Publications by authors named "Marco Raffaele"

27 Publications

  • Page 1 of 1

Mild exacerbation of obesity- and age-dependent liver disease progression by senolytic cocktail dasatinib + quercetin.

Cell Commun Signal 2021 Apr 8;19(1):44. Epub 2021 Apr 8.

International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.

Background: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. A minority of affected patients develops inflammation, subsequently fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCC is a leading cause of cancer-related death. An increased number of senescent cells correlate with age-related tissue degeneration during NAFLD-induced HCC. Senolytics are promising agents that target selectively senescent cells. Previous studies showed that whereas a combination of the senolytic drugs dasatinib and quercetin (D + Q) reduced NAFLD in mice, D + Q lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells in human HCC xenografted mice. Whether D + Q has an effect on the age-associated spectrum of NAFLD-inflammation-HCC remains unknown.

Methods: Here, we utilized an established model of age- and obesity-associated HCC, the low dose diethylnitrosamine (DEN)/high fat diet (HFD), a regimen promoting liver inflammation and tumorigenesis over a long period of 9 months. Four groups of mice each were created: group 1 included control untreated mice; group 2 included mice treated with D + Q; group 3 included mice undergoing the DEN/HFD protocol; group 4 included mice undergoing the DEN/HFD protocol with the administration of D + Q. At the end of the chemical/dietary regimen, we analyzed liver damage and cell senescence by histopathology, qPCR and immunoblotting approaches.

Results: Unexpectedly, D + Q worsened liver disease progression in the DEN/HFD mouse model, slightly increasing histological damage and tumorigenesis, while having no effect on senescent cells removal.

Conclusions: In summary, using an animal model that fully recapitulates NAFLD, we demonstrate that these compounds are ineffective against age-associated NAFLD-induced HCC. Video Abstract.
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http://dx.doi.org/10.1186/s12964-021-00731-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034117PMC
April 2021

Skull base reconstruction: A question of flow? A critical analysis of 521 endoscopic endonasal surgeries.

PLoS One 2021 15;16(3):e0245119. Epub 2021 Mar 15.

Department of Neuroscience "Rita Levi Montalcini", Neurosurgery Unit, University of Turin, Turin, Italy.

Introduction: Post-operative CSF leak still represents the main drawback of Endoscopic Endonasal Approach (EEA), and different reconstructive strategies have been proposed in order to decrease its rate.

Objective: To critically analyze the effectiveness of different adopted reconstruction strategies in patients that underwent EEA.

Materials And Methods: Adult patients with skull base tumor surgically treated with EEA were retrospectively analyzed. Data recorded for each case concerned patient demographics, type of surgical approach, histotype, anatomical site of surgical approach, intra-operative CSF leak grade (no leak (INL), low flow (ILFL), high flow (IHFL)), reconstructive adopted strategy, Lumbar Drain positioning, post-operative CSF leak rate and intra/post-operative complications.

Results: A total number of 521 patients (January 2012-December 2019) was included. Intra-operative CSF leak grade showed to be associated with post-operative CSF leak rate. In particular, the risk to observe a post-operative CSF leak was higher when IHFL was encountered (25,5%; Exp(B) 16.25). In particular, vascularized multilayered reconstruction and fat use showed to be effective in lowering post-operative CSF leaks in IHFL (p 0.02). No differences were found considering INL and ILFL groups. Yearly post-operative CSF leak rate analysis showed a significative decreasing trend.

Conclusion: Intra-operative CSF leak grade strongly affected post-operative CSF leak rate. Multilayer reconstruction with fat and naso-septal flap could reduce the rate of CSF leak in high risk patients. Reconstructive strategies should be tailored according also to the type and the anatomical site of the approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959384PMC
March 2021

Lenz microphthalmia syndrome in neurosurgical practice: a case report and review of the literature.

Childs Nerv Syst 2021 Jan 25. Epub 2021 Jan 25.

Neurosurgery Unit, Department of Neuroscience "Rita Levi Montalcini", "Città della Salute e della Scienza" University Hospital, Turin University, Via Cherasco, 15, 10126, Turin, Italy.

Lenz microphthalmia syndrome (LMS) is an allelic X-linked syndrome correlated to a null mutation of B cell lymphoma (BCL-6) corepressor (BCOR) gene, which is essential in the early embryonic development. Phenotypically, this rare hereditary syndrome is characterized by microphthalmia/anophthalmia and other eye disorders; mental disability; dental, ear, and digital abnormalities; and variable malformations affecting the heart, skeleton (limbs and/or spine), and genitourinary tract. In this paper, a case of a young adult with LMS affected additionally by immuno-hematological disturbances was treated with decompressive craniectomy after domestic accidental fall. Case description and a brief review of the current literature about this rare condition are presented here.
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http://dx.doi.org/10.1007/s00381-020-05035-1DOI Listing
January 2021

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

Senescence-like phenotype in post-mitotic cells of mice entering middle age.

Aging (Albany NY) 2020 08;12(14):13979-13990

International Clinical Research Center (FNUSA-ICRC), St’ Anne University Hospital, Brno, Czech Republic.

Staining mice tissues for β-galactosidase activity is a fundamental tool to detect age- or disease-associated cellular senescence. However, reported analyses of positivity for senescence-associated β-galactosidase activity or for other markers of senescence in post-mitotic cells of healthy murine tissues have been fragmentary or inconclusive. Here, we attempted to independently deepen this knowledge using multiple senescence markers within the same cells of wild type mice entering middle age (9 months of age). A histochemistry protocol for the pH-dependent detection of β-galactosidase activity in several tissues was used. At pH 6, routinely utilized to detect senescence-associated β-galactosidase activity, only specific cellular populations in the mouse body (including Purkinje cells and choroid plexus in the central nervous system) were detected as strongly positive for β-galactosidase activity. These post-mitotic cells were also positive for other established markers of senescence (p16, p21 and DPP4), detected by immunofluorescence, confirming a potential senescent phenotype. These data might contribute to understanding the functional relation between the senescence-associated β-galactosidase activity and senescence markers in post-mitotic cells in absence of disease or advanced aging.
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http://dx.doi.org/10.18632/aging.103637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425512PMC
August 2020

Redox and Epigenetics in Human Pluripotent Stem Cells Differentiation.

Antioxid Redox Signal 2021 02 17;34(4):335-349. Epub 2020 Jul 17.

International Clinical Research Center, St' Anne's University Hospital, Brno, Czech Republic.

Since their discovery, induced pluripotent stem cells (iPSCs) had generated considerable interest in the scientific community for their great potential in regenerative medicine, disease modeling, and cell-based therapeutic approach, due to their unique characteristics of self-renewal and pluripotency. Technological advances in iPSC genome-wide epigenetic profiling led to the elucidation of the epigenetic control of cellular identity during nuclear reprogramming. Moreover, iPSC physiology and metabolism are tightly regulated by oxidation-reduction events that mainly occur during the respiratory chain. In theory, iPSC-derived differentiated cells would be ideal for stem cell transplantation as autologous cells from donors, as the risks of rejection are minimal. However, iPSCs experience high oxidative stress that, in turn, confers a high risk of increased genomic instability, which is most often linked to DNA repair deficiencies. Genomic instability has to be assessed before iPSCs can be used in therapeutic designs. This review will particularly focus on the links between redox balance and epigenetic modifications-in particular based on the histone variant macroH2A1-that determine DNA damage response in iPSCs and derived differentiated cells, and that might be exploited to decrease the teratogenic potential on iPSC transplantation. 34, 335-349.
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http://dx.doi.org/10.1089/ars.2019.7983DOI Listing
February 2021

Could ZI have a role in DBS for Parkinson's Disease? An observational study to optimize DBS target localization.

J Clin Neurosci 2020 Jul 10;77:89-93. Epub 2020 May 10.

The Walton Centre for Neurology and Neurosurgery, Liverpool, UK.

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is a well-recognized intervention for Parkinson's Disease (PD). We used LEAD-DBS, a toolbox facilitating DBS electrode reconstructions and computer simulations based on postoperative MRI and CT imaging, to investigate the interaction and followed benefits of electrical field generated by STN-DBS and surrounding areas, such as caudal Zona Incerta (cZI). Thirty-two PD patients, treated with directional STN-DBS in the period 2016-2018 at the Walton Center NHS Foundation Trust, were retrospectively recruited. Their MRI and CT imaging were analyzed with LEAD-DBS to measure the volume of tissue activated (VTA). Considering the clinical outcome based on the UPDRS III score improvement of 62.65% at 6 months follow up, we found a VTA intersection of 21.5% with motor STN and 61.7% with cZI. These observations may support the contribution of cZI deep stimulation to improve clinical outcome of PD patients treated with DBS, promoting the intriguing path of dual targeting.
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http://dx.doi.org/10.1016/j.jocn.2020.05.029DOI Listing
July 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

Ginseng and heme oxygenase-1: The link between an old herb and a new protective system.

Fitoterapia 2019 Nov 17;139:104370. Epub 2019 Oct 17.

Department of Drug Science, Medicinal Chemistry Section, University of Catania, 95125 Catania, Italy. Electronic address:

Ginseng is an ancient herb, belonging to Asian traditional medicine, that has been considered as a restorative to enhance vitality for centuries. It has been demonstrated that the antioxidant action of ginseng may be mediated through activation of different cellular signaling pathways involving the heme oxygenase (HO) system. Several compounds derived from ginseng have been studied for their potential role in brain, heart and liver protection, and the Nrf2 pathway seems to be the most affected by these natural molecules to exert this effect. Ginseng is also popularly used in cancer patients therapy for the demonstrated capability to defend tissues from chemotherapy-induced damage. Reported results suggest that the effect of ginseng is primarily associated with ROS scavenging, mainly exerted through the activation of Nrf2 pathway, and the consequent induction of HO-1 levels. This review aims to discuss the connection between the antioxidant properties of ginseng and the activation of the HO system, as well as to outline novel therapeutic applications of this medicinal plant to human health.
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http://dx.doi.org/10.1016/j.fitote.2019.104370DOI Listing
November 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

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

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

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

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

(+)-Pentazocine attenuates SH-SY5Y cell death, oxidative stress and microglial migration induced by conditioned medium from activated microglia.

Neurosci Lett 2017 03 3;642:86-90. Epub 2017 Feb 3.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 64, 95100 Catania, Italy; Euro-Mediterranean Institute of Science and Technology, Via Emerico Amari 131, 90100 Palermo, Italy. Electronic address:

Background: Sigma receptors (σR) are expressed both in neurons and microglia and can be considered as a promising target for developing pharmacological strategies for neuroprotection in various experimental models. The aim of the present study was to test the effect of (+)-pentazocine, a putative σ R agonist, in an in vitro model of neuron/microglia crosstalk following hypoxia/reoxygenation.

Methods: Microglia (BV2 cells) was exposed (3h) to 1% oxygen and reoxygenation was allowed for 24h. Conditioned media obtained from this experimental condition was used to treat neuroblast-like cell line (SH-SY5Y cells) in the presence or absence of (+)-pentazocine (25μM). Cell viability was measured by cytofluorimetric analysis, whereas inflammation and oxidative stress were evaluated by the expression of Hsp70, GAD, SOD and p65. Microglial cell migration was also evaluated by Xcelligence technology.

Results: Our results showed that (+)-pentazocine was able to increase SH-SY5Y cell viability following exposure to microglial-conditioned medium. Furthermore, (+)-pentazocine was also able to inhibit microglial cell toward neuron treated with hypoxic conditioned medium. Finally, pharmacological treatment reduced the expression of inflammatory and oxidative stress markers (GAD, SOD and p65). Interestingly, hypoxic medium was able to reduce the expression of Hsp70 and such effect was prevented by (+)-pentazocine treatment.

Conclusions: (+)-Pentazocine exhibits significant neuroprotective effects in our in vitro model of SH-SY5Y/microglial crosstalk thus suggesting that σR may represent a possible strategy for neuroprotection.
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http://dx.doi.org/10.1016/j.neulet.2017.02.005DOI Listing
March 2017

Therapeutic Efficacy of Stem Cells Transplantation in Diabetes: Role of Heme Oxygenase.

Front Cell Dev Biol 2016 5;4:80. Epub 2016 Aug 5.

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

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.
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http://dx.doi.org/10.3389/fcell.2016.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974271PMC
August 2016

Olive Leaf Extract from Sicilian Cultivar Reduced Lipid Accumulation by Inducing Thermogenic Pathway during Adipogenesis.

Front Pharmacol 2016 31;7:143. Epub 2016 May 31.

Biochemistry Section, Department of Drug Sciences, University of CataniaCatania, Italy; Euro-Mediterranean Institute of Science and TechnologyPalermo, Italy.

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.
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http://dx.doi.org/10.3389/fphar.2016.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885843PMC
June 2016