Publications by authors named "Luca Vanella"

112 Publications

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions.

Biomolecules 2021 Apr 16;11(4). Epub 2021 Apr 16.

Department of Drug and Health Sciences, Biochemistry Section, University of Catania, 95124 Catania, Italy.

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 (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.
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http://dx.doi.org/10.3390/biom11040589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072688PMC
April 2021

Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure.

Int J Mol Sci 2020 Dec 15;21(24). Epub 2020 Dec 15.

Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.

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 , and 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.
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http://dx.doi.org/10.3390/ijms21249541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765375PMC
December 2020

Milk thistle seed cold press oil attenuates markers of the metabolic syndrome in a mouse model of dietary-induced obesity.

J Food Biochem 2020 12 12;44(12):e13522. Epub 2020 Oct 12.

Department of Medicine, New York Medical College, Valhalla, NY, USA.

Milk thistle cold press oil (MTO) is an herbal remedy derived from Silybum marianum which contains a low level of silymarin and mixture of polyphenols and flavonoids. The effect of MTO on the cardiovascular and metabolic complications of obesity was studied in mice that were fed a high-fat diet (HFD) for 20 weeks and treated with MTO for the final 8 weeks of the diet. MTO treatment attenuated HFD-induced obesity, fasting hyperglycemia, hypertension, and induced markers of mitochondrial fusion and browning of white adipose. Markers of inflammation were also attenuated in both adipose and the liver of MTO-treated mice. In addition, MTO resulted in the improvement of liver fibrosis. These results demonstrate that MTO has beneficial actions to attenuate dietary obesity-induced weight gain, hyperglycemia, hypertension, inflammation, and suggest that MTO supplementation may prove beneficial to patients exhibiting symptoms of metabolic syndrome. PRACTICAL APPLICATIONS: Natural supplements are increasingly being considered as potential therapies for many chronic cardiovascular and metabolic diseases. Milk thistle cold press oil (MTO) is derived from Silybum marianum which is used as a dietary supplement in different parts of the world. The results of the present study demonstrate that MTO supplementation normalizes several metabolic and cardiovascular complications arising from dietary-induced obesity. MTO supplementation also had anti-inflammatory actions in the adipose as well as the liver. These results suggest that supplementation of MTO into the diet of obese individuals may afford protection against the worsening of cardiovascular and metabolic disease and improve inflammation and liver fibrosis.
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http://dx.doi.org/10.1111/jfbc.13522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770619PMC
December 2020

Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

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 ( = 6) (2) HF diet; group ( = 6) (3) HF diet treated with PSO (40 mL/kg food) ( = 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 ( < 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-, p-IRB tyr, 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.
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http://dx.doi.org/10.3390/ijms21155469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432301PMC
July 2020

Evaluation of lipid and cholesterol-lowering effect of bioflavonoids from bergamot extract.

Nat Prod Res 2020 May 22:1-6. Epub 2020 May 22.

Council for Agricultural Research and Economics (CREA) - Research Centre for Olive, Fruit and Citrus Crops, Acireale, Italy.

Several natural products have been reported to be involved in the suppression of adipogenesis. In this study, we reveal that a bergamot extract (BE) decreased the accumulation of intracellular lipids in murine pre-adipocytes 3T3-L1 cells during adipogenic differentiation. Both the inhibition of HMG-CoA reductase activity and the differentiation and proliferation of adipocytes could be used as a strategy for the treatment and prevention of obesity. The results of this study show a reduction of HMG-CoA activity and of lipid droplet accumulation in the presence of the BE, suggesting the potential of BE as an anti-adipogenic agent to lower the content of cholesterol and body fat and prevent a gain in body weight. Moreover, BE as the result of high percentages of flavonoid compounds such as neoriocitrin, naringin and neohesperidin, the main flavonoids contained in BE, led to significant inhibition of DPPH free radical, demonstrating a strong radical scavenging activity.
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http://dx.doi.org/10.1080/14786419.2020.1768085DOI Listing
May 2020

New Arylethanolimidazole Derivatives as HO-1 Inhibitors with Cytotoxicity against MCF-7 Breast Cancer Cells.

Int J Mol Sci 2020 Mar 11;21(6). Epub 2020 Mar 11.

Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125 Catania, Italy.

In this paper, a novel series of imidazole-based heme oxygenase-1 (HO-1) inhibitors is reported. These compounds were obtained by modifications of previously described high potent and selective arylethanolimidazoles. In particular, simplification of the central linker and repositioning of the hydrophobic portion were carried out. Results indicate that a hydroxyl group in the central region is crucial for the potency as well as the spatial distribution of the hydrophobic portion. Docking studies revealed a similar interaction of the classical HO-1 inhibitors with the active site of the protein. The most potent and selective compound () was tested for its potential cytotoxic activity against hormone-sensitive and hormone-resistant breast cancer cell lines (MCF-7 and MDA-MB-231).
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http://dx.doi.org/10.3390/ijms21061923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139504PMC
March 2020

Pathophysiology of chronic peripheral ischemia: new perspectives.

Ther Adv Chronic Dis 2020 5;11:2040622319894466. Epub 2020 Feb 5.

Departments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY, USA.

Peripheral arterial disease (PAD) affects individuals particularly over 65 years old in the more advanced countries. Hemodynamic, inflammatory, and oxidative mechanisms interact in the pathophysiological scenario of this chronic arterial disease. We discuss the hemodynamic, muscle tissue, and oxidative stress (OxS) conditions related to chronic ischemia of the peripheral arteries. This review summarizes the results of evaluating both metabolic and oxidative markers, and also therapy to counteract OxS. In conclusion, we believe different pathways should be highlighted to discover new drugs to treat patients suffering from PAD.
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http://dx.doi.org/10.1177/2040622319894466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003198PMC
February 2020

Non-competitive heme oxygenase-1 activity inhibitor reduces non-small cell lung cancer glutathione content and regulates cell proliferation.

Mol Biol Rep 2020 Mar 13;47(3):1949-1964. Epub 2020 Feb 13.

Department of Drug Science, Biochemistry Section, University of Catania, Viale A. Doria 6, 95125, Catania, Italy.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death mainly due to its high metastatic rate. Impairment of redox homeostasis mechanisms has been previously described in NSCLC and is associated with the disease itself as well as with comorbidities such as smoking. The aim of the present in vitro study was to evaluate the effect of selective and non-competitive inhibition of heme oxygenase-1 (HO-1) on cancer redox homeostasis with particular regards to glutathione (GSH) metabolism related enzymes. NSCLC cell line (A549) was treated with the HO-1 activity inhibitor VP13/47 (10 µM) and we further evaluated cell viability, apoptosis, mitochondrial dysfunction and oxidative stress. Our results showed that VP13/47 significantly reduced HO-1 expression and total HO activity thus, resulting in a significant reduction of cell viability, proliferation and increased apoptosis, mitochondrial dysfunction and oxidative stress. Consistently with increased oxidative stress, we also showed that reduced GSH was significantly decreased and such effect was also accompanied by a significant downregulation of the enzymes involved in its biosynthesis. Taken all together our results show that selective HO-1 inhibition significantly impairs NSCLC progression and may represent a possible pharmacological strategy for new chemotherapy agents.
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http://dx.doi.org/10.1007/s11033-020-05292-yDOI Listing
March 2020

In vitro effects of bioflavonoids rich lemon extract on pre-adipocyte differentiation.

Nat Prod Res 2020 Feb 3:1-5. Epub 2020 Feb 3.

Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy.

Lemon fruit is a source of bioactive compounds, which has many beneficial effects on health. Obesity is characterized by over-accumulation of adipose tissue as a result of increased adipocyte size and number. Adipogenesis is mediated and assisted by various transcription factors that induce lipid-metabolizing enzymes followed by an increase of perilipin expression and lipid droplets generation. Here, we evaluate the effect of lemon extract (LE) as radical scavenger and the consequent regulation of adipocyte differentiation and lipid accumulation. 3T3-L1 murine pre-adipocytes were differentiated and treated with different LE concentrations. The high percentages of flavonoid contained in LE led to a significant inhibition of DPPH radical and reactive oxygen species, demonstrating a strong radical scavenger activity. Treatment of 3T3-cells with LE showed a significant decrease of perilipin expression, subsequently confirmed by the reduction of lipid droplet accumulation, resulting from Oil Red O Staining and by the downregulation of PPARγ and DGAT-1mRNA.
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http://dx.doi.org/10.1080/14786419.2020.1721493DOI Listing
February 2020

Tissue-Derived Stem Cell Research 2019.

Stem Cells Int 2019 19;2019:4765684. Epub 2019 Dec 19.

Department of Drug Science, Section of Biochemistry, University of Catania, 95125 Catania, Italy.

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http://dx.doi.org/10.1155/2019/4765684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942902PMC
December 2019

Synthesis, and studies of HO-1 inducers and lung antifibrotic agents.

Future Med Chem 2019 07;11(13):1523-1536

Department of Drug Sciences, University of Catania, Viale A. Doria 6, Sicily, 95125, Italy.

Dimethyl fumarate (DMF) analogs were synthesized to obtain inducers of HO-1 and antifibrotic agents. HO-1 expression levels were measured on lung fibroblasts (MRC5). NMR and docking studies were performed. Heme oxygenase activity, gene levels and protein expression have been measured for the most active compound . Collagen production by fibroblast after exposure to TGF-β was measured. Compound showed to be a strong HO-1 inducer. Its activity seems to be mediated by activation of nuclear factor erythroid 2 related factor 2 (Nrf2). TGF-β-induced collagen production was significantly decreased on MRC5, pretreated with DMF or . DMF and have a high potential for treatment of lung fibrotic injuries.
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http://dx.doi.org/10.4155/fmc-2018-0448DOI Listing
July 2019

Inhibition of Heme Oxygenase Antioxidant Activity Exacerbates Hepatic Steatosis and Fibrosis .

Antioxidants (Basel) 2019 Aug 5;8(8). Epub 2019 Aug 5.

Department of Drug Science, Biochemistry Section, University of Catania, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.3390/antiox8080277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719023PMC
August 2019

L. Leaf Extract Induces Adiponectin and Regulates Adipogenesis.

Int J Mol Sci 2019 Jun 29;20(13). Epub 2019 Jun 29.

Department of Drug Science, Biochemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

Natural bioactive compounds may be used in obese patients because of their ability to impact on various key mechanisms involved in the complex pathophysiological mechanisms of such condition. The aim of this study was to investigate the effect of a L. leaf extract (MLE) on adipogenic differentiation of murine preadipocyte cells. 3T3-L1 cells were treated during their differentiation with various concentrations of ( L.) leaves extract (MLE) (750, 380, 150, 75 and 35 μg) in order to assess their lipid content, adiponectin production, expression profile of genes involved in lipid metabolism, oxidative stress and inflammation. Our results showed that MLE was particularly enriched in polyphenols (46.30 ± 0.083 mg/g) and that pharmacological treatment of cells resulted in a significant increase of adiponectin levels and reduction of intracellular lipid content. Consistently with these results, MLE resulted in a significant decrease of the expression of genes involved in lipid metabolism (FAS, PPARG, DGAT1, DGAT2, and SCD-1). In conclusion, our results suggest that MLE may represent a possible pharmacological tool for obese or metabolic syndrome patients.
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http://dx.doi.org/10.3390/ijms20133211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651838PMC
June 2019

Heme Oxygenase-1 Inhibition Sensitizes Human Prostate Cancer Cells towards Glucose Deprivation and Metformin-Mediated Cell Death.

Int J Mol Sci 2019 May 27;20(10). Epub 2019 May 27.

Department of Drug Science, Biochemistry Section, University of Catania, 95125 Catania, Italy.

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.
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http://dx.doi.org/10.3390/ijms20102593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566853PMC
May 2019

Protective Effects of Caffeic Acid Phenethyl Ester (CAPE) and Novel Cape Analogue as Inducers of Heme Oxygenase-1 in Streptozotocin-Induced Type 1 Diabetic Rats.

Int J Mol Sci 2019 May 17;20(10). Epub 2019 May 17.

Department of Drug Science, Biochemistry Section, University of Catania, 95125 Catania, Italy.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease resulting in the destruction of insulin producing β-cells of the pancreas, with consequent insulin deficiency and excessive glucose production. Hyperglycemia results in increased levels of reactive oxygen species (ROS) and nitrogen species (RNS) with consequent oxidative/nitrosative stress and tissue damage. Oxidative damage of the pancreatic tissue may contribute to endothelial dysfunction associated with diabetes. The aim of the present study was to investigate if the potentially protective effects of phenethyl ester of caffeic acid (CAPE), a natural phenolic compound occurring in a variety of plants and derived from honeybee hive propolis, and of a novel CAPE analogue, as heme oxygenase-1 (HO-1) inducers, could reduce pancreatic oxidative damage induced by excessive amount of glucose, affecting the nitric oxide synthase/dimethylarginine dimethylaminohydrolase (NOS/DDAH) pathway in streptozotocin-induced type 1 diabetic rats. Our data demonstrated that inducible nitric oxide synthase/gamma-Glutamyl-cysteine ligase (iNOS/GGCL) and DDAH dysregulation may play a key role in high glucose mediated oxidative stress, whereas HO-1 inducers such as CAPE or its more potent derivatives may be useful in diabetes and other stress-induced pathological conditions.
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http://dx.doi.org/10.3390/ijms20102441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567686PMC
May 2019

Mesenteric lymph nodes as alternative site for pancreatic islet transplantation in a diabetic rat model.

BMC Surg 2019 Apr 24;18(Suppl 1):126. Epub 2019 Apr 24.

Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy.

Background: Islet transplantation has progressively become a safe alternative to pancreas transplantation for the treatment of type 1 diabetes. However, the long-term results of islet transplantation could be significantly increased by improving the quality of the islet isolation technique even exploring alternative islet transplantation sites to reduce the number of islets required to mitigate hyperglycemia. The goal of the study was to test the lymph node as a suitable anatomical location for islet engraftment in a rodent model.

Methods: Forty Lewis rats, 6-8 weeks old, body weight 250-300 g, have been used as islet donors and recipients in syngeneic islet transplantation experiments. Ten rats were rendered diabetic by one injection of 65 mg/Kg of streptozotocin. After pancreas retrieval from non diabetic donors, islet were isolated and transplanted in the mesenteric lymph nodes of 7 diabetic rats. Rats were followed for 30 days after islet transplantation.

Results: A total of 7 islet transplantations in mesenteric lymph nodes have been performed. Two rats died 24 and 36 h after transplantation due to complications. No transplanted rat acquired normal glucose blood levels and insulin independence after the transplantation. However, the mean blood levels of glycemia were significantly lower in transplanted rats compared with diabetic rats (470.4 mg/dl vs 605 mg/dl, p 0.04). Interestingly, transplanted rats have a significant weight increase after transplantation compared to diabetic rats (mean value 295 g in transplanted rats vs 245 g in diabetic rats, p < 0.05), with an overall improvement of social activities and health. Immunohistochemical analysis of the 5 mesenteric lymph nodes of transplanted rats demonstrated the presence of living islets in one lymph node.

Conclusions: Although islet engraftment in lymph nodes is possible, islet transplantation in lymph nodes in rats resulted in few improvements of glucose parameters.
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http://dx.doi.org/10.1186/s12893-018-0452-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402566PMC
April 2019

Epoxyeicosatrienoic intervention improves NAFLD in leptin receptor deficient mice by an increase in PGC1α-HO-1-PGC1α-mitochondrial signaling.

Exp Cell Res 2019 07 27;380(2):180-187. Epub 2019 Apr 27.

Department of Drug Science, University of Catania, Catania, Italy. Electronic address:

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD.

Methods: We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks.

Results: db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration.

Conclusions: EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD.
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http://dx.doi.org/10.1016/j.yexcr.2019.04.029DOI Listing
July 2019

Beneficial Effects of Pomegranate Peel Extract and Probiotics on Pre-adipocyte Differentiation.

Front Microbiol 2019 3;10:660. Epub 2019 Apr 3.

Dipartimento di Scienze del Farmaco, Sezione di Biochimica, Università di Catania, Catania, Italy.

The beneficial effects of pomegranate are due to the ellagitannins and anthocyanins content, which are protective toward a wide variety of diseases including inflammatory diseases. Many investigators have reported that pomegranate waste (peel and seeds) extracts, made from waste product of industrial processing, show free radical scavenger and a potent antioxidant capacity. Pomegranate extracts (PEs) were also reported to possess noteworty antibacterial, antiviral, hypolipidemic, and anti-inflammatory bioactivities thanks to the polyphenolic compounds content, which includes punicalagins, gallic acid, and ellagic acid derivatives. The focus of the present manuscript was to study the prebiotic potentiality of a PE, soluble in water, and characterized through HPLC-PDA-ESI/MS for its phenolic content. Moreover, since it has been reported that pomegranate extracts decreased the level of lipids in the blood and that a number of probiotic strains have been shown to affect adipogenesis in cell culture, this study was also performed to test the effects of PE and probiotic GG ATCC 53103 strain (LGG) on 3T3-L1 cell line. PE and probiotics substantially reduced the triglyceride content and intracellular lipid increase, compared to the control group. However, the combination treatment of PE and LGG filtered spent broth (SB) was the most effective in reducing triglyceride content and intracellular lipid accumulation. The mRNA expression levels of the main transcriptional factors implicated in adipocyte differentiation were substantially lower in 3T3-L1 cells treated with PE and LGG filtered SB. These results evidenced that a synergistic effect of probiotics and polyphenols contained in PE may affect adipogenesis and may contribute in development of new nutraceutical/probiotic-based remedies to prevent and to treat obesity.
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http://dx.doi.org/10.3389/fmicb.2019.00660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456667PMC
April 2019

N-Acetylcysteine (NAC) Ameliorates Lipid-Related Metabolic Dysfunction in Bone Marrow Stromal Cells-Derived Adipocytes.

Evid Based Complement Alternat Med 2018 17;2018:5310961. Epub 2018 Oct 17.

Department of Drug Science, Biochemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

Recent experimental data suggest that fatty acids and lipotoxicity could play a role in the initiation and evolution of metabolic bone diseases such as osteoporosis. A functional bone marrow adipose tissue (BMAT) may provide support to surrounding cells and tissues or may serve as a lipid reservoir that protects skeletal osteoblasts from lipotoxicity. The present study examined the effect of N-acetylcysteine (NAC), a powerful antioxidant and precursor of glutathione, commonly used to treat chronic obstructive pulmonary disease, on triglycerides accumulation in bone marrow stromal cells-derived adipocytes. Quantification of Oil Red O stained cells showed that lipid droplets decreased following NAC treatment. Additionally, exposure of bone marrow stromal cells (HS-5) to NAC increased adiponectin, PPAR, HO-1, and SIRT-1 and increased beta-oxidation markers such as PPAR and PPAR mRNA levels. As there is now substantial interest in alternative medicine, the observed therapeutic value of NAC should be taken into consideration in diabetic patients.
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http://dx.doi.org/10.1155/2018/5310961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207898PMC
October 2018

Targeting heme Oxygenase-1 with hybrid compounds to overcome Imatinib resistance in chronic myeloid leukemia cell lines.

Eur J Med Chem 2018 Oct 17;158:937-950. Epub 2018 Sep 17.

Department of Drug Sciences, University of Catania, viale A. Doria 6, 95125, Catania, Italy. Electronic address:

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme and a survival-enhancing factor in a number of cancers. Chronic myeloid leukemia (CML) is a blood cancer caused by pathological kinase activity of the BCR-ABL protein, currently treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM). However, resistance to TKIs persists in a number of patients and HO-1 overexpression has been linked with the induction of chemoresistance in CML. With this in mind, in this study, we designed and synthesized the first series of hybrid compounds obtained by combining the structures of IM, as BCR-ABL inhibitor, with imidazole-based HO-1 inhibitors. We found that many hybrids were able to inhibit the enzymatic activity of both targets and to reduce the viability of CML-IM resistant cells, showing that a single molecular entity may reduce the resistance phenomenon.
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http://dx.doi.org/10.1016/j.ejmech.2018.09.048DOI Listing
October 2018

Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress.

Int J Hepatol 2018 2;2018:3484107. Epub 2018 Jul 2.

Departments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USA.

Aim: Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice.

Methods: Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology.

Results: NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue.

Conclusions: These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH.
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http://dx.doi.org/10.1155/2018/3484107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051135PMC
July 2018

Ablation of soluble epoxide hydrolase reprogram white fat to beige-like fat through an increase in mitochondrial integrity, HO-1-adiponectin in vitro and in vivo.

Prostaglandins Other Lipid Mediat 2018 09 21;138:1-8. Epub 2018 Jul 21.

Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA; Joan Edward School of Medicine, Marshall University, Huntington, WV, 25701, USA. Electronic address:

We have shown that epoxyeicosatrienoic acids (EETs), specifically 11,12- and 14,15-EETs, reduce adipogenesis in human mesenchymal stem cells and mouse preadipocytes (3T-3L1). In this study, we explore the effects of soluble epoxide hydrolase (sEH) deletion on various aspects of adipocyte-function, including programing for white vs. beige-like fat, and mitochondrial and thermogenic gene-expressions. We further hypothesize that EETs and heme-oxygenase 1 (HO-1) form a synergistic, functional module whose effects on adipocyte and vascular function is greater than the effects of sEH deletion alone. In in vitro studies, we examined the effect of sEH inhibitors on MSC-derived adipocytes. MSC-derived adipocytes exposed to AUDA, an inhibitor of sEH, exhibit an increased number of small and healthy adipocytes, an effect reproduced by siRNA for sEH. in vivo studies indicate that sEH deletion results in a significant decrease in adipocyte size, inflammatory adipokines NOV, TNFα, while increasing adiponectin (p < 0.05). These findings are associated with a decrease in body weight (p < 0.05), and visceral fat (p < 0.05). Importantly, sEH deletion was associated with a significant increase in Mfn1, COX 1, UCP1 and adiponectin (p < 0.03). sEH deletion was manifested by a significant increase in EETs isomers 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET and an increased EETs/DHETEs ratio. Notably, activation of HO-1 gene expression further increased the levels of EETs, suggesting that the antioxidant HO-1 system protects EETs from degradation by ROS. These results are novel in that sEH deletion, while increasing EET levels, resulted in reprograming of white fat to express mitochondrial and thermogenic genes, a phenotype characteristic of beige-fat. Thus, EETs agonist(s) and sEH inhibitors may have therapeutic potential in the treatment of metabolic syndrome and obesity.
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http://dx.doi.org/10.1016/j.prostaglandins.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314013PMC
September 2018

Heme Oxygenase Inhibition Sensitizes Neuroblastoma Cells to Carfilzomib.

Mol Neurobiol 2019 Feb 10;56(2):1451-1460. Epub 2018 Jun 10.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 97, 95125, Catania, Italy.

Neuroblastoma (NB) is an embryonic malignancy affecting the physiological development of adrenal medulla and paravertebral sympathetic ganglia in early infancy. Proteasome inhibitors (PIs) (i.e., carfilzomib (CFZ)) may represent a possible pharmacological treatment for solid tumors including NB. In the present study, we tested the effect of a novel non-competitive inhibitor of heme oxygenase-1 (HO-1), LS1/71, as a possible adjuvant therapy for the efficacy of CFZ in neuroblastoma cells. Our results showed that CFZ increased both HO-1 gene expression (about 18-fold) and HO activity (about 8-fold), following activation of the ER stress pathway. The involvement of HO-1 in CFZ-mediated cytotoxicity was further confirmed by the protective effect of pharmacological induction of HO-1, significantly attenuating cytotoxicity. In addition, HO-1 selective inhibition by a specific siRNA increased the cytotoxic effect following CFZ treatment in NB whereas SnMP, a competitive pharmacological inhibitor of HO, showed no changes in cytotoxicity. Our data suggest that treatment with CFZ produces ER stress in NB without activation of CHOP-mediated apoptosis, whereas co-treatment with CFZ and LS1/71 led to apoptosis activation and CHOP expression induction. In conclusion, our study showed that treatment with the non-competitive inhibitor of HO-1, LS1 / 71, increased cytotoxicity mediated by CFZ, triggering apoptosis following ER stress activation. These results suggest that PIs may represent a possible pharmacological treatment for solid tumors and that HO-1 inhibition may represent a possible strategy to overcome chemoresistance and increase the efficacy of chemotherapic regimens.
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http://dx.doi.org/10.1007/s12035-018-1133-6DOI Listing
February 2019

Tissue-Derived Stem Cell Research 2017.

Stem Cells Int 2018 29;2018:8203537. Epub 2018 Apr 29.

Department of Drug Science, Section of Biochemistry, University of Catania, 95125 Catania, Italy.

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http://dx.doi.org/10.1155/2018/8203537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949162PMC
April 2018

Metformin: A Bridge between Diabetes and Prostate Cancer.

Front Oncol 2017 11;7:243. Epub 2017 Oct 11.

Department of Drug Science, Biochemistry Section, University of Catania, Catania, Italy.

Prostate cancer (PCa) has become the most frequent type of cancer in men. Recent data suggest that diabetic patients taking metformin have a lower incidence of certain cancer, including PCa. Metformin is the most common drug used in type II diabetes mellitus; its use has been shown to lower the incidence of several cancers, although there are ambiguous data about the anticancer activity of metformin. A large number of studies examined the potential antineoplastic mechanism of metformin although it is not still completely understood. This review summarizes the literature concerning the effects of metformin on PCa cells, highlighting its numerous mechanisms of action through which it can act. We analyze the possible causes of the discordances regarding the impact of metformin on risk of PCa; we discuss the latest findings in this field, suggesting that metformin may have a future role in the management of PCa both as monotherapy and in combination with other drugs.
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http://dx.doi.org/10.3389/fonc.2017.00243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641539PMC
October 2017

Effects of Polyphenolic Derivatives on Heme Oxygenase-System in Metabolic Dysfunctions.

Curr Med Chem 2018 ;25(13):1577-1595

Department of Drug Sciences, Section of Biochemistry, University of Catania, viale A. Doria 6, 95125 - Catania, Italy.

Background: The aim of this review is to summarize the effects of various naturally occurring polyphenols in the management of metabolic dysfunctions. This cluster of metabolic abnormalities comprises insulin resistance, increased levels of free fatty acids, hypercholesterolemia, obesity, hyperglycemia and hypertension, diabetes mellitus (DM) type 1 (T1DM) and type 2 (T2DM) along with DM-induced complications. Most of them are included in the well-known metabolic syndrome (MS). These metabolic dysfunctions in turn are tightly associated to a high risk of development of cardiovascular diseases. Although molecular mechanisms underlying the onset of metabolic dysfunctions and related complications are not yet clear, it is widely recognized that they are associated to oxidative stress and chronic low-grade of inflammatory levels.

Methods: We undertook a structured search of bibliographic references through the use of SciFinder. The database was provided by a division of ACS (American Chemical Society) and guarantees access to the world's most extensive and authoritative source of references. The search was performed using "heme oxygenase-1" as research topic and a subsequent refinement was done by using inclusion/exclusion criteria. The quality of retrieved papers was evaluated on the basis of standard tools.

Results: From a careful review of the selected literature, of interest, the use of natural antioxidant polyphenols seems to be the ideal pharmacological treatment since they are endowed with strong antioxidant and anti-inflammatory properties. In particular, some polyphenols such as curcumin, quercetin, genistein, and caffeic acid phenethyl ester are able to potently activate nuclear factor erythroid 2-related factor 2 (Nrf2) and related downstream expression of enzymes such as heme oxygenase-1 (HO-1). Indeed, an overexpression of HO-1 has been demonstrated to play a beneficial role in metabolic diseases.

Conclusion: The following review is intended to stimulate interest in the role of natural occurring HO-1 inducers in metabolic dysfunction, focusing on the clinical potential of HO-1 activity to restore the balance between pro-oxidant and anti-oxidants systems.
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http://dx.doi.org/10.2174/0929867324666170616110748DOI Listing
February 2019

EET intervention on Wnt1, NOV, and HO-1 signaling prevents obesity-induced cardiomyopathy in obese mice.

Am J Physiol Heart Circ Physiol 2017 Aug 2;313(2):H368-H380. Epub 2017 Jun 2.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York;

We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1α, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a "browning" pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome. The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure.Listen to this article's corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017.
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http://dx.doi.org/10.1152/ajpheart.00093.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582926PMC
August 2017

Inhibition of Cx43 mediates protective effects on hypoxic/reoxygenated human neuroblastoma cells.

J Cell Mol Med 2017 10 9;21(10):2563-2572. Epub 2017 May 9.

Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania, Italy.

Olfactory ensheathing cells (OECs), a special population of glial cells, are able to synthesise several trophic factors exerting a neuroprotective action and promoting growth and functional recovery in both in vitro and in vivo models. In the present work, we investigated the neuroprotective effects of OEC-conditioned medium (OEC-CM) on two different human neuron-like cell lines, SH-SY5Y and SK-N-SH (neuroblastoma cell lines), under normoxic and hypoxic conditions. In addition, we also focused our attention on the role of connexins (Cxs) in the neuroprotective processes. Our results confirmed OEC-CM mediated neuroprotection as shown by cell adherence, proliferation and cellular viability analyses. Reduced connexin 43 (Cx43) levels in OEC-CM compared to unconditioned cells in hypoxic conditions prompted us to investigate the role of Cx43-Gap junctions (GJs) and Cx43-hemichannels (HCs) in hypoxic/reoxygenation injury using carbenoxolone (non-selective GJ inhibitor), ioxynil octanoato (selective Cx43-GJ inhibitor) and Gap19 (selective Cx43-HC inhibitor). We found that Cx43-GJ and Cx43-HC inhibitors are able to protect SH-SY5Y and allow to these cultures to overcome the injury. Our findings support the hypothesis that both OEC-CM and the inhibition of Cx43-GJs and Cx43-HCs offer a neuroprotective effect by reducing Cx43-mediated cell-to-cell and cell-to-extracellular environment communications.
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http://dx.doi.org/10.1111/jcmm.13177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618696PMC
October 2017

The Heme Oxygenase System in Hematological Malignancies.

Antioxid Redox Signal 2017 08 19;27(6):363-377. Epub 2017 May 19.

4 Department of Drug Sciences, University of Catania , Catania, Italy .

Significance: Several lines of evidence suggest that hematological malignancies exhibit an altered redox balance homeostasis that can lead to the activation of various survival pathways that, in turn, lead to the progression of disease and chemoresistance. Among these pathways, the heme oxygenase-1 (HO-1) pathway is likely to play a major role. HO catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe), and biliverdin. This review focuses on the role of HO-1 in various hematological malignancies and the possibility of exploiting such targets to improve the outcome of well-established chemotherapeutic regimens. Recent Advances and Critical Issues: Interestingly, the inhibition of the expression of HO-1 (e.g., with siRNA) or HO activity (with competitive inhibitors) contributes to the increased efficacy of chemotherapy and improves the outcome in animal models. Furthermore, some hematological malignancies (e.g., chronic myeloid leukemia and multiple myeloma) have served to explore the non-canonical functions of HO-1, such as the association between nuclear compartmentalization and genetic instability and/or chemoresistance.

Future Directions: The HO system may serve as an important tool in the field of hematological malignancies because it can be exploited to counteract chemoresistance and to monitor the outcome of bone marrow transplants and may be an additional target for combined therapies. Antioxid. Redox Signal. 27, 363-377.
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http://dx.doi.org/10.1089/ars.2016.6735DOI Listing
August 2017

Novel Caffeic Acid Phenethyl Ester (Cape) Analogues as Inducers of Heme Oxygenase-1.

Curr Pharm Des 2017 ;23(18):2657-2664

Department of Drug Sciences, Section of Biochemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy.

Background: Heme Oxygenase-1 (HO-1) is a metabolic enzyme strongly involved in processes including cytoprotection, modulation of inflammatory response, anti-oxidative functions, regulation of cellular proliferation, angiogenesis, cardiovascular homeostasis, and immuno-modulation. HO-1 induction and/or activation is able to counterbalance, at least in part, oxidative stress and inflammation. For this reason, HO-1 can be regarded as an attractive target to ameliorate different stress-related pathologies. Caffeic acid phenethyl ester, a natural polyphenolic compound, behaves as HO-1 inducer and possesses a plethora of beneficial effects under oxidative stress conditions.

Objectives: A small focused series of caffeic acid phenethyl ester (Cape) analogues was designed and synthesized with the aim of obtaining more potent HO-1 inducers.

Method: The capacity of these new compounds to modify the levels of HO-1 was evaluated in human mesenchymal stem cells (hMSCs) derived from bone marrow.

Results And Conclusion: Some of tested compounds were found to be good HO-1 inducers and 3-(3,4- dihydroxyphenyl)-(2E)-2-propenoic acid 2-(3,4-dimethoxyphenyl) ethyl ester (VP961) was the most potent. VP961 tested to measure HO-1 protein expression and HO activity in in vitro system resulted more potent than the parent compound Cape both as inducer and as direct activator of the enzyme. VP961, selected as lead compound for further characterization, showed antioxidant properties in a model of H2O2-mediated ROS production and cytoprotective effects in a model of H2O2 cells viability impairment. To the best of our knowledge, VP961 is the first known compound able to activate directly HO-1 enzyme and to induce at the same time its protein expression.
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http://dx.doi.org/10.2174/1381612823666170210151411DOI Listing
May 2018