Publications by authors named "Monica Montagnani"

52 Publications

Potential beneficial role of probiotics on the outcome of COVID-19 patients: An evolving perspective.

Diabetes Metab Syndr 2021 Jan-Feb;15(1):295-301. Epub 2021 Jan 13.

Department of Biomedical Sciences and Human Oncology - Section of Pharmacology, Medical School, University of Bari "Aldo Moro", Policlinico University Hospital of Bari, p.zza G. Cesare 11, 70124, Bari, Italy.

Background And Aims: Probiotics can support the body's systems in fighting viral infections. This review is aimed to focus current knowledge about the use of probiotics as adjuvant therapy for COVID-19 patients.

Methods: We performed an extensive research using the PubMed-LitCovid, Cochrane Library, Embase databases, and conducting manual searches on Google Scholar, Elsevier Connect, Web of Science about this issue.

Results: We have found several papers reporting data about the potential role of probiotics as well as contrasting experimental data about it.

Conclusions: Most data show good results demonstrating that probiotics can play a significant role in fighting SARS-CoV-2 infection, also compared with their use in the past for various diseases. They seem effective in lowering inflammatory status, moreover in patients with chronic comorbidities such as cancer and diabetes, improving clinical outcomes.
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http://dx.doi.org/10.1016/j.dsx.2020.12.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804381PMC
March 2021

Management of metabolic adverse events of targeted therapies and immune checkpoint inhibitors in cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper.

Crit Rev Oncol Hematol 2020 Oct 15;154:103066. Epub 2020 Aug 15.

Oncological Endocrinology Unit, Department of Medical Sciences, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy.

The growing insights in the next-generation immunotherapy and the state-of-the-art advancement in targeted-agents significantly improved clinical outcome of cancer patients by pointing towards a unexplored Achilles' heel. Novel toxicity profiles have been uncovered, representing unmet medical needs. Thus, a panel of expert provide comprehensive pharmacological and clinical evidence, to provide a patient-tailored approach to metabolic adverse events associated with novel anti-cancer treatments. Prompted by the need of a multidisciplinary cooperation, a working group of Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD) and Società Italiana Farmacologia (SIF) examined the available literature data. The identification of patient risk profile and the characterization of metabolic effects of novel anti-tumour drugs is clearly a clinical challenge that can be addressed by a multidisciplinary clinical approach. Therefore, this review pinpoints the relevance of the challenging profiling of the patient suffering from dysmetabolic conditions induced by the novel therapeutics in medical oncology.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103066DOI Listing
October 2020

Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling.

Am J Physiol Endocrinol Metab 2020 09 10;319(3):E629-E646. Epub 2020 Aug 10.

Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Previously, we have used mathematical modeling to gain mechanistic insights into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data, independent of those used for model development. Simulations of pathological stimuli directly impairing only insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with insulin resistance caused by glucotoxicity, lipotoxicity, or inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of insulin signaling in vascular endothelium supports the hypothesis that pathway-selective insulin resistance accounts, in part, for relationships between insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for the treatment of diabetes and its cardiovascular complications.
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http://dx.doi.org/10.1152/ajpendo.00247.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642854PMC
September 2020

The Intrinsic Virtues of EGCG, an , on Prevention and Treatment of Diabesity Complications.

Molecules 2020 Jul 4;25(13). Epub 2020 Jul 4.

Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", 70124 Bari, Italy.

The pandemic proportion of diabesity-a combination of obesity and diabetes-sets a worldwide health issue. Experimental and clinical studies have progressively reinforced the pioneering epidemiological observation of an inverse relationship between consumption of polyphenol-rich nutraceutical agents and mortality from cardiovascular and metabolic diseases. With chemical identification of epigallocatechin-3-gallate (EGCG) as the most abundant catechin of green tea, a number of cellular and molecular mechanisms underlying the activities of this unique catechin have been proposed. Favorable effects of EGCG have been initially attributed to its scavenging effects on free radicals, inhibition of ROS-generating mechanisms and upregulation of antioxidant enzymes. Biologic actions of EGCG are concentration-dependent and under certain conditions EGCG may exert pro-oxidant activities, including generation of free radicals. The discovery of 67-kDa laminin as potential EGCG membrane target has broaden the likelihood that EGCG may function not only because of its highly reactive nature, but also via receptor-mediated activation of multiple signaling pathways involved in cell proliferation, angiogenesis and apoptosis. Finally, by acting as epigenetic modulator of DNA methylation and chromatin remodeling, EGCG may alter gene expression and modify miRNA activities. Despite unceasing research providing detailed insights, ECGC composite activities are still not completely understood. This review summarizes the most recent evidence on molecular mechanisms by which EGCG may activate signal transduction pathways, regulate transcription factors or promote epigenetic changes that may contribute to prevent pathologic processes involved in diabesity and its cardiovascular complications.
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http://dx.doi.org/10.3390/molecules25133061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411588PMC
July 2020

Endothelial Dysfunction May Link Interatrial Septal Abnormalities and MTHFR-Inherited Defects to Cryptogenic Stroke Predisposition.

Biomolecules 2020 06 4;10(6). Epub 2020 Jun 4.

Department of Biomedical Sciences and Human Oncology-Section of Pharmacology, Medical School, University of Bari "Aldo Moro", 70124 Bari, Italy.

We explored the significance of the L-Arginine/asymmetric dimethylarginine (L-Arg/ADMA) ratio as a biomarker of endothelial dysfunction in stroke patients. To this aim, we evaluated the correlation, in terms of severity, between the degree of endothelial dysfunction (by L-Arg/ADMA ratio), the methylene tetrahydrofolate reductase (MTHFR) genotype, and the interatrial septum (IAS) phenotype in subject with a history of stroke. L-Arg, ADMA, and MTHFR genotypes were evaluated; the IAS phenotype was assessed by transesophageal echocardiography. Patients were grouped according to the severity of IAS defects and the residual enzymatic activity of MTHFR-mutated variants, and values of L-Arg/ADMA ratio were measured in each subgroup. Of 57 patients, 10 had a septum integrum (SI), 38 a patent foramen ovale (PFO), and 9 an ostium secundum (OS). The L-Arg/ADMA ratio differed across septum phenotypes ( ≤ 0.01), and was higher in SI than in PFO or OS patients ( ≤ 0.05, ≤ 0.01, respectively). In the PFO subgroup a negative correlation was found between the L-Arg/ADMA ratio and PFO tunnel length/height ratio ( ≤ 0.05; r = - 0.37; R = 0.14). Interestingly, the L-Arg/ADMA ratio varied across MTHFR genotypes ( ≤ 0.0001) and was lower in subgroups carrying the most impaired enzyme with respect to patients carrying the conservative MTHFR ( ≤ 0.0001, ≤ 0.05, respectively). Consistently, OS patients carried the most dysfunctional MTHFR genotypes, whereas SI patients the least ones. A low L-Arg/ADMA ratio correlates with impaired activity of MTHFR and with the jeopardized IAS phenotype along a severity spectrum encompassing OS, PFO with long/tight tunnel, PFO with short/large tunnel, and SI. This infers that genetic MTHFR defects may underlie endothelial dysfunction-related IAS abnormalities, and predispose to a cryptogenic stroke. Our findings emphasize the role of the L-Arg/ADMA ratio as a reliable marker of stroke susceptibility in carriers of IAS abnormalities, and suggest its potential use both as a diagnostic tool and as a decision aid for therapy.
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http://dx.doi.org/10.3390/biom10060861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355772PMC
June 2020

Can Epigenetics of Endothelial Dysfunction Represent the Key to Precision Medicine in Type 2 Diabetes Mellitus?

Int J Mol Sci 2019 Jun 17;20(12). Epub 2019 Jun 17.

Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro", 70124 Bari, Italy.

In both developing and industrialized Countries, the growing prevalence of Type 2 Diabetes Mellitus (T2DM) and the severity of its related complications make T2DM one of the most challenging metabolic diseases worldwide. The close relationship between genetic and environmental factors suggests that eating habits and unhealthy lifestyles may significantly affect metabolic pathways, resulting in dynamic modifications of chromatin-associated proteins and homeostatic transcriptional responses involved in the progression of T2DM. Epigenetic mechanisms may be implicated in the complex processes linking environmental factors to genetic predisposition to metabolic disturbances, leading to obesity and type 2 diabetes mellitus (T2DM). Endothelial dysfunction represents an earlier marker and an important player in the development of this disease. Dysregulation of the endothelial ability to produce and release vasoactive mediators is recognized as the initial feature of impaired vascular activity under obesity and other insulin resistance conditions and undoubtedly concurs to the accelerated progression of atherosclerotic lesions and overall cardiovascular risk in T2DM patients. This review aims to summarize the most current knowledge regarding the involvement of epigenetic changes associated with endothelial dysfunction in T2DM, in order to identify potential targets that might contribute to pursuing "precision medicine" in the context of diabetic illness.
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http://dx.doi.org/10.3390/ijms20122949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628049PMC
June 2019

Activation of AMPK/SIRT1 axis is required for adiponectin-mediated preconditioning on myocardial ischemia-reperfusion (I/R) injury in rats.

PLoS One 2019 17;14(1):e0210654. Epub 2019 Jan 17.

Department of Biomedical Sciences and Human Oncology-Pharmacology Section, Medical School-University of Bari "Aldo Moro", Bari, Italy.

Background: Adiponectin (AD) cardioprotective activities are mediated by AMPK, a fuel-sensing molecule sharing common targets and cellular activities with SIRT-1. Whether AD preconditioning may involve SIRT-1 activity is not known; however, the protective role of SIRT-1 during ischemia and the potential interplay between AMPK and SIRT-1 suggest this possibility.

Methods: Isolated hearts from male Sprague-Dawley rats (n = 85) underwent ischemia/reperfusion (I/R, 30/180 min). Preconditioning with resveratrol (RSV, SIRT-1 activator) was compared to preconditioning with AD alone, or in combination with compound C (CC, AMPK inhibitor) or sirtinol (STN, SIRT-1 inhibitor). For each heart, left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (dLVP), coronary flow (CF) and left ventricular infarct mass (IM) were measured, together with the phosphorylation/activation status of AMPK, LKB1, eNOS and SIRT-1, at the beginning (15 min) and at the end (180 min) of reperfusion.

Results And Conclusions: When compared to I/R, both RSV and AD improved cardiac function and reduced IM (p < 0.01, p < 0.05, respectively). Cardioprotective effects of AD were completely reversed in the AD+CC group, and significantly attenuated in the AD+STN group. Both RSV and AD increased eNOS, AMPK and LKB1 phosphorylation (for each parameter: p < 0.05 vs. I/R, in both RSV and AD treatment groups) at 15 min of reperfusion, and SIRT-1 activity at the end of reperfusion (p < 0.01, p < 0.05 vs. I/R, respectively). Interestingly, AD-mediated phosphorylation of AMPK and LKB1, and SIRT-1 deacetylation activity was markedly reduced in both the AD+CC and AD+STN groups (p < 0.05 vs. AD). Thus, AD-mediated cardioprotection requires both AMPK and SIRT-1 signaling pathways, that act as a component of a cycle and regulate each other's activities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336234PMC
October 2019

Calcimimetic R-568 vasodilatory effect on mesenteric vascular beds from normotensive (WKY) and spontaneously hypertensive (SHR) rats. Potential involvement of vascular smooth muscle cells (vSMCs).

PLoS One 2018 9;13(8):e0202354. Epub 2018 Aug 9.

Aging and Translational Medicine Research Center (CeSI-MeT), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy.

The potential role of calcimimetics as vasculotropic agents has been suggested since the discovery that calcium sensing receptors (CaSRs) are expressed in cardiovascular tissues. However, whether this effect is CaSR-dependent or -independent is still unclear. In the present study the vascular activity of calcimimetic R-568 was investigated in mesenteric vascular beds (MVBs) isolated from Spontaneously Hypertensive rats (SHR) and the relative age-matched Wistar-Kyoto (WKY) control rats. Pre-constricted MBVs were perfused with increasing concentrations of R-568 (10 nM- 30 μM) resulting in a rapid dose-dependent vasodilatation. However, in MVBs from SHR this was preceded by a small but significant vasoconstriction at lowest nanomolar concentrations used (10-300 nM). Pre-treatment with pharmacological inhibitors of nitric oxide (NO) synthase (NOS, L-NAME), KCa channels (CTX), cyclo-oxygenase (INDO) and CaSR (Calhex) or the endothelium removal suggest that NO, CaSR and the endothelium itself contribute to the R-568 vasodilatory/vasoconstrictor effects observed respectively in WKY/SHR MVBs. Conversely, the vasodilatory effects resulted by highest R-568 concentration were independent of these factors. Then, the ability of lower R-568 doses (0.1-1 μM) to activate endothelial-NOS (eNOS) pathway in MVBs homogenates was evaluated. The Akt and eNOS phosphorylation levels resulted increased in WKY homogenates and Calhex significantly blocked this effect. Notably, this did not occur in the SHR. Similarly, vascular smooth muscle cells (vSMCs) stimulation with lower R-568 doses resulted in Akt activation and increased NO production in WKY but not in SHR cells. Interestingly, in these cells this was associated with the absence of the biologically active dimeric form of the CaSR thus potentially contributing to explain the impaired vasorelaxant effect observed in response to R-568 in MVB from SHR compared to WKY. Overall, these findings provide new insight on the mechanisms of action of the calcimimetic R-568 in modulating vascular tone both in physiological and pathological conditions such as hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202354PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084966PMC
February 2019

Discovery of N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamide dihydrochloride: A new potent and selective inhibitor of the inducible nitric oxide synthase as a promising agent for the therapy of malignant glioma.

Eur J Med Chem 2018 May 13;152:53-64. Epub 2018 Apr 13.

Department of Pharmacy - University of Chieti "G. d'Annunzio", Italy.

In mammalian cells, aberrant iNOS induction may have detrimental consequences, and seems to be involved in the proliferation and progression of different tumors, such as malignant gliomas. Therefore, selective inhibition of iNOS could represent a feasible therapeutic strategy to treat these conditions. In this context, we have previously disclosed new acetamidines able to inhibit iNOS with a very high selectivity profile over eNOS or nNOS. Here we report the synthesis of a new series of compounds structurally related to the leading scaffold of N-[(3-aminomethyl)benzyl] acetamidine (1400 W), together with their in vitro activity and selectivity. Compound 39 emerged as the most promising molecule of this series, and it was ex vivo evaluated on isolated and perfused resistance arteries, confirming a high selectivity toward iNOS inhibition. Moreover, C6 rat glioma cell lines biological response to 39 was investigated, and preliminary MTT assay showed a significant decrease in cell metabolic activity of C6 rat glioma cells. Finally, results of a docking study shed light on the binding mode of 39 into NOS catalytic site.
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http://dx.doi.org/10.1016/j.ejmech.2018.04.027DOI Listing
May 2018

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options.

Pharmacol Res 2017 Jun 10;120:226-241. Epub 2017 Apr 10.

Department of Biomedical Sciences and Human Oncology-Pharmacology Section, Medical School-University of Bari "Aldo Moro", Bari, Italy. Electronic address:

The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelial-derived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.
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http://dx.doi.org/10.1016/j.phrs.2017.04.009DOI Listing
June 2017

Carbon monoxide contributes to the constipating effects of granisetron in rat colon.

World J Gastroenterol 2016 Nov;22(42):9333-9345

Carmela Nacci, Maria Assunta Potenza, Valentina Leo, Monica Montagnani, Maria Antonietta De Salvia, Department of Biomedical Sciences and Human Oncology - Pharmacology Section, Medical School, University of Bari "Aldo Moro", Piazza G. Cesare, 70124 Bari, Italy.

Aim: To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron.

Methods: For studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or N-nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).

Results: Administration of granisetron (50, 75 μg/kg) significantly increased the time to first defecation ( = 0.045 vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered , granisetron alone (3 μmol/L) did not significantly modify the colon's contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon's contractile response to EFS ( = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the ZnPPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3 (400 μmol/L) alone increased both the contractile response to EFS at 10 Hz (10 Hz: 71.02 ± 19.16 116.25 ± 53.70, = 0.01) and the contractile response to ACh (100 μmol/L) ( = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated with ZnPPIX, the ZnPPIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3 (400 μmol/L) further increased the colon's contractile response to EFS (at 5 Hz: = 0.007; at 10 Hz: = 0.001) and to ACh (ACh 10 μmol/L: = 0.001; ACh 100 μmol/L: = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFS-induced and ACh-induced contractile response.

Conclusion: Taken together, findings from and studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.
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http://dx.doi.org/10.3748/wjg.v22.i42.9333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107697PMC
November 2016

Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes.

Vascul Pharmacol 2016 12 24;87:83-91. Epub 2016 Aug 24.

Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

Increased TNFα-mediated JNK signaling in the perivascular adipose tissue (PVAT) may contribute to the pathogenesis of vascular complications in T1DM by reducing adiponectin (Ad) synthesis and therefore impairing Ad-mediated activity in the contiguous blood vessel system. We evaluated whether in vivo treatment with the TNFα blocking antibody infliximab normalized expression of Ad and Ad receptors in various fat depots, and whether this effect correlated with improved endothelial activity and vasodilator function in streptozotocin (STZ)-induced diabetic mice. STZ mice were studied at 1 and 2weeks after diabetes onset, and compared to age-matched infliximab-treated diabetic (I-STZ) and control animals (CTRL) (n=10 each group). In STZ mice, activation of pro-inflammatory JNK signaling was faster in PVAT (P<0.01) than in visceral (VAT), epididymal (EAT) and subcutaneous (SAT) adipose depots, and associated with decreased Ad synthesis and dysregulated AdipoR1/R2 levels. In parallel, activation of JNK in aortic endothelial cells and mesenteric arteries was associated with decreased expression/phosphorylation of eNOS and impaired ACh-mediated vasodilation (P<0.05 vs. CTRL). Treatment with infliximab abrogated JNK activation, ameliorated Ad protein expression, and normalized expression of both AdipoR1 and AdipoR2 in PVAT, concomitantly improving eNOS expression and vessel relaxation in mesenteric arteries from I-STZ mice (P<0.01 vs. STZ). These observations underline the early susceptibility of PVAT to activation of pro-inflammatory JNK signaling, and highlight its potential importance in early vascular changes of T1DM. Further elucidation of the role of PVAT in cardiovascular complications may allow for the design of novel therapeutic strategies directly addressing PVAT pathophysiology.
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http://dx.doi.org/10.1016/j.vph.2016.08.007DOI Listing
December 2016

Assessment of resveratrol, apocynin and taurine on mechanical-metabolic uncoupling and oxidative stress in a mouse model of duchenne muscular dystrophy: A comparison with the gold standard, α-methyl prednisolone.

Pharmacol Res 2016 Apr 27;106:101-113. Epub 2016 Feb 27.

Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

Antioxidants have a great potential as adjuvant therapeutics in patients with Duchenne muscular dystrophy, although systematic comparisons at pre-clinical level are limited. The present study is a head-to-head assessment, in the exercised mdx mouse model of DMD, of natural compounds, resveratrol and apocynin, and of the amino acid taurine, in comparison with the gold standard α-methyl prednisolone (PDN). The rationale was to target the overproduction of reactive oxygen species (ROS) via disease-related pathways that are worsened by mechanical-metabolic impairment such as inflammation and over-activity of NADPH oxidase (NOX) (taurine and apocynin, respectively) or the failing ROS detoxification mechanisms via sirtuin-1 (SIRT1)-peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (resveratrol). Resveratrol (100mg/kg i.p. 5days/week), apocynin (38mg/kg/day per os), taurine (1g/kg/day per os), and PDN (1mg/kg i.p., 5days/week) were administered for 4-5 weeks to mdx mice in parallel with a standard protocol of treadmill exercise and the outcome was evaluated with a multidisciplinary approach in vivo and ex vivo on pathology-related end-points and biomarkers of oxidative stress. Resveratrol≥taurine>apocynin enhanced in vivo mouse force similarly to PDN. All the compounds reduced the production of superoxide anion, assessed by dihydroethidium staining, with apocynin being as effective as PDN, and ameliorated electrophysiological biomarkers of oxidative stress. Resveratrol also significantly reduced plasma levels of creatine kinase and lactate dehydrogenase. Force of isolated muscles was little ameliorated. However, the three compounds improved histopathology of gastrocnemius muscle more than PDN. Taurine>apocynin>PDN significantly decreased activated NF-kB positive myofibers. Thus, compounds targeting NOX-ROS or SIRT1/PGC-1α pathways differently modulate clinically relevant DMD-related endpoints according to their mechanism of action. With the caution needed in translational research, the results show that the parallel assessment can help the identification of best adjuvant therapies.
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http://dx.doi.org/10.1016/j.phrs.2016.02.016DOI Listing
April 2016

Endothelial and Metabolic Function Interactions in Overweight/Obese Children.

J Atheroscler Thromb 2016 Aug 22;23(8):950-9. Epub 2016 Feb 22.

Cardiovascular Diseases Section, Department of Emergency and Organ Transplantation (DETO), University.

Aim: Although the underlined mechanisms are still unknown, metabolic/coagulation alterations related to childhood obesity can induce vascular impairments. The aim of this study was to investigate the relationship between metabolic/coagulation parameters and endothelial function/vascular morphology in overweight/obese children.

Methods: Thirty-five obese/overweight children (22 pre-pubertal, mean age: 9.52±3.35 years) were enrolled. Body mass index (BMI), homeostasis model assessment index (HOMAIR), metabolic and coagulation parameters, [adiponectin, fibrinogen, high molecular weight adiponectin (HMW), endothelin-1, and vonWillebrand factor antigen] ultrasound early markers of atherosclerosis [flow-mediated dilatation (FMD), common carotid intima-media thickness (C-IMT), and anteroposterior diameter of infra-renal abdominal aorta (APAO)] were assessed.

Results: APAO was related to anthropometric (age: r=0.520, p=0.001; height: r=0.679, p<0.001; weight: r=0.548, p=0.001; BMI: r=0.607, p<0.001; SBP: r=0.377, p=0.026) and metabolic (HOMAIR: r=0.357, p=0.035; HMW: r=-0.355, p=0.036) parameters. Age, height, and systolic blood pressure were positively related to increased C-IMT (r=0.352, p=0.038; r=0.356, p=0.036; r=0.346, p=0.042, respectively). FMD was not related to any clinical and biochemical characteristics of the pediatric population. Age, HOMAIR, fasting glucose levels, and HMW were independent predictors for APAO increase. Each unit decrease in HMW concentrations (1 μg/ml) induced a 0.065 mm increase in APAO.

Conclusion: High molecular weight adiponectin is related to cardiovascular risk in overweight/obese children.
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http://dx.doi.org/10.5551/jat.31740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399297PMC
August 2016

Chronic treatment with epigallocatechin gallate reduces motor hyperactivity and affects in vitro tested intestinal motility of spontaneously hypertensive rats.

Food Nutr Res 2016 17;60:28373. Epub 2016 Feb 17.

Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', Bari, Italy;

Background: Green tea catechins seem to contribute toward reducing body weight and fat.

Objective: We aimed to investigate whether chronic administration of (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, reduces weight gain in spontaneously hypertensive rats (SHR), an animal model of metabolic syndrome, by increasing motor activity and/or by altering gastrointestinal motility.

Design: Nine-week-old SHR were randomly assigned to two groups and treated by gavage for 3 weeks with vehicle dimethyl sulfoxide or EGCG (200 mg/kg/day). Age-matched Wistar-Kyoto (WKY) control rats were treated with vehicle alone. The effect of chronic administration of EGCG was evaluated on open-field motor activity and on ex vivo colonic and duodenal motility. Moreover, in vitro acute effect of 20-min incubation with EGCG (100 µM) or vehicle was evaluated in colonic and duodenal specimens from untreated WKY rats and SHR.

Results: Vehicle-treated SHR were normoglycemic and hyperinsulinemic, and showed a reduction of plasma adiponectin when compared to vehicle-treated WKY rats. In addition, consistent with fasting glucose and insulin values, vehicle-treated SHR were more insulin resistant than age-matched vehicle-treated WKY rats. Chronic treatment for 3 weeks with EGCG improved insulin sensitivity, raised plasma adiponectin levels, and reduced food intake and weight gain in SHR. Vehicle-treated SHR showed increased open-field motor activity (both crossings and rearings) when tested after each week of treatment. The overall hyperactivity of vehicle-treated SHR was significantly reduced to the levels of vehicle-treated WKY rats after 2 and 3 weeks of EGCG treatment. Colonic and duodenal preparations obtained from SHR chronically treated in vivo with EGCG showed reduced responses to carbachol (0.05-5 µM) and increased inhibitory response to electrical field stimulation (EFS, 1-10 Hz, 13 V, 1 msec, 10-sec train duration), respectively. In vitro acute EGCG incubation (100 µM, 20 min) of colonic and duodenum strips obtained from untreated SHR and WKY rats showed a reduced contractile colonic response to a fixed dose of carbachol (1.5 µM) only in SHR with respect to its own vehicle, whereas the inhibitory duodenal response to a fixed EFS frequency (5 Hz) was significantly reduced in both WKY rats and SHR groups with respect to their own vehicle.

Conclusions: These data suggest that EGCG affects body weight gain in rats and this effect seems to be due to the altered intestinal motility and not to increased motor activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761688PMC
http://dx.doi.org/10.3402/fnr.v60.28373DOI Listing
February 2016

Vitamin D Supplementation for Premenstrual Syndrome-Related Mood Disorders in Adolescents with Severe Hypovitaminosis D.

J Pediatr Adolesc Gynecol 2016 Aug 24;29(4):357-61. Epub 2015 Dec 24.

Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

Study Objective: Premenstrual syndrome (PMS) might become severe enough to interfere with normal interpersonal relationships. This study was planned to assess whether administration of vitamin D (200,000 IU at first, followed by 25,000 IU every 2 weeks) for a 4-month period might lessen the appearance and the intensity of mood disorders associated with PMS in young girls with severe hypovitaminosis D. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: One hundred fifty-eight young girls (15-21 years old) with PMS-related severe symptoms of the emotional and cognitive domains and low serum 25-hydroxycholecalciferol (25-OH-D) levels (≤10 ng/mL) were randomly assigned to two treatment groups and treated for 4 months with vitamin D (group 1; n = 80) or placebo (group 2; n = 78). Clinical and hormonal effects were compared between the two groups.

Results: In patients from group 1, levels of vitamin D reached the normal range (35-60 ng/mL) after the first month and remained stable throughout the whole study. At the end of treatment, anxiety score decreased from 51 to 20 (P < .001 vs baseline); irritability score declined from 130 to 70 (P < .001 vs baseline). Crying easily and sadness decreased by a score of 41 and 51 to a score of 30 and 31, respectively (P < .001). For disturbed relationships, the score decreased from 150 to 70 (P < .001). Conversely, no appreciable changes were noted in symptom intensity from patients of group 2. The frequency of adverse events (nausea and constipation) was not different between participants of group 1 and group 2.

Conclusion: On the basis of the present findings, vitamin D therapy can be proposed as a safe, effective, and convenient method for improving the quality of life in young women with severe hypovitaminosis D and concomitant mood disorders associated with PMS.
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http://dx.doi.org/10.1016/j.jpag.2015.12.006DOI Listing
August 2016

Males with low serum levels of vitamin D have lower pregnancy rates when ovulation induction and timed intercourse are used as a treatment for infertile couples: results from a pilot study.

Reprod Biol Endocrinol 2015 Nov 21;13:127. Epub 2015 Nov 21.

Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari "Aldo Moro", Bari, Italy.

Background: Vitamin D (Vit D) is important for the regulation of reproductive physiology. In humans, maternal Vit D deficiency has been implicated in several reproductive- and pregnancy-related disorders. Very few data are available regarding the Vit D status in male partners of couples attempting pregnancy. This observational study (IRB Prot. N. 078/13) aimed to evaluate whether low Vit D serum levels in males might decrease the rate of successful conception in couples attempting pregnancy.

Methods: Male and female partners of infertile couples (n = 102) were classified into 2 GROUPS according to normal (≥30 ng/ml) or low (below 30 ng/ml) serum Vit D levels in male partners. Semen analysis was performed in each male participant based on the WHO reference criteria. The female partners of both groups were subjected to 3 consecutive cycles of gonadotropin-induced mono-ovulation. The main outcome measures included the clinical pregnancy rate, delivery per patient and per cycle, and miscarriage rate between the 2 groups evaluated at the end of the three-month period of the study.

Results: In male partners of both groups, standard semen analysis did not highlight substantial differences in sperm concentration, sperm progressive motility, or typical form. The pregnancy rates per patient and per cycle and delivery rates per patient and per cycle were all significantly higher (p< 0.05) in couples with normal Vit D levels.

Conclusions: These results suggest the existence of a relationship between male Vit D serum levels and semen ability to begin a pregnancy during cycles of timed vaginal intercourse.
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http://dx.doi.org/10.1186/s12958-015-0126-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654914PMC
November 2015

Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies.

ACS Med Chem Lett 2015 Jun 28;6(6):635-40. Epub 2015 Apr 28.

Department of Pharmacy, University of Chieti "G. d'Annunzio" , 66100 Chieti, Italy.

N-[(3-Aminomethyl)benzyl]acetamidine derivatives were synthesized and in vitro evaluated as inhibitors of the inducible isoform of nitric oxide synthase (iNOS). Because of the high potency of action and the excellent selectivity over the endothelial nitric oxide synthase (eNOS), compound 10 was ex vivo evaluated on isolated and perfused resistance arteries. The results confirm that compound 10 selectively inhibits the iNOS, without affecting the endothelial isoform. The outcome of the docking studies showed that the hydrophobic interaction is the driving force of the binding process, especially for iNOS, where the binding pocket is characterized by a significant lipophilic region.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468396PMC
June 2015

Galloyl benzamide-based compounds modulating tumour necrosis factor α-stimulated c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signalling pathways.

J Pharm Pharmacol 2015 Oct 16;67(10):1380-92. Epub 2015 Jun 16.

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Bari, Italy.

Objectives: The aim of this work is to investigate whether and how two newly synthesized 3,4,5-trimethoxygalloyl-containing compounds 1 and 3 interfere with the mitogen-activated protein kinase (MAPK) signalling pathways involved in several pathological events, ranging from inflammatory diseases to cancer.

Methods: The effects on the phosphorylation of MAP kinases (c-Jun N-terminal kinases (JNKs), p38) and activation of nuclear factor-kappa B (NF-κB) pathways of 1 and its 1H-indazole-containing analogue 3, compared with those elicited by the known Adenosine Triphosphate (ATP)-competitive JNK inhibitor SP600125, were evaluated through Western blot analysis in murine fibroblasts NIH-3T3 and human endothelial cells EA.hy926 acutely treated with tumour necrosis factor-α (TNF-α). Their effects on cell viability were also assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay.

Key Findings: In cultured murine fibroblasts, 1 inhibited JNK signalling with a different mechanism from SP600125. It reduced c-Jun phosphorylation without altering phosphorylation levels of JNK protein. Compound 3, showing a profile similar to SP600125, inhibited JNK phosphorylation and partially inhibited p38 MAPK at 50 μm concentration. Compound 3 and SP600125 showed similar behaviour in both cell cultures. In contrast, compound 1 in EA.hy926 cells significantly interfered with JNK phosphorylation, did not decrease phosphorylation of c-Jun (Ser73), whereas significantly suppressed phosphorylation of p38 MAPK and reversed degradation of NF-κB signalling components.

Conclusions: 3,4,5-Trimethoxygalloyl-based compounds 1 and 3, which did not show significant cell toxicity, modulate the TNF-α-induced activation of MAPK signalling, mainly inhibiting phosphorylation of JNK, c-Jun and p38 MAPK, in murine fibroblasts and human endothelial cells with different MAPK selectivity profiles. These compounds deserve future investigation in specific cell-based disease models and in-vivo pharmacology.
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http://dx.doi.org/10.1111/jphp.12438DOI Listing
October 2015

Dehydroepiandrosterone decreases the age-related decline of the in vitro fertilization outcome in women younger than 40 years old.

Reprod Biol Endocrinol 2015 Mar 9;13:18. Epub 2015 Mar 9.

Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari "Aldo Moro", Bari, Italy.

Background: With infertility populations rapidly aging, treatments improving pregnancy chances assume increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy rates and lower miscarriage rates in women with diminished ovarian function. This study was planned to evaluate whether pretreatment with DHEA may improve in vitro fertilization (IVF) parameters and pregnancy outcomes in infertile women with advanced reproductive age and normal ovarian reserve.

Methods: In this double-blind, randomized, placebo-controlled study, 109 infertile patients aging 36-40 years old were selected to undergo the long protocol IVF. Eight weeks before starting the IVF cycle and during treatment, patients in Group 1 received 75 mg of DHEA once a day; patients in control group (Group 2) received placebo. The primary endpoint of the study was number of clinical pregnancy, live birth and miscarriage rates; secondary endpoint was modification of standard IVF parameters, including stimulation duration (days of rhFSH administration), E2 on HCG-day, endometrial thickness, number of retrieved oocytes, metaphase II oocytes, number of transferred embryos and score of leading embryos transferred.

Results: Patients in the DHEA group had a significantly higher live birth rate compared with controls (P<0.05). Conversely, miscarriage rate was higher for patients in the control group (P<0.05).

Conclusions: DHEA supplementation may significantly improve IVF outcomes in infertile women with advanced reproductive age and normal ovarian reserve.
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http://dx.doi.org/10.1186/s12958-015-0014-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355976PMC
March 2015

Intermittent low-dose finasteride administration is effective for treatment of hirsutism in adolescent girls: a pilot study.

J Pediatr Adolesc Gynecol 2014 Jun 20;27(3):161-5. Epub 2014 Feb 20.

Department of Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Bari "Aldo Moro", Bari, Italy.

Study Objective: Hirsutism has negative impact on adolescent psychosocial development for both cosmetic and endocrine reasons. This study evaluated the effectiveness of a new intermittent, low-dose finasteride regimen consisting of 2.5 mg of drug given every 3 days (1 day of treatment, 2 days of drug withdrawal) for 6 months in girls with hirsutism by polycystic ovarian syndrome (PCOS) or idiopathic hirsutism (IH).

Design And Participants: Twenty-eight girls (15-19 y old) with hirsutism were randomly assigned to 2 treatment groups and treated for 6 months. Fourteen patients (7 with IH, 7 with PCOS) received finasteride; fourteen patients (7 with IH, 7 with PCOS) received placebo. Hirsutism score (HS), clinical, and hormonal effects were compared between the 2 groups.

Results: In patients treated with finasteride, the HS value at 6 months was 52.9% lower than that observed at baseline in girls with IH, and 52.8% lower in girls with PCOS (P < .0001 for both). Similarly, the 3α-17 β-androstenediol glucuronide serum levels were decreased by 34.8% in patients with IH, and by 47.5% in patients with PCOS (P < .0001, respectively). Finasteride treatment was well tolerated and did not alter values of BMI, serum levels of sexual hormones, metabolic parameters related to liver and kidney function as well as glycemic and lipidic asset.

Conclusions: A low-dose of finasteride, given every 3 days, reduces the HS in young patients affected by PCOS or IH. Compared with conventional continuous finasteride administration, the intermittent low-dose regimen has similar efficacy with the advantage to be safer and less expensive.
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http://dx.doi.org/10.1016/j.jpag.2013.09.010DOI Listing
June 2014

Intermittent losartan administration triggers cardiac post-conditioning in isolated rat hearts: role of BK2 receptors.

PLoS One 2014 10;9(2):e88542. Epub 2014 Feb 10.

Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro," Bari, Italy.

Introduction: The angiotensin (Ang) and bradykinin (BK) tissue-system plays a pivotal role in post-conditioning, but the efficacy of angiotensin type 1 receptor (AT1R) blockers (ARBs) in post-ischemic strategies is still under investigation. We evaluated functional and morphological outcomes, together with activation of cytosolic RISK pathway kinases, in rat hearts subjected to losartan (LOS) or irbesartan (IRB) post-ischemic administration.

Methods: Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Post-conditioning was obtained by intermittent (10 s/each) or continuous drug infusion during the first 3 min of reperfusion. Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (dLVP), coronary flow (CF), and left ventricular infarct mass (IM) were measured together with the activation status of RISK kinases Akt, p42/44 MAPK and GSK3β.

Results: When compared to hearts subjected to ischemia/reperfusion (iI/R) alone, continuous IRB or LOS administration did not significantly reduce total infarct mass (cIRB or cLOS vs. iI/R, p = 0.2). Similarly, intermittent IRB (iIRB) was not able to enhance cardioprotection. Conversely, intermittent LOS administration (iLOS) significantly ameliorated cardiac recovery (iLOS vs iI/R, p<0.01). Differences between iLOS and iIRB persisted under continuous blockade of AT2R (iLOS+cPD vs. iIRB+cPD, p<0.05). Interestingly, iLOS cardioprotection was lost when BK2R was simultaneously blocked (iLOS+cHOE vs. iI/R, p = 0.6), whereas concurrent administration of iBK and iIRB replicated iLOS effects (iIRB+iBK vs. iLOS, p = 0.7). At the molecular level, iIRB treatment did not significantly activate RISK kinases, whereas both iLOS and iBK treatments were associated with activation of the Akt/GSK3β branch of the RISK pathways (p<0.05 vs. iI/R, for both).

Conclusions: Our results suggest that intermittent losartan is effective in mediating post-conditioning cardioprotection, whereas irbesartan is not. The infarct mass reduction by intermittent losartan seem mainly related on its specific ability to modulate BK2R, and only modestly associated on AT1R blocking properties.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919762PMC
October 2014

Increased antioxidant defense mechanism in human adventitia-derived progenitor cells is associated with therapeutic benefit in ischemia.

Antioxid Redox Signal 2014 Oct 1;21(11):1591-604. Epub 2014 Apr 1.

1 Expermental Cardiovascular Medicine, School of Clinical Sciences, University of Bristol , Bristol, United Kingdom .

Aims: Vascular wall-resident progenitor cells hold great promise for cardiovascular regenerative therapy. This study evaluates the impact of oxidative stress on the viability and functionality of adventitia-derived progenitor cells (APCs) from vein remnants of coronary artery bypass graft (CABG) surgery. We also investigated the antioxidant enzymes implicated in the resistance of APCs to oxidative stress-induced damage and the effect of interfering with one of them, the extracellular superoxide dismutase (EC-SOD/SOD3), on APC therapeutic action in a model of peripheral ischemia.

Results: After exposure to hydrogen peroxide, APCs undergo apoptosis to a smaller extent than endothelial cells (ECs). This was attributed to up-regulation of antioxidant enzymes, especially SODs and catalase. Pharmacological inhibition of SODs increases reactive oxygen species (ROS) levels in APCs and impairs their survival. Likewise, APC differentiation results in SOD down-regulation and ROS-induced apoptosis. Oxidative stress increases APC migratory activity, while being inhibitory for ECs. In addition, oxidative stress does not impair APC capacity to promote angiogenesis in vitro. In a mouse limb ischemia model, an injection of naïve APCs, but not SOD3-silenced APCs, helps perfusion recovery and neovascularization, thus underlining the importance of this soluble isoform in protection from ischemia.

Innovation: This study newly demonstrates that APCs are endowed with enhanced detoxifier and antioxidant systems and that SOD3 plays an important role in their therapeutic activity in ischemia.

Conclusions: APCs from vein remnants of CABG patients express antioxidant defense mechanisms, which enable them to resist stress. These properties highlight the potential of APCs in cardiovascular regenerative medicine.
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http://dx.doi.org/10.1089/ars.2013.5404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174427PMC
October 2014

The putative metabolic role of d-chiro inositol phosphoglycan in human pregnancy and preeclampsia.

J Reprod Immunol 2014 Mar 2;101-102:140-147. Epub 2013 Aug 2.

Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University "Aldo Moro" of Bari, Policlinico, Bari, Italy.

Immunological alterations, systemic inflammation, endothelial dysfunction, and insulin resistance are prominent features of preeclampsia, although the reciprocal relationship between them is poorly understood. The metabolic syndrome that occurs during preeclampsia can be exacerbated by the systemic inflammation and linked to placental metabolism/development and endothelial dysfunction. Under healthy conditions, insulin and insulin-like growth factor-integrated pathways not only promote cell metabolism and proliferation, but also regulate endothelial synthesis and release of vasodilators (e.g., nitric oxide, NO) and opposing vasoconstrictors (e.g., endothelin-1) to maintain vascular homeostasis. d-chiro inositol phosphoglycans (DCI), second messengers of insulin, are increased during preeclampsia and contribute directly to insulin resistance. The dynamic balanced control of vascular function may be altered by excessive DCI that impairs the PI3-kinase-dependent pathway and may result in reduced bioavailability of NO, contributing to elevated peripheral vascular resistance and hypertension.
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http://dx.doi.org/10.1016/j.jri.2013.05.006DOI Listing
March 2014

Augmenter of liver regeneration, a protective factor against ROS-induced oxidative damage in muscle tissue of mitochondrial myopathy affected patients.

Int J Biochem Cell Biol 2013 Nov 31;45(11):2410-9. Epub 2013 Jul 31.

Section of Gastroenterology, Dept. of Emergency and Transplant of Organs (DETO), Univ. of Bari, Italy; IRSSC "S. de Bellis" Castellana Grotte, Bari, Italy; Center Interdept. of Res. on Gastroent. and Evolut. Hepatology (CIRGEE), Italy. Electronic address:

Mitochondria-related myopathies (MM) are a group of different diseases defined by a varying degree of dysfunctions of the mitochondrial respiratory chain which leads to reactive oxygen species (ROS) generation followed by oxidative stress and cellular damage. In mitochondrial myopathy muscle tissue an overexpression of antioxidant enzymes has been documented probably as an attempt to counteract the free radical generation. We previously documented, in human non-pathological muscle fibres, the expression of the augmenter of liver regeneration (ALR), a sulfhydryl oxidase enzyme, whose presence is related to the mitochondria; indeed it has been demonstrated that ALR mainly localizes in the mitochondrial inter-membrane space. Furthermore we reported, in different experimental models, in vivo and in vitro, the anti-apoptotic and anti-oxidative capacities of ALR, achieved by up-regulating Bcl-2 anti-apoptotic family factors and the anti-apoptotic/anti-oxidative secretory isoform of clusterin (sClu). With the present study we aimed to determine ALR, Bcl-2 protein, clusterin and ROS expression in muscle tissue biopsies from MM-affected patients. Non-pathological muscle tissue was used as control. Enzymatic, histochemical, immunohistochemical and immune electron microscopy techniques were performed. The data obtained revealed in MM-derived muscle tissue, compared to non-pathological tissue, the over-expression of ROS, ALR and Bcl-2 and the induction of the nuclear, pro-apoptotic, isoform of clusterin (nCLU).
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http://dx.doi.org/10.1016/j.biocel.2013.07.010DOI Listing
November 2013

Hemin and Zinc Protoporphyrin IX Affect Granisetron Constipating Effects In Vitro and In Vivo.

ISRN Gastroenterol 2013 20;2013:612037. Epub 2013 Jun 20.

Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Piazza Giulio Cesare, 70124 Bari, Italy.

Granisetron is a 5-HT3 receptors antagonist used in the management of emesis associated with anticancer chemotherapy. It affects intestinal motility with constipating effect. Since the pathway heme oxygenase/carbon monoxide (HO/CO) is involved in gastrointestinal motility, we evaluated the possible interplay between granisetron and agents affecting HO/CO pathways such as zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, or hemin, an HO-1 inducer. ZnPPIX (10 µM) or hemin (10 µM), but not granisetron (0.1, 0.3, 1 µM), affected spontaneous basal activity recorded in rat duodenal strips, in noncholinergic nonadrenergic conditions. Granisetron restored spontaneous basal activity after ZnPPIX, but not after hemin. ZnPPIX decreased and hemin increased the inhibition of activity after electrical field stimulation (EFS), but they did not affect the contraction that follows the relaxation induced by EFS called off contraction. Granisetron did not alter the response to EFS per se but abolished both ZnPPIX and hemin effect when coadministered. In vivo study showed constipating effect of granisetron (25, 50, 75 µg/kg/sc) but no effect of either ZnPPIX (50 µg/kg/i.p.) or hemin (50 µM/kg/i.p.). When coadministered, granisetron effect was abolished by ZnPPIX and increased by hemin. Specimens from rats treated in vivo with hemin (50 µM/kg/i.p.) showed increased HO-1 protein levels. In conclusion, granisetron seems to interact with agents affecting HO/CO pathway both in vitro and in vivo.
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http://dx.doi.org/10.1155/2013/612037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705784PMC
July 2013

Elevated endothelin-1 (ET-1) levels may contribute to hypoadiponectinemia in childhood obesity.

J Clin Endocrinol Metab 2013 Apr 1;98(4):E683-93. Epub 2013 Mar 1.

Department of Biomedical Sciences and Human Oncology, University of Bari, Medical School, 70124 Bari, Italy.

Context: Pediatric obesity is associated with endothelial dysfunction and hypoadiponectinemia, but the relationship between these two conditions remains to be fully clarified. Whether enhanced release of endothelin-1 (ET-1) may directly impair adiponectin (Ad) production in obese children is not known.

Objective: The aim of the study was to explore whether and how high circulating levels of ET-1 may contribute to impair Ad production, release, and vascular activity.

Design And Participants: Sixty children were included into obese (Ob; n = 30), overweight (OW; n = 11), and lean (n = 19) groups. Total and high-molecular-weight Ad, ET-1, vascular cell adhesion molecule-1, and von Willebrand factor levels were measured in serum samples. Adipocytes were stimulated with exogenous ET-1 or with sera from lean, OW, and Ob, and Ad production and release measured in the absence or in the presence of ETA (BQ-123) and ETB (BQ-788) receptor blockers, p42/44 MAPK inhibitor PD-98059, or c-Jun NH2-terminal protein kinase inhibitor SP-600125. Vasodilation to Ad was evaluated in rat isolated arteries in the absence or in the presence of BQ-123/788.

Results: Total and high-molecular-weight Ad was significantly decreased and ET-1 levels significantly increased in OW (P < .01) and Ob (P < .001) children. A statistically significant linear regression (P < .01) was found between Ad and ET-1. Exposure of adipocytes to exogenous ET-1 or serum from OW and Ob significantly decreased Ad mRNA and protein levels (P < 0.001). The inhibitory effect of ET-1 on Ad was reverted by BQ-123/788 or PD-98059 but not SP-600125. Ad-mediated vasodilation was further increased in arteries pretreated with BQ-123/788.

Conclusions: ET-1-mediated inhibition of Ad synthesis via p42/44 MAPK signaling may provide a possible explanation for hypoadiponectinemia in pediatric obesity and contribute to the development of cardiovascular complications.
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http://dx.doi.org/10.1210/jc.2012-4119DOI Listing
April 2013

Role of lipotoxicity in endothelial dysfunction.

Heart Fail Clin 2012 Oct 10;8(4):589-607. Epub 2012 Aug 10.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35294-0012, USA.

Vascular endothelial dysfunction is determined by both genetic and environmental factors that cause decreased bioavailability of the vasodilator nitric oxide. This is a hallmark of atherosclerosis, hypertension, and coronary heart disease, which are major complications of metabolic disorders, including diabetes and obesity. Several therapeutic interventions, including changes in lifestyle as well as pharmacologic treatments, are useful for improving endothelial dysfunction in the face of lipotoxicity. This review discusses the current understanding of molecular and physiologic mechanisms underlying lipotoxicity-mediated endothelial dysfunction as well as relevant therapeutic approaches to ameliorate dyslipidemia and consequent endothelial dysfunction that have the potential to improve cardiovascular and metabolic outcomes.
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http://dx.doi.org/10.1016/j.hfc.2012.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126197PMC
October 2012

Determinants of evolving metabolic and cardiovascular benefit/risk profiles of rosiglitazone therapy during the natural history of diabetes: molecular mechanisms in the context of integrated pathophysiology.

Am J Physiol Endocrinol Metab 2012 May 28;302(10):E1171-82. Epub 2012 Feb 28.

Department of Biomedical Sciences and Human Oncology, Medical School, University of Bari, Bari, Italy.

Rosiglitazone is a thiazolidinedione, a synthetic PPARγ receptor agonist with insulin-sensitizing properties that is used as an antidiabetic drug. In addition to improving glycemic control through actions in metabolic target tissues, rosiglitazone has numerous biological actions that impact on cardiovascular homeostasis. Some of these actions are helpful (e.g., improving endothelial function), whereas others are potentially harmful (e.g., promoting fluid retention). Since cardiovascular morbidity and mortality are major endpoints for diabetes, it is essential to understand how the natural history of diabetes alters the net benefits and risks of rosiglitazone therapy. This complex issue is an important determinant of optimal use of rosiglitazone and is critical for understanding cardiovascular safety issues. We give special attention to the effects of rosiglitazone in diabetic patients with stable coronary artery disease and the impact of rosiglitazone actions on atherosclerosis and plaque instability. This provides a rational conceptual framework for predicting evolving benefit/risk profiles that inform optimal use of rosiglitazone in the clinical setting and help explain the results of recent large clinical intervention trials where rosiglitazone had disappointing cardiovascular outcomes. Thus, in this perspective, we describe what is known about the molecular mechanisms of action of rosiglitazone on cardiovascular targets in the context of the evolving pathophysiology of diabetes over its natural history.
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http://dx.doi.org/10.1152/ajpendo.00038.2012DOI Listing
May 2012

In-vivo administration of CLC-K kidney chloride channels inhibitors increases water diuresis in rats: a new drug target for hypertension?

J Hypertens 2012 Jan;30(1):153-67

Section of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Bari, Italy.

Objective: The human kidney-specific chloride channels ClC-Ka (rodent ClC-K1) and ClC-Kb (rodent ClC-K2) are important determinants of renal function, participating to urine concentration and blood pressure regulation mechanisms. Here we tested the hypothesis that these chloride channels could represent new drug targets for inducing diuretic and antihypertensive effects.

Methods: To this purpose, the CLC-K blockers benzofuran derivatives MT-189 and RT-93 (10, 50, 100 mg/kg), were acutely administered by gavage in Wistar rats, and pharmacodynamic and pharmacokinetic parameters determined by functional, bioanalytical, biochemical and molecular biology assays.

Results: Plasma concentration values for MT-189 and RT-93 were indicative of good bioavailability. Both MT-189 and RT-93 dose-dependently increased urine volume without affecting electrolyte balance. A comparable reduction of SBP was observed in rats after MT-189, RT-93 or furosemide administration. Benzofuran derivatives treatment did not affect kidney CLC-K mRNA level or inner medulla osmolality, whereas a significant vasopressin-independent down-regulation of aquaporin water channel type 2 was observed at protein and transcriptional levels. In rats treated with benzofuran derivatives, the observed polyuria was mainly water diuresis; this finding indirectly supports a cross-talk between chloride and water transport in nephron. Moreover, preliminary in-vitro evaluation of the drugs capability to cross the blood-inner ear barrier suggests that these compounds have a limited ability to induce potential auditory side effects.

Conclusion: CLC-K blockers may represent a new class of drugs for the treatment of conditions associated with expanded extracellular volume, with a hopeful high therapeutic potential for hypertensive patients carrying ClC-K gain-of-function polymorphisms.
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http://dx.doi.org/10.1097/HJH.0b013e32834d9eb9DOI Listing
January 2012