Showing papers by "Luca Vanella published in 2016"
TL;DR: This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation.
Abstract: Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1α-dependent manner, P < 0.05. The increase in PGC-1α was associated with an increase in β-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EE...
69 citations
TL;DR: Three potential signaling mechanisms are discussed that are referred to as the non-canonical functions of the HO isoforms: protein-protein interaction, intracellular compartmentalization, and extracellular secretion.
Abstract: // Luca Vanella 1,* , Ignazio Barbagallo 1,* , Daniele Tibullo 2 , Stefano Forte 3,4 , Agata Zappala 3 and Giovanni Li Volti 3,5 1 Department of Drug Sciences, University of Catania, Catania, Italy 2 Division of Haematology, AOU “Policlinico - Vittorio Emanuele”, University of Catania, Catania, Italy 3 Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy 4 Istituto Oncologico del Mediterraneo Ricerca srl Viagrande, Catania, Italy 5 EuroMediterranean Institute of Science and Technology, Palermo, Italy * The first and second author contributed equally to this manuscript Correspondence to: Giovanni Li Volti, email: // Keywords : heme oxygenase, nuclear translocation, protein-protein interaction, non-canonical functions, extracellular space Received : June 02, 2016 Accepted : September 05, 2016 Published : September 09, 2016 Abstract Heme oxygenase (HO) isoforms catalyze the conversion of heme to carbon monoxide (CO) and biliverdin with a concurrent release of iron, which can drive the synthesis of ferritin for iron sequestration. Most of the studies so far were directed at evaluating the protective effect of these enzymes because of their ability to generate antioxidant and antiapoptotic molecules such as CO and bilirubin. Recent evidences are suggesting that HO may possess other important physiological functions, which are not related to its enzymatic activity and for which we would like to introduce for the first time the term “non canonical functions”. Recent evidence suggest that both HO isoforms may form protein-protein interactions (i.e. cytochrome P450, adiponectin, CD91) thus serving as chaperone-like protein. In addition, truncated HO-1 isoform was localized in the nuclear compartment under certain experimental conditions (i.e. excitotoxicity, hypoxia) regulating the activity of important nuclear transcription factors (i.e. Nrf2) and DNA repair. In the present review, we discuss three potential signaling mechanisms that we refer to as the non-canonical functions of the HO isoforms: protein-protein interaction, intracellular compartmentalization, and extracellular secretion. The aim of the present review is to describe each of this mechanism and all the aspects warranting additional studies in order to unravel all the functions of the HO system.
63 citations
TL;DR: The data suggest that BTZ sensitivity depends on HO-1 nuclear compartmentalization and not on its enzymatic activity and this finding may represent an important tool to overcome BTZ chemoresistance in MM patients.
Abstract: Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells in the bone marrow leading to bone destruction and bone marrow failure. Several molecular mechanisms underlie chemoresistance among which heme oxygenase-1 (HO-1) could play a major role. The aim of the present research was to evaluate the impact of HO-1 in MM following bortezomib (BTZ) treatment and how HO-1 is implicated in the mechanisms of chemoresistance. MM cells were treated for 24h with BTZ (15 nM), a boronic acid dipeptide inhibitor of the 26S proteasome used in the treatment of patients with MM as first-line therapy. We evaluated cell viability, reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress, HO-1 expression and compartmentalization and cellular genetic instability. Results showed that BTZ significantly reduced cell viability in different MM cell lines and induced ER-stress and ROS formation. Concomitantly, we observed a significant overexpression of both HO-1 gene and protein levels. This effect was abolished by concomitant treatment with 4-phenybutirric acid, a molecular chaperone, which is known to reduce ER-stress. Surprisingly, inhibition of HO activity with SnMP (10μM) failed to increase BTZ sensitivity in MM cells whereas inhibition of HO-1 nuclear translocation by E64d, a cysteine protease inhibitor, increased sensitivity to BTZ and decreased genetic instability as measured by cytokinesis-block micronucleus assay. In conclusion, our data suggest that BTZ sensitivity depends on HO-1 nuclear compartmentalization and not on its enzymatic activity and this finding may represent an important tool to overcome BTZ chemoresistance in MM patients.
53 citations
TL;DR: The findings suggest the need for more research to assess if miRs can serve as useful markers for the early diagnosis and monitoring of PAD.
Abstract: Some emerging risk factors such as oxidative stress biomarkers and microRNAs (miRs) may add additional value to the established risk factors for peripheral artery disease (PAD). We enrolled 27 patients with PAD and 27 age-matched controls. We examined the levels of a series of miRs (miR-130a, miR-27b, and miR-210) in serum samples. The level of well-established oxidative stress biomarkers, such as lipid hydroperoxides, isoprostanes, hemeoxygenase-1 (HO-1) and reduced glutathione, was also measured in plasma and their relationship with the miRs was determined. Levels of miR-130a, miR-27b, and miR-210 were significantly increased in patients with PAD when compared to the controls. The level of miR-130 was positively correlated with body mass index, whereas miR-210 was inversely associated with pain-free walking distance (PfWD). None of the evaluated miRs was associated with lowered PfWD of patients with PAD (stage IIa > 250 m, IIb < 250 m) or oxidative stress parameters. In conclusion, our findings suggest the need for more research to assess if miRs can serve as useful markers for the early diagnosis and monitoring of PAD.
46 citations
TL;DR: The findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα, and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes.
Abstract: Silibinin, a natural plant flavonoid, is the main active constituent found in milk thistle (Silybum marianum). It is known to have hepatoprotective, anti-neoplastic effect and suppresses lipid accumulation in adipocytes. Objective of this study was to investigate the effect of silibinin on adipogenic differentiation and thermogenic capacity of human adipose tissue derived mesenchymal stem cells. Silibinin (10 μM) treatment, either at the beginning or at the end of adipogenic differentiation, resulted in an increase of SIRT-1, PPARα, Pgc-1α and UCPs gene expression. Moreover, silibinin administration resulted in a decrease of PPARγ, FABP4, FAS and MEST/PEG1 gene expression during the differentiation, confirming that this compound is able to reduce fatty acid accumulation and adipocyte size. Our data showed that silibinin regulated adipocyte lipid metabolism, inducing thermogenesis and promoting a brown remodelling in adipocyte. Taken together, our findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes.
35 citations
TL;DR: Females with increased BMI exhibit a marked increase in OX-HDL and isoprostane levels, which was associated with an increase in 20-HETE, TNF α and Ang II and decreased levels of adiponectin when compared to a group with a low BMI.
35 citations
TL;DR: EET is identified as an upstream positive regulator of PGC-1α that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome.
Abstract: Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondrial function and induction of HO-1 via activation of PGC-1α in adipose and hepatic tissue. Methods. Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess the functional relationship among EETs, PGC-1α, HO-1, and mitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-A is a potent inducer of PGC-1α, HO-1, mitochondrial biogenesis (cytochrome oxidase subunits 1 and 4 and SIRT3), fusion proteins (Mfn 1/2 and OPA1) and fission proteins (DRP1 and FIS1) (p < 0.05), fasting glucose, BW, and blood pressure. These beneficial effects were prevented by administration of lenti-PGC-1α(sh). EET-A administration prevented HF diet induced mitochondrial and dysfunction in adipose tissue and restored VO2 effects that were abrogated in PGC-1α-deficient mice. Conclusion. EET is identified as an upstream positive regulator of PGC-1α that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome.
33 citations
TL;DR: The results suggest that OLE may promote the brown remodeling of white adipose tissue inducing thermogenesis and improving metabolic homeostasis.
Abstract: Olive leaves contain a wide variety of phenolic compounds belonging to phenolic acids, phenolic alcohols, flavonoids, and secoiridoids, and include also many other pharmacological active compounds. They could play an important role in human diet and health because of their ability to lower blood pressure, increase coronary arteries blood flow and decrease the risk of cardiovascular diseases. The aim of this study was to investigate the effect of olive leaf extract (OLE) from Sicilian cultivar on adipogenic differentiation of human adipose derived mesenchymal stem cells and its impact on lipid metabolism. We showed that OLE treatment during adipogenic differentiation reduces inflammation, lipid accumulation and induces thermogenesis by activation of uncoupling protein uncoupling protein 1, sirtuin 1, peroxisome proliferator-activated receptor alpha, and coactivator 1 alpha. Furthermore, OLE significantly decreases the expression of molecules involved in adipogenesis and upregulates the expression of mediators involved in thermogenesis and lipid metabolism. Taken together, our results suggest that OLE may promote the brown remodeling of white adipose tissue inducing thermogenesis and improving metabolic homeostasis.
25 citations
TL;DR: The following review proposes to stimulate interest in the role of heme oxygenase-1 over-expression on transplantation of stem cells in diabetes, focusing on the clinical potential of he me oxygenase protein and activity to restore tissue damage and/or to improve the immunomodulatory properties of transplanted stem cells.
Abstract: The growing data obtained from in vivo studies and clinical trials demonstrated the benefit of adult stem cells transplantation in diabetes; although an important limit is represented by their survival after the transplant. To this regard, recent reports suggest that genetic manipulation of stem cells prior to transplantation can lead to enhanced survival and better engraftment. The following review proposes to stimulate interest in the role of heme oxygenase-1 over-expression on transplantation of stem cells in diabetes, focusing on the clinical potential of heme oxygenase protein and activity to restore tissue damage and/or to improve the immunomodulatory properties of transplanted stem cells.
25 citations
TL;DR: The present study supports the growing body of data suggesting the bioactivities of Celtis aetnensis (Tornab.) Strobl and its potential impact on cancer therapy and on human health.
Abstract: Cancers of the digestive tract, in particular colorectal cancer (CRC), are among those most responsive to dietary modification. Research has shown that approximately 75% of all sporadic cases of CRC are directly influenced by diet. Many natural compounds have been investigated for their potential usefulness as cancer chemopreventive agents as they have been thought to suppress carcinogenesis mainly during the initiation phase due to their radical scavenger activity. Since there is an increasing interest in the in vivo protective effects of natural compounds contained in plants against oxidative damage involved in several human diseases such as cancer, the aim of the present research was to test the effects of a Celtis aetnensis (Tornab.) Strobl twig extract on a human colon carcinoma cell line (Caco2). In order to elucidate the mechanisms of action of this extract, LDH release, GSH content, ROS levels, caspase-3 and γ-GCS expression were also evaluated. The results revealed that the Celtis aetnensis extract reduced the cell viability of the Caco2 cells inducing apoptosis at the lowest concentration and necrosis at higher dosages. In addition, this extract caused an increase in the levels of ROS, a decrease in RSH levels and in the expression of HO-1. The expression of γ-GCS was not modified in the Celtis aetnensis-treated Caco-2 cells. These results suggest an interference of this extract on the oxidant/antioxidant cell balance with consequent cell damage. The present study supports the growing body of data suggesting the bioactivities of Celtis aetnensis (Tornab.) Strobl and its potential impact on cancer therapy and on human health.
22 citations
TL;DR: The main role of PPARγ in the adipocyte function and during ASC differentiation is revealed and the observed therapeutic value of Cape in insulin-resistance related diseases should be taken into consideration.
Abstract: Hypertrophic obesity inhibits activation of peroxisome proliferators-activated receptor gamma (PPARγ), considered the key mediator of the fully differentiated and insulin sensitive adipocyte phenotype. We examined the effects of Caffeic Acid Phenethyl Ester (Cape), isolated from propolis, a honeybee hive product, on Adipose Stem Cells (ASCs) differentiation to the adipocyte lineage. Finally we tested the effects of Cape on insulin-resistant adipocytes. Quantification of Oil Red O-stained cells showed that lipid droplets decreased following Cape treatment as well as radical oxygen species formation. Additionally, exposure of ASC to high glucose levels decreased adiponectin and increased proinflammatory cytokines mRNA levels, which were reversed by Cape-mediated increase of insulin sensitivity. Cape treatment resulted in decreased triglycerides synthesis and increased beta-oxidation. Exposure of ASCs to Lipopolysaccharide (LPS) induced a reduction of PPARγ, an increase of IL-6 levels associated with a well-known stimulation of lipolysis; Cape partially attenuated the LPS-mediated effects. These observations reveal the main role of PPARγ in the adipocyte function and during ASC differentiation. As there is now substantial interest in functional food and nutraceutical products, the observed therapeutic value of Cape in insulin-resistance related diseases should be taken into consideration.
Journal Article•
TL;DR: The results suggest that Moringa oleifera Lam.
Abstract: Objective Moringa oleifera Lam., a multipurpose tree, is used traditionally for its nutritional and medicinal properties. It has been used for the treatment of a variety of conditions, including inflammation, cancer and metabolic disorders. Materials and methods We investigated the effect of Moringa oleifera Lam. on adipogenic differentiation of human adipose-derived mesenchymal stem cells and its impact on lipid metabolism and cellular antioxidant systems. Results We showed that Moringa oleifera Lam. treatment during adipogenic differentiation reduces inflammation, lipid accumulation and induces thermogenesis by activation of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor alpha (PPARα), and coactivator 1 alpha (PGC1α). In addition, Moringa oleifera Lam. induces heme oxygenase-1 (HO-1), a well established protective and antioxidant enzyme. Finally Moringa oleifera Lam. significantly decreases the expression of molecules involved in adipogenesis and upregulates the expression of mediators involved in thermogenesis and lipid metabolism. Conclusions Our results suggest that Moringa oleifera Lam. may promote the brown remodeling of white adipose tissue inducing thermogenesis and improving metabolic homeostasis.
TL;DR: Prostate metaflammation is inversely related to intra-prostatic HO-1 levels, serum HDL and positively with triglycerides, and may play a key role in BPH.
Abstract: To investigate the relationship between intra-prostatic levels of heme oxygenase (HO), metaflammation in benign prostatic hyperplasia (BPH) tissue in patients with MetS and moderate–severe lower urinary tract symptoms (LUTS). Between January 2012 and June 2013, 132 consecutive patients, who underwent transurethral resection of the prostate for moderate–severe LUTS, secondary to clinical BPH, were enrolled. Prostate samples were investigated for the presence of an inflammatory infiltrate, according to the Irani score, and for HO-1 and HO-2 levels measurements. Patients were evaluated for the presence of metabolic syndrome (MetS) defined by the International Diabetes Federation. We observed that subjects with MetS exhibited greater Irani score (3.0 vs. 2.0; p < 0.05), Irani grade (2.0 vs. 1.0; p < 0.05) and lower value of HO-1 (4.55 vs. 6.01; p < 0.05) and HO-2 (0.81 vs. 2.66; p < 0.05). HO-1 (3.91 vs. 5.67; p < 0.05) and HO-2 (1.06 vs. 1.37; p < 0.05) were significantly reduced in patients with high intra-prostatic inflammation (Irani score ≥4). At the multivariate logistic regression analysis, HO-1 reduction (OR 0.588; p < 0.01), waist circumference (OR 1.09; p < 0.01), triglycerides (OR 1.013; p < 0.05) and HDL (OR 0.750; p < 0.05) were independent predictors of high intra-prostatic inflammation. We also found that HO-1 reduction (OR 0.598; p < 0.01) and the presence of MetS (OR 34.846; p < 0.01) were associated with Irani score ≥4. MetS-induced inflammation may play a key role in BPH. In detail, prostate metaflammation is inversely related to intra-prostatic HO-1 levels, serum HDL and positively with triglycerides.
TL;DR: In this article, the effect of (+)-pentazocine, a putative σ 1 R agonist, in an in vitro model of microglia activation was investigated.
27 Apr 2016
TL;DR: The development of adipocytes in mice and humans follows a well-defined pathway that commences with a common pluripotent mesenchymal stem cell (MSC), ie.
Abstract: The development of adipocytes in mice and humans follows a well-defined pathway that commences with a common pluripotent mesenchymal stem cell (MSC), ie., adipogenesis [1]. The early steps of the pathway leading to the generation and the commitment of MSCs to an adipocyte lineage are unknown. Hypothetically, the determination of the fate of MSCs occurs early in cell differentiation (“commitment”) and involves the interplay of intrinsic (genetic) and environmental (local and systemic) conditions that ultimately define the fate of the cell. Factors that determine MSC proliferation and differentiation also govern early adipocyte development and function. Currently, little is known about this process; from MSC-to-preadipocyte differentiation. However, the steps governing the transition from preadipocyte to adipocyte differentiation are not well defined (Figure 1). During adipogenesis MSCs or preadipocytes differentiate into lipid-laden adipocytes [2]. Ox-HDL increases adipogenic properties with a marked effect on the last step of adipocyte-terminal differentiation and release of adipokines including 20-HETE and Ang II.
TL;DR: The significance and possible clinical applications of TDSCs were presented and important biochemical cascade underlying the processes of osteogenesis, adipogenesis, angiogenesis, and their possible applications in new therapy development were described.
Abstract: Tissue-derived stem cells (TDSCs) are undifferentiated cells, presented in tissues such as bone marrow, blood vessels, and adipose tissues and with the ability to repair damaged areas by generation of new cells and tissues. TDSCs have proven to be a feasible source of cells for tissue regeneration medicine in recent experimental and clinical studies. Mesenchymal stem cells revealed potential benefits in atherosclerosis [1] and endothelial progenitor cells reduced lung damage and improved lung function [2]. Moreover, there were some reports that suggested that adipose derived stem cells may improve injured lung function [3], infracted heart function [4], and injured kidney and its function [5]. Regulation of the process to successfully trigger proper differentiation into the desired cell types is important. Moreover, it is more important to confirm safety of transplantation when stem cells are used to treat diseases.
In the present special issue, the significance and possible clinical applications of TDSCs were presented. Some manuscripts described important biochemical cascade underlying the processes of osteogenesis, adipogenesis, angiogenesis, and their possible applications in new therapy development. All findings and experiences of TDSCs research will open up new possibilities for the treatment of various diseases and extend the human life span.
Ming Li
Kequan Guo
Dong Hyun Kim
Luca Vanella