation of cancerous cells—or as tumor angiogenesis inhibitors. In this review, we will focus on the methylation status of the vascular epigenome, based on the genomic DNA methylation patterns with DNA methylation being mainly transcriptionally repressive, and lysine/arginine histone post-translational modifications which either promote or repress the chromatin transcriptional state. Finally, we discuss the potential use of “epidrugs” in efficient control of tumor growth and tumor angiogenesis.
Publisher: Elsevier BV
Date: 06-2017
Publisher: Wiley
Date: 30-04-2003
DOI: 10.1016/S0014-5793(03)00438-1
Abstract: The insulin receptor substrate (IRS) proteins act as important mediators of insulin action. Their regulation serves to augment the specificity of the insulin signalling cascade. They can be regulated--both positively and negatively--at the level of phosphorylation, and signalling through these proteins can be further modulated through the actions of SOCS (suppressor of cytokine signalling) proteins. Understanding the mechanisms of IRS regulation will provide further insight into the pathophysiology of insulin resistance and type 2 diabetes.
Publisher: American Society for Cell Biology (ASCB)
Date: 03-1998
DOI: 10.1091/MBC.9.3.561
Abstract: The ability of signaling via the JNK (c-Jun NH 2 -terminal kinase)/stress-activated protein kinase cascade to stimulate or inhibit DNA synthesis in primary cultures of adult rat hepatocytes was examined. Treatment of hepatocytes with media containing hyperosmotic glucose (75 mM final), tumor necrosis factor α (TNFα, 1 ng/ml final), and hepatocyte growth factor (HGF, 1 ng/ml final) caused activation of JNK1. Glucose, TNFα, or HGF treatments increased phosphorylation of c-Jun at serine 63 in the transactivation domain and stimulated hepatocyte DNA synthesis. Infection of hepatocytes with poly-l-lysine–coated adenoviruses coupled to constructs to express either dominant negatives Ras N17 , Rac1 N17 , Cdc42 N17 , SEK1 − , or JNK1 − blunted the abilities of glucose, TNFα, or HGF to increase JNK1 activity, to increase phosphorylation of c-Jun at serine 63, and to stimulate DNA synthesis. Furthermore, infection of hepatocytes by a recombinant adenovirus expressing a dominant-negative c-Jun mutant (TAM67) also blunted the abilities of glucose, TNFα, and HGF to stimulate DNA synthesis. These data demonstrate that multiple agonists stimulate DNA synthesis in primary cultures of hepatocytes via a Ras/Rac1/Cdc42/SEK/JNK/c-Jun pathway. Glucose and HGF treatments reduced glycogen synthase kinase 3 (GSK3) activity and increased c-Jun DNA binding. Co-infection of hepatocytes with recombinant adenoviruses to express dominant- negative forms of PI 3 kinase (p110α 110γ) increased basal GSK3 activity, blocked the abilities of glucose and HGF treatments to inhibit GSK3 activity, and reduced basal c-Jun DNA binding. However, expression of dominant-negative PI 3 kinase (p110α 110γ) neither significantly blunted the abilities of glucose and HGF treatments to increase c-Jun DNA binding, nor inhibited the ability of these agonists to stimulate DNA synthesis. These data suggest that signaling by the JNK/stress-activated protein kinase cascade, rather than by the PI 3 kinase cascade, plays the pivotal role in the ability of agonists to stimulate DNA synthesis in primary cultures of rat hepatocytes.
Publisher: Elsevier BV
Date: 06-2004
Publisher: MDPI AG
Date: 17-03-2020
DOI: 10.3390/NU12030788
Abstract: Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies’ biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies’ consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation (ii) inflammatory responses to a KD (iii) proven benefits of the KD in the context of neuronal disease and cancer and (iv) consequences of the KD’s application on cardiovascular health and on physical performance.
Publisher: Wiley
Date: 09-2010
DOI: 10.1002/BIOF.112
Abstract: Sirtuins are evolutionary conserved NAD(+)-dependent acetyl-lysine deacetylases and ADP ribosyltransferases dual-function enzymes involved in the regulation of metabolism and lifespan. Sirtuins are also implicated in determining the balance between apoptosis, cell survival, and cell proliferation. In humans, seven sirtuins isoforms (SIRT₁₋₇) have been identified that localize either in the nucleus, cytoplasm, or mitochondria. The genetic demonstration that increasing gene dosage of sirtuin orthologs in eukaryotes, including yeast and multicellular Caenorhabditis elegans and Drosophila melanogaster, leads to prolonged lifespan induced considerable interest toward the discovery of sirtuin-activating molecules, on the ground that the phenomenon of sirtuin-induced lifespan prolongation-which is consequential to improved metabolic control-can be exploited therapeutically to counteract insulin resistance and diabetes. Conversely, le evidence that either pharmacological inhibition or activation of sirtuin isoforms is potentially beneficial in study models of cancer and neurodegenerative diseases have been obtained. Here, we (i) survey the key roles of sirtuin isoforms and discuss the evidence in favor of activatory versus inhibitory targeting of sirtuins, (ii) discuss some of the inhibitors and activators of the sirtuin family members that have been described in the literature, (iii) review model systems in which these molecules have proved to exert therapeutic effects, and (iv) discuss the outcome of pharmacokinetic studies and phase I and II clinical trials employing sirtuin modulators.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2004
DOI: 10.1007/S00125-003-1313-3
Abstract: Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. Insulin acts by binding to its cell surface receptor, thus activating the receptor's intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and phosphorylation of several substrates. Tyrosine phosphorylated residues on the receptor itself and on subsequently bound receptor substrates provide docking sites for downstream signalling molecules, including adapters, protein serine/threonine kinases, phosphoinositide kinases and exchange factors. Collectively, those molecules orchestrate the numerous insulin-mediated physiological responses. A clear picture is emerging of the way in which insulin elicits several intracellular signalling pathways to mediate its physiologic functions. A further challenge, being pursued by several laboratories, is to understand the molecular mechanisms that underlie insulin action at the peripheral level, deregulation of which ultimately leads to hyperglycaemia and Type 2 diabetes. We review how circulating factors such as insulin itself, TNF-alpha, interleukins, fatty acids and glycation products influence insulin action through insulin signalling molecules themselves or through other pathways ultimately impinging on the insulin-signalling pathway. Understanding how the mechanism by which molecular insulin action is modulated by these factors will potentially provide new targets for pharmacological agents, to enable the control of altered glucose and lipid metabolism and diabetes.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2016
DOI: 10.1007/S00125-016-4097-Y
Abstract: Despite the strong correlation between non-alcoholic fatty liver disease and insulin resistance, hepatic steatosis is associated with greater whole-body insulin sensitivity in several models. We previously reported that the inhibition of hepatic glucose production (HGP) protects against the development of obesity and diabetes despite severe steatosis, thanks to the secretion of specific hepatokines such as fibroblast growth factor 21 (FGF21) and angiopoietin-related growth factor. In this work, we focused on adipose tissue to assess whether liver metabolic fluxes might, by interorgan communication, control insulin signalling in lean animals. Insulin signalling was studied in the adipose tissue of mice lacking the catalytic subunit of glucose 6-phosphatase, the key enzyme in endogenous glucose production, in the liver (L-G6pc Mice lacking HGP exhibited improved insulin sensitivity of the phosphoinositide 3-kinase/Akt pathway in the subcutaneous adipose tissue associated with a browning of adipocytes. The suppression of HGP increased FGF21 levels in lean animals, and increased FGF21 was responsible for the metabolic changes in the subcutaneous adipose tissue but not for its greater insulin sensitivity. The latter might be linked to an increase in the ratio of monounsaturated to saturated fatty acids released by the liver. Our work provides evidence that HGP controls subcutaneous adipose tissue browning and insulin sensitivity through two pathways: the release of beneficial hepatokines and changes in hepatic fatty acids profile.
Publisher: Baishideng Publishing Group Inc.
Date: 2017
Publisher: MDPI AG
Date: 16-06-2019
DOI: 10.3390/NU11061356
Abstract: Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency—especially in obesity and associated metabolic disorders—and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.MCE.2016.09.006
Abstract: Dietary administration of the histone deacetylase (HDAC) inhibitor butyric acid - a short chain fatty acid present in milk products and also bacterially produced in the intestine - has been shown to increase energy expenditure and favour insulin sensitivity in mice through induction of PGC1α (peroxisome proliferator-activated receptor gamma co-activator 1α) and AMPK (AMP-activated protein kinase) in skeletal muscle, and a consequential increase of mitochondrial fatty acid oxidation. Here, we investigate whether such physiological improvements are associated to epigenetic effects dependent on increased histone acetylation and whether butyrate exerts a direct action on skeletal muscle insulin signalling. We show that sodium butyrate (NaBut) ameliorates the insulin-resistant phenotype, induced in L6 myotubes by prolonged exposure to palmitate, by i) increasing the insulin-induced phosphorylation of both PKB (protein kinase B) and MAPK (mitogen activated protein kinase), the two branches of insulin signalling and ii) increasing histone H3 acetylation - even in the presence of palmitate - on chromatin in proximity of the Irs1 (insulin receptor substrate 1) transcriptional start site. Consequently, NaBut induced Irs1 mRNA and protein overexpression, which in turn relayed higher insulin-stimulated IRS1 tyrosine phosphorylation and PI 3-kinase (phosphoinositide 3-kinase) association, suggesting that the increased IRS1 expression may mediate the insulin-sensitizing effects of NaBut. Furthermore, downstream of PKB, NaBut induced GSK3β gene upregulation. Our observations indicate that NaBut - through its action as HDAC inhibitor - can promote insulin responsiveness in L6 myotubes under conditions of lipid-induced insulin resistance.
Publisher: FapUNIFESP (SciELO)
Date: 2018
Publisher: Springer Science and Business Media LLC
Date: 24-01-2019
DOI: 10.1038/S41598-018-36941-9
Abstract: Butyrate and R-β-hydroxybutyrate are two related short chain fatty acids naturally found in mammals. Butyrate, produced by enteric butyric bacteria, is present at millimolar concentrations in the gastrointestinal tract and at lower levels in blood R-β-hydroxybutyrate, the main ketone body, produced by the liver during fasting can reach millimolar concentrations in the circulation. Both molecules have been shown to be histone deacetylase (HDAC) inhibitors, and their administration has been associated to an improved metabolic profile and better cellular oxidative status, with butyrate inducing PGC1α and fatty acid oxidation and R-β-hydroxybutyrate upregulating oxidative stress resistance factors FOXO3A and MT2 in mouse kidney. Because of the chemical and functional similarity between the two molecules, we compared here their impact on multiple cell types, evaluating i) histone acetylation and hydroxybutyrylation levels by immunoblotting, ii) transcriptional regulation of metabolic and inflammatory genes by quantitative PCR and iii) cytokine secretion profiles using proteome profiling array analysis. We confirm that butyrate is a strong HDAC inhibitor, a characteristic we could not identify in R-β-hydroxybutyrate in vivo nor in vitro . Butyrate had an extensive impact on gene transcription in rat myotubes, upregulating PGC1α, CPT1b, mitochondrial sirtuins (SIRT3-5), and the mitochondrial anti-oxidative genes SOD2 and catalase. In endothelial cells, butyrate suppressed gene expression and LPS-induced secretion of several pro-inflammatory genes, while R-β-hydroxybutyrate acted as a slightly pro-inflammatory molecule. Our observations indicate that butyrate induces transcriptional changes to a higher extent than R-β-hydroxybutyrate in rat myotubes and endothelial cells, in keep with its HDAC inhibitory activity. Also, in contrast with previous reports, R-β-hydroxybutyrate, while inducing histone β-hydroxybutyrylation, did not display a readily detectable HDAC inhibitor activity and exerted a slight pro-inflammatory action on endothelial cells.
Publisher: The Endocrine Society
Date: 12-2003
DOI: 10.1210/ME.2003-0261
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-02-2000
DOI: 10.1126/SCIENCE.287.5455.1049
Abstract: Phosphoinositide 3-kinase (PI3K) activity is crucial for leukocyte function, but the roles of the four receptor-activated isoforms are unclear. Mice lacking heterotrimeric guanine nucleotide-binding protein (G protein)–coupled PI3Kγ were viable and had fully differentiated neutrophils and macrophages. Chemoattractant-stimulated PI3Kγ −/− neutrophils did not produce phosphatidylinositol 3,4,5-trisphosphate, did not activate protein kinase B, and displayed impaired respiratory burst and motility. Peritoneal PI3Kγ-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model. These results demonstrate that PI3Kγ is a crucial signaling molecule required for macrophage accumulation in inflammation.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.YGCEN.2015.12.028
Abstract: Prenatal and early postnatal life determines future health, and intrauterine growth restriction (IUGR) - associated low birth weight predisposes to metabolic syndrome in adulthood. We hypothesize here that IUGR might induce hormonal and gene expression alterations predisposing to metabolic disease. Using a porcine model of spontaneous IUGR, we determined in utero (71, 112days post-conception) and early-postnatal (2days post-birth) IGF-1, insulin and leptin levels, and in parallel we investigated, in skeletal muscle, the developmental expression patterns of sirtuins and metabolic and signaling genes IRS1, GLUT4, HK2 and GAPDH. IUGR was associated with impaired IGF-1 plasmatic levels. Gene expression of sirtuin 1, 5, 6, 7, GLUT4 and HK2 exhibited significant correlations with gestational age or body weight. SIRT1 and HK2 expression displayed an age- and weight-dependent downregulation in controls, which was lost in IUGR pigs. Conversely, SIRT2 and GLUT4 were upregulated in IUGR pigs. Within the set of genes studied, we found a significant correlation between IGF-1 levels and gene expression in control, but not IUGR s les, indicating that lower IGF-1 may be a limiting factor in IUGR. IUGR-dependent gene alterations were partly linked to epigenetic changes on histone H3 acetylation and methylation. Overall, our data indicate that several sirtuins and metabolic genes display specific gene expression trajectories during fetal and early postnatal life. Gene expression alterations observed in IUGR are correlated to IGF-1 dysregulation. Given the importance of the genes studied in metabolic control, their perinatal alterations might contribute to the predisposition to metabolic disease of adulthood.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2010
Abstract: Diabetes mellitus (type 1 and type 2) and the complications associated with this condition are an urgent public health problem, as the incidence of diabetes mellitus is steadily increasing. Environmental factors, such as diet and exposure to hyperglycemia, contribute to the etiology of diabetes mellitus and its associated microvascular and macrovascular complications. These vascular complications are the main cause of the morbidity and mortality burden of diabetes mellitus. The DCCT-EDIC and UKPDS epidemiological studies correlated poor glycemic control with the development of vascular complications in patients with type 1 or type 2 diabetes mellitus. The findings of these studies suggest that early exposure to hyperglycemia predisposes in iduals to the development of diabetic complications, a phenomenon referred to as metabolic memory or the legacy effect. The first experimental evidence for metabolic memory was reported >20 years ago and the underlying molecular mechanisms are currently being characterized. Interestingly, transient exposure to hyperglycemia results in long-lasting epigenetic modifications that lead to changes in chromatin structure and gene expression, which mediate these persistent metabolic characteristics.
Publisher: Cambridge University Press (CUP)
Date: 17-06-2019
DOI: 10.1017/S2040174419000333
Abstract: Maternal physical activity induces brain functional changes and neuroplasticity, leading to an improvement of cognitive functions, such as learning and memory in the offspring. This study investigated the effects of voluntary maternal physical activity on the gene expression of the neurotrophic factors (NTFs): BDNF, NTF4, NTRK2, IGF-1 and IGF-1r in the different areas of mother’s brain, placenta and foetus brain of rats. Female Wistar rats (n = 15) were in idually housed in voluntary physical activity cages, containing a running wheel, for 4 weeks (period of adaptation) before gestation. Rats were classified as inactive (I, n = 6) active (A, n = 4) and very active (VA, n = 5) according to daily distance spontaneously travelled. During gestation, the dams continued to have access to the running wheel. At the 20 th day of gestation, gene expression of NTFs was analysed in different areas of mother’s brain (cerebellum, hypothalamus, hippoc us and cortex), placenta and the offspring’s brain. NTFs gene expression was evaluated using quantitative PCR. Very active mothers showed upregulation of IGF-1 mRNA in the cerebellum (36.8%) and NTF4 mRNA expression in the placenta (24.3%). In the cortex, there was a tendency of up-regulation of NTRK2 mRNA (p = 0.06) in the A and VA groups when compared to I group. There were no noticeable changes in the gene expression of NTFs in the offspring’s brain. Our findings suggest the existence of a developmental plasticity induced by maternal physical activity in specific areas of the brain and placenta representing the first investment for offspring during development.
Publisher: Wiley
Date: 24-09-2017
DOI: 10.1113/EP086400
No related grants have been discovered for Luciano Pirola.