• chronic wounds
• diabetic foot
• inflammation
• inflammatory biomarkers
• leg ulcer
• mendelian randomization analysis
• obesity
• pressure injuries
• venous ulcer

• Humans
• Obesity/complications
• Obesity/genetics
• Biomarkers/analysis
• Biomarkers/blood
• Inflammation/genetics
• Polymorphism, Single Nucleotide
• Genome-Wide Association Study
• Mendelian Randomization Analysis
• Male
• Female
• Chronic Disease
• Middle Aged
• Diabetic Foot/genetics
• Pressure Ulcer/genetics
• Varicose Ulcer/genetics
• Varicose Ulcer/etiology

• Adipose-derived mesenchymal stem cells
• Extracellular matrix
• Liver fibrosis
• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
• Tissue scaffolds

• Seoul St. Mary's Hospital, Catholic University of Korea

• Experimental diabetes
• Heme oxygenase
• Hormones
• Rodents

• Animals
• Heme Oxygenase (Decyclizing)/metabolism
• Heme Oxygenase (Decyclizing)/genetics
• Humans
• Metabolic Diseases/metabolism
• Metabolic Diseases/pathology
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Type 2/pathology
• Diabetes Mellitus, Experimental/metabolism
• Diabetes Mellitus/metabolism
• Oxidative Stress

• Metabolic syndrome
• Nrf2/HO-1
• cardiovascular diseases
• mitochondrial
• reactive oxygen stress

• Humans
• Metabolic Syndrome/complications
• Heme Oxygenase-1/metabolism
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/metabolism
• NF-E2-Related Factor 2/metabolism
• Metabolic Diseases
• Cholesterol

• Fatty liver disease
• Metabolic-associated fatty liver disease
• Non-alcoholic steatohepatitis
• Oxidative stress
• Reactive oxidation species

Objective: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. Methods: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the heart of mice fed a high-fat diet. Mice were randomly divided into three groups (five per group): (1) lean (normal diet), (2) high-fat diet (HFD)+ sham virus, and (3) HFD + shNOV lentivirus. Blood pressure, tissue inflammation, and oxygen consumption were measured. Metabolic and mitochondrial markers were studied in fat and heart tissues. Results: Mice fed an HFD developed adipocyte hypertrophy, fibrosis, inflammation, and decreased mitochondrial respiration. Inhibiting NOV expression in the adipose tissue of obese mice by shNOV increased mitochondrial markers for biogenesis (PGC-1α, the nuclear co-activator of HO-1) and functional integrity (FIS1) and insulin signaling (AKT). The upregulation of metabolic and mitochondrial markers was also evident in the hearts of the shNOV mice with the activation of mitophagy. Using RNA arrays, we identified a subgroup of genes that highly correlated with increased adipocyte mitochondrial autophagy in shNOV-treated mice. A heat map analysis in obese mice confirmed that the suppression of NOV overrides the genetic susceptibility of adiposity and the associated detrimental metabolic changes and correlates with the restoration of anti-inflammatory, thermogenic, and mitochondrial genes. Conclusion: Our novel findings demonstrate that inhibiting NOV expression improves adipose tissue function in a positive way in cardiometabolic function by inducing mitophagy and improving mitochondrial function by the upregulation of PGC-1α, the insulin sensitivity signaling protein. Inhibiting NOV expression increases PGC-1, a key component of cardiac bioenergetics, as well as key signaling components of metabolic change, resulting in improved glucose tolerance, improved mitochondrial function, and decreased inflammation. These metabolic changes resulted in increased oxygen consumption, decreased adipocyte size, and improved cardiac metabolism and vascular function at the structural level. The crosstalk of the adipose tissue-specific deletion of NOV/CCN3 improved cardiovascular function, representing a novel therapeutic strategy for obesity-related cardiometabolic dysfunction.

• Adipokines/metabolism
• Adiponectin/metabolism
• Animals
• Cardiovascular Diseases/genetics
• Glucose
• Heme Oxygenase (Decyclizing)/metabolism
• Heme Oxygenase (Decyclizing)/therapeutic use
• Inflammation
• Insulin Resistance/genetics
• Insulins/metabolism
• Insulins/therapeutic use
• Mice
• Mice, Knockout
• Mice, Obese
• Obesity/complications
• Obesity/drug therapy
• Obesity/genetics
• Oxidative Stress
• Proto-Oncogene Proteins c-akt/metabolism
• RNA/metabolism

Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1α (transgenic-adipocyte-PGC-1α) at week 20, and continued on H.F.D. for weeks 20–28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1α and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial respiration. Mice with adipose-specific overexpression of PGC1-α exhibited improvement in HO-1, mitochondrial biogenesis and respiration, with a decrease in fasting glucose, reduced blood pressure and fibrosis, and increased oxygen consumption. PGC-1α led to the upregulated expression of processes associated with the browning of fat tissue, including UCP1, FGF21, and pAMPK signaling, with a reduction in inflammatory adipokines, NOV/CCN3 expression, and TGFβ. These changes required HO-1 expression. The R.N.A. array analysis identified subgroups of genes positively correlated with contributions to the browning of adipose tissue, all dependent on HO-1. Our observations reveal a positive impact of adipose-PGC1-α on distal organ systems, with beneficial effects on HO-1 levels, reversing obesity-linked cardiometabolic disturbances.

• PGC-1α
• brown fat
• inflammation
• mitochondria
• obesity
• type 2 diabetes

Non alcoholic steatohepatitis (NASH) is the inflammatory reaction of the liver to excessive accumulation of lipids in the hepatocytes. NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Fatty liver is the hepatic manifestation of metabolic syndrome. A subclinical inflammatory state is present in patients with metabolic alterations like insulin resistance, type-2 diabetes, obesity, hyperlipidemia, and hypertension. Platelets participate in immune cells recruitment and cytokines-induced liver damage. It is hypothesized that lipid toxicity cause accumulation of platelets in the liver, platelet adhesion and activation, which primes the immunoinflammatory reaction and activation of stellate cells. Recent data suggest that antiplatelet drugs may interrupt this cascade and prevent/improve NASH. They may also improve some metabolic alterations. The pathophysiology of inflammatory liver disease and the implication of platelets are discussed in details.

• Brown adipocyte
• Diabetes
• Fatty liver
• Leptin resistance
• Pericardial fat
• Stem cells
• hypertension

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system.

• GSH
• Nrf2
• TIGAR
• heme oxygenase

• cardiovascular disease
• gene expression
• obesity
• platelet
• transcriptome

• Adult
• Aged
• Bariatric Surgery
• Blood Platelets/metabolism
• Cardiometabolic Risk Factors
• Cardiovascular Diseases/blood
• Cardiovascular Diseases/epidemiology
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/prevention & control
• Female
• Gene Expression Profiling
• Gene Expression Regulation
• Gene Regulatory Networks
• High-Throughput Nucleotide Sequencing
• Humans
• Incidence
• Longitudinal Studies
• Male
• Middle Aged
• Obesity/blood
• Obesity/epidemiology
• Obesity/genetics
• Obesity/surgery
• Platelet Aggregation
• Prospective Studies
• RNA-Seq
• Risk Assessment
• Time Factors
• Transcriptome
• Treatment Outcome
• Weight Loss/genetics
• Young Adult

• HHSN268201500001C NHLBI NIH HHS
• U54 HL112311 NHLBI NIH HHS
• U01 HL126495 NHLBI NIH HHS
• HHSN268201500001I NHLBI NIH HHS
• N01HC25195 NHLBI NIH HHS
• 16SFRN31740000 American Heart Association-American Stroke Association

Novel heme oxygenase-1 (HO-1) inducers based on dimethyl fumarate (DMF) structure are reported in this paper. These compounds are obtained by modification of the DMF backbone. Particularly, maintaining the α, β-unsaturated dicarbonyl function as the central chain crucial for HO-1 induction, different substituted or unsubstituted phenyl rings are introduced by means of an ester or amide linkage. Symmetric and asymmetric derivatives are synthesized. All compounds are tested on a human hepatic stellate cell line LX-2 to assay their capacity for modifying HO-1 expression. Compounds 1b, 1l and 1m stand out for their potency as HO-1 inducers, being 2–3 fold more active than DMF, and for their ability to reverse reactive oxygen species (ROS) production mediated using palmitic acid (PA). These properties, coupled with a low toxicity toward LX-2 cell lines, make these compounds potentially useful for treatment of diseases in which HO-1 overexpression may counteract inflammation, such as hepatic fibrosis. Docking studies show a correlation between predicted binding free energy and experimental HO-1 expression data. These preliminary results may support the development of new approaches in the management of liver fibrosis.

• HO-1 inducers
• LX-2 cells
• dimethyl fumarate (DMF)
• heme oxygenase (HO)
• hepatic fibrosis

• heme oxygenase
• metabolism
• mitochondria
• type II diabetes

• Animals
• Diet, High-Fat/adverse effects
• Humans
• Metabolic Syndrome/drug therapy
• Metabolic Syndrome/etiology
• Mice
• Silybum marianum
• Obesity/chemically induced
• Obesity/drug therapy
• Seeds

• P01 HL051971 NHLBI NIH HHS
• P20 GM104357 NIGMS NIH HHS
• P20 GM121334 NIGMS NIH HHS
• R01 DK121748 NIDDK NIH HHS
• R56 HL139561 NHLBI NIH HHS

• Antioxidant
• Heme protein
• Hepatocyte
• Liver
• Liver fibrosis
• Obesity

• Na/K-ATPase
• adipocytes
• coronavirus disease
• heart failure
• heme oxygenase
• obesity
• reactive oxygen species

• Animals
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1/genetics
• Humans
• Liver
• Liver Transplantation
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Reperfusion Injury

• P01 AI120944 NIAID NIH HHS
• R01 DK062357 NIDDK NIH HHS
• R01 DK102110 NIDDK NIH HHS
• R01 DK107533 NIDDK NIH HHS

Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-⁹⁷², p-IRB tyr¹¹⁴⁶, and pAMPK, thereby decreasing insulin resistance. Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.

• PGC-1α
• ROS
• heme-oxygenase (HO-1)
• insulin resistance
• obesity
• oxygen consumption

• Animals
• Antioxidants/therapeutic use
• Blood Pressure/drug effects
• Insulin Resistance
• Lipid Metabolism/drug effects
• Liver Cirrhosis/drug therapy
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Mitochondria/drug effects
• Mitochondria/pathology
• Obesity/drug therapy
• Plant Oils/therapeutic use
• Pomegranate/chemistry
• Seeds/chemistry

• Health R 56-139561,1R01 DK121748-01A1, P01 HL05197-11 NIH HHS
• P01 HL051971 NHLBI NIH HHS
• P20 GM104357 NIGMS NIH HHS
• R01 DK121748 NIDDK NIH HHS
• P20GM104357-02 NIGMS NIH HHS
• P20 GM121334 NIGMS NIH HHS

• PGC-1α
• antioxidant
• diabetes
• diabetic cardiomyopathy
• heme oxygenase

• Animals
• Antioxidants/metabolism
• Diabetic Cardiomyopathies/metabolism
• Heme Oxygenase-1/metabolism
• Humans
• Transcription Factors/metabolism

• R56 HL139561 NHLBI NIH HHS

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant Nigella Sativa and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5′ adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser³⁰⁷ expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr⁹⁷²), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser³⁰⁷ and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.

• beige adipocyte
• inflammation
• insulin resistance
• obesity
• omega 3
• thymoquinone

• adipocytes
• cardiovascular disease
• heme oxygenase
• obesity
• oxidative stress

CD62L (L-Selectin) dependent lymphocyte infiltration is known to induce inflammatory bowel disease (IBD), while its function in the liver, especially in non-alcoholic steatohepatitis (NASH), remains unclear. We here investigated the functional role of CD62L in NASH in humans as well as in two mouse models of steatohepatitis. Hepatic expression of a soluble form of CD62L (sCD62L) was measured in patients with steatosis and NASH. Furthermore, CD62L^−/− mice were fed with a methionine and choline deficient (MCD) diet for 4 weeks or with a high fat diet (HFD) for 24 weeks. Patients with NASH displayed increased serum levels of sCD62L. Hepatic CD62L expression was higher in patients with steatosis and increased dramatically in NASH patients. Interestingly, compared to wild type (WT) mice, MCD and HFD-treated CD62L^−/− mice were protected from diet-induced steatohepatitis. This was reflected by less fat accumulation in hepatocytes and a dampened manifestation of the metabolic syndrome with an improved insulin resistance and decreased cholesterol and triglyceride levels. Consistent with ameliorated disease, CD62L^−/− animals exhibited an enhanced hepatic infiltration of Treg cells and a strong activation of an anti-oxidative stress response. Those changes finally resulted in less fibrosis in CD62L^−/− mice. Additionally, this effect could be reproduced in a therapeutic setting by administrating an anti-CD62L blocking antibody. CD62L expression in humans and mice correlates with disease activity of steatohepatitis. CD62L knockout and anti-CD62L-treated mice are protected from diet-induced steatohepatitis suggesting that CD62L is a promising target for therapeutic interventions in NASH.

• CD62L
• L-Selectin
• NASH
• insulin resistance
• non-alcoholic steatohepatitis

• Animals
• Cells, Cultured
• Diet, High-Fat/adverse effects
• Disease Models, Animal
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Humans
• L-Selectin/metabolism
• Liver/metabolism
• Male
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease/metabolism

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.

• PGC1-α
• adipocytes
• adiponectin
• antioxidant
• gene-HO-1
• hyperglycemia
• hypertension

• Na/K-ATPase signaling
• heme oxygenase 1
• non-alcoholic steatohepatitis
• obesity
• oxidative stress

• Animals
• Heme Oxygenase-1/metabolism
• Humans
• Non-alcoholic Fatty Liver Disease/metabolism
• Obesity/metabolism
• Oxidative Stress
• Signal Transduction
• Sodium-Potassium-Exchanging ATPase/metabolism

• Antioxidant
• Ginseng
• Ginsenoside
• Heme oxygenase
• Nrf2

• Antineoplastic Agents, Phytogenic/pharmacology
• Antioxidants/pharmacology
• Cardiotonic Agents/pharmacology
• Ginsenosides/pharmacology
• Heme Oxygenase-1/physiology
• Humans
• NF-E2-Related Factor 2/physiology
• Neuroprotective Agents/pharmacology
• Panax/chemistry
• Phytochemicals/pharmacology
• Plants, Medicinal/chemistry
• Signal Transduction

• Adiponectin
• NAFLD
• Obesity
• PPAR

• Adiponectin/metabolism
• Animals
• Humans
• Non-alcoholic Fatty Liver Disease/metabolism
• Obesity/metabolism
• Peroxisome Proliferator-Activated Receptors/metabolism

• Adipocyte inflammation
• Bilirubin
• Fatty liver
• Hyperbilirubinemia
• Hypertension
• Obesity

The progression of non-alcoholic fatty liver disease (NAFLD) and the development of hepatic fibrosis is caused by changes in redox balance, leading to an increase of reactive oxygen species (ROS) levels. NAFLD patients are at risk of progressing to non-alcoholic steatohepatitis (NASH), associated to cardiovascular diseases (CVD), coronary heart disease and stroke. Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. The present work was directed to determine whether use of an inhibitor of HO-1 activity affects lipid metabolism and fibrosis process in hepatic cells. Oil Red assay and mRNA analysis were used to evaluate the triglycerides content and the lipid metabolism pathway in HepG2 cells. ROS measurement, RT-PCR and Soluble collagen assay were used to assess the intracellular oxidant, the fibrosis pathway and the soluble collagen in LX2 cells. The activity of HO-1 was inhibited using Tin Mesoporphyrin IX (SnMP). Our study demonstrates that a non-functional HO system results in an increased lipid storage and collagen release in hepatocytes. Consequently, an increase of HO-1 levels may provide a therapeutic approach to address the metabolic alterations associated with NAFLD and its progression to NASH.

• HO-1 inhibitor
• NAFLD
• collagen
• heme oxygenase
• hepatocytes
• oxidative stress

• BNIP3
• acute-on-chronic liver failure
• apoptosis
• autophagy
• mitofusin2

High levels of heme oxygenase (HO)-1 have been frequently reported in different human cancers, playing a major role in drug resistance and regulation of cancer cell redox homeostasis. Metformin (MET), a drug widely used for type 2 diabetes, has recently gained interest for treating several cancers. Recent studies indicated that the anti-proliferative effects of metformin in cancer cells are highly dependent on glucose concentration. The present work was directed to determine whether use of a specific inhibitor of HO-1 activity, alone or in combination with metformin, affected metastatic prostate cancer cell viability under different concentrations of glucose. MTT assay and the xCELLigence system were used to evaluate cell viability and cell proliferation in DU145 human prostate cancer cells. Cell apoptosis and reactive oxygen species were analyzed by flow cytometry. The activity of HO-1 was inhibited using a selective imidazole-based inhibitor; genes associated with antioxidant systems and cell death were evaluated by qRT-PCR. Our study demonstrates that metformin suppressed prostate cancer growth in vitro and increased oxidative stress. Disrupting the antioxidant HO-1 activity, especially under low glucose concentration, could be an attractive approach to potentiate metformin antineoplastic effects and could provide a biochemical basis for developing HO-1-targeting drugs against solid tumors.

• ER stress
• HO-1 activity inhibitor
• apoptosis
• heme oxygenase
• metformin
• prostate cancer

• Apoptosis/drug effects
• Cell Line, Tumor
• Enzyme Inhibitors/pharmacology
• Glucose/metabolism
• Heme Oxygenase-1/antagonists & inhibitors
• Heme Oxygenase-1/metabolism
• Humans
• Male
• Metformin/pharmacology
• Prostatic Neoplasms/metabolism
• Reactive Oxygen Species/metabolism

Objective: Heme oxygenase (HO-1) plays a critical role in adipogenesis and it is important to understand its function in obesity. Many studies have shown that upregulation of HO-1 can affect the biologic parameters in obesity-mediated diabetes, hypertension and vascular endothelial cell function. Thus, we aimed to explore the hypothesis that upregulation of HO-1, using a pharmacologic approach as well as gene targeting, would improve both adiposity and endothelial cell dysfunction by direct targeting of endothelial cells. Our second aim was to compare the short-term effect of a HO-1 inducer, cobalt-protoporphrin IX (CoPP), with the long-term effects of gene targeted therapy on vascular and adipocyte stem cells in obese mice. Method: We examined the effect of CoPP on fat pre-adipocytes and mesenchymal stem cells (MSC) in mice fed a high-fat diet (HFD). We also used a lentiviral construct that expressed heme oxygenase (HO-1) that was under the control of an endothelium specific promoter, vascular endothelium cadherin (VECAD) heme oxygenase (VECAD-HO-1). We targeted endothelial cells using vascular endothelium cadherin/green fluorescent protein fusion construct (VECAD-GFP) as the control. Conditioned media (CM) from endothelial cells (EC) was added to fat derived adipocytes. Additionally, we treated renal interlobar arteries with phenylephrine and dosed cumulative increments of acetylcholine both with and without exposure to CoPP. We did the same vascular reactivity experiments with VECAD-HO-1 lentiviral construct compared to the control. Results: CoPP improved vascular reactivity and decreased adipogenesis compared to the control. MSCs exposed to CM from EC transfected with VECAD-HO-1 showed decreased adipogenesis, smaller lipid droplet size and decreased PPAR-γ, C/EBP and increased Wnt 10b compared to the control. HO-1 upregulation had a direct effect on reducing adipogenesis. This effect was blocked by tin mesoporphrin (SnMP). EC treated with VECAD-HO-1 expressed lower levels of ICAM and VCAM compared to the control, suggesting improved EC function. This also improved ACH induced vascular reactivity. These effects were also reversed by SnMP. The effect of viral transfection was much more specific and sustained than the effects of pharmacologic therapy, CoPP. Conclusion: This study demonstrates that a pharmacological inducer of HO-1 such as CoPP improves endothelial cell function while dampening adipogenesis, but long-term HO-1 expression by direct targeting of endothelial cells by gene transfer therapy may offer a more specific and ideal solution. This was evidenced by smaller healthier adipocytes that had improved insulin sensitivity, suggesting increased adiponectin levels. HO-1 upregulation reestablished the “crosstalk” between perivascular adipose tissue and the vascular system that was lost in the chronic inflammatory state of obesity. This study demonstrates that gene targeting of EC may well be the future direction in treating obesity induced EC dysfunction, with the finding that targeting the vasculature had a direct and sustained effect on adipogenesis.

• bilirubin
• carbon monoxide
• cardiovascular disease
• cell cycle
• circulating endothelial progenitor cells
• diabetes
• endothelial cell function
• gene transfer adipocytes
• heme oxygenase-1
• hypertension
• inflammation
• lentiviral transfection
• statin

• Adiposity/drug effects
• Animals
• Cell Line
• Endothelial Cells/drug effects
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Enzyme Activators/therapeutic use
• Gene Targeting
• Genetic Therapy
• Heme Oxygenase-1/genetics
• Male
• Mice, Inbred C57BL
• Obesity/genetics
• Obesity/pathology
• Obesity/physiopathology
• Obesity/therapy
• Pyrazines/therapeutic use
• Pyrroles/therapeutic use
• Up-Regulation/drug effects
• Vasodilation/drug effects

As an irreversible and perennial process, aging is accompanied by functional and morphological declines in organs. Generally, aging liver exhibits a decline in volume and hepatic blood flow. Even with a preeminent regenerative capacity to restore its functions after liver cell loss, its biosynthesis and metabolism abilities decline, and these are difficult to restore to previous standards. Apoptosis is a programmed death process via intrinsic and extrinsic pathways, in which Bcl-2 family proteins and apoptosis-related genes, such as p21 and p53, are involved. Apoptosis inflicts both favorable and adverse influences on liver aging. Apoptosis eliminates transformed abnormal cells but promotes age-related liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, and liver cancer. We summarize the roles of apoptosis in liver aging and age-related liver diseases.

• Apoptosis
• Liver aging
• Oxidative stress
• Caloric restriction
• Cirrhosis

• Biliverdin reductase-a
• Insulin signaling
• Metabolic disorders
• Obesity