Publications by authors named "Matteo Antonio Russo"

56 Publications

Novel dilated cardiomyopathy associated to Calreticulin and Myo7A gene mutation in Usher syndrome.

ESC Heart Fail 2021 Apr 9. Epub 2021 Apr 9.

MEBIC Consortium, San Raffaele Open University and IRCCS San Raffaele Pisana, Rome, Italy.

We report a novel cardiomyopathy associated to Usher syndrome and related to combined mutation of MYO7A and Calreticulin genes. A 37-year-old man with deafness and vision impairment because of retinitis pigmentosa since childhood and a MYO7A gene mutation suggesting Usher syndrome, developed a dilated cardiomyopathy with ventricular tachyarrhythmias and recurrent syncope. At magnetic resonance cardiomyopathy was characterized by left ventricular dilatation with hypo-contractility and mitral prolapse with valve regurgitation. At left ventricular endomyocardial biopsy, it was documented cardiomyocyte disconnection because of cytoskeletal disorganization of cell-to-cell contacts, including intercalated discs, and mitochondrial damage and dysfunction with significant reduction of adenosine triphosphate production in patient cultured fibroblasts. At an extensive analysis by next-generation-sequencing of 4183 genes potentially related to the cardiomyopathy a pathogenic mutation of calreticulin was found. The cardiomyopathy appeared to be functionally and electrically stabilized by a combination therapy including carvedilol and amiodarone at a follow-up of 18 months.
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http://dx.doi.org/10.1002/ehf2.13260DOI Listing
April 2021

Taking Advantage of Plant Defense Mechanisms to Promote Human Health. Exploitation of Plant Natural Products for Preventing or Treating Human Disease. Second of Two Parts.

Endocr Metab Immune Disord Drug Targets 2020 Dec 29. Epub 2020 Dec 29.

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, School of Medicine, University of Bari, Bari. Italy.

Background: Plants have represented an essential source of foods for human beings, as confirmed by archeological studies that have revealed on old pottery the presence of proteins from cereal and legumes.

Specific Aims: In this review, major healthy effects derived from the consumption of plant fibers, polyunsaturated fatty acids (PUFAs) and polyphenols, respectively, will be described with special emphasis on their mechanisms of action, both at cellular and molecular levels. Dietary compounds: Fibers exhibit a prevalent prebiotic effect, acting on the intestinal microbiota with the production of protective metabolites, such as short chain fatty acids. Plant PUFAs include α-linolenic and stearidonic acids, which are precursors of other two major PUFAs, namely, eicosapentaenoic and docosahexaenoic acids. Some clinical trials demonstrated the ability of PUFAs to lower the risk of coronary disease, while other trials did not confirm such a finding. Polyphenols are endowed with anti-oxidant and anti-inflammatory activity in view of their property to inhibit NF-κB activation, to induce the anti-inflammatory T regulatory cells and to normalize the intestinal microbiota. The beneficial effects of polyphenols on obesity/diabetes, allergic/autoimmune and inflammatory disease are elucidated.

Conclusion: Plants are one of the major sources of healthy dietary products, whose exploitation may promote prevention of chronic disease.
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http://dx.doi.org/10.2174/1871530321666201229125400DOI Listing
December 2020

Natural Antioxidant Control of Neuropathic Pain-Exploring the Role of Mitochondrial SIRT3 Pathway.

Antioxidants (Basel) 2020 Nov 9;9(11). Epub 2020 Nov 9.

Department of Health Sciences, Institute of Research for Food Safety & Health (IRC-FSH), University "Magna Graecia" of Catanzaro, 88201 Catanzaro, Italy.

Neuropathic pain is a chronic painful disease. Data have shown that reactive oxygen species (ROS) are implicated in chronic pain. Particularly, the enhanced ROS production alters the mitochondrial genome and proteome through the accumulation of lipid peroxidation products, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Sirtuin 3 (SIRT3) is a mitochondrial protein and its activity can reduce ROS levels by modulating key antioxidant enzymes, such as manganese superoxide dismutase (MnSOD). Here, we evaluated the role of SIRT3 in the maintenance of basal levels of ROS in a model of chronic constriction injury (CCI) of the sciatic nerve and the protective effects of a natural antioxidant, the bergamot polyphenolic fraction (BPF). Rats were exposed to CCI of the sciatic nerve in the presence or absence of BPF (25-75 mg/kg). Level of acetylation, post-translational modulation on cysteine residues of proteins by HNE and SIRT3 activation, were detected in the spinal cord through western blotting, WES methodology and enzymatic assays. Our results reported that SIRT3 carbonylation and therefore its inactivation contributes to mitochondrial MnSOD hyperacetylation during CCI induced neuropathic pain in rats. In particular, we have demonstrated a close relation between oxidative stress, hyperalgesia, allodynia and sirtuins inactivation reverted by BPF administration.
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http://dx.doi.org/10.3390/antiox9111103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698145PMC
November 2020

HMGB1-mediated apoptosis and autophagy in ischemic heart diseases.

Vasc Biol 2019 12;1(1):H89-H96. Epub 2019 Aug 12.

Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, Rome, Italy.

Acute myocardial infarction (MI) and its consequences are the most common and lethal heart syndromes worldwide and represent a significant health problem. Following MI, apoptosis has been generally seen as the major contributor of the cardiomyocyte fate and of the resultant myocardial remodeling. However, in recent years, it has been discovered that, following MI, cardiomyocytes could activate autophagy in an attempt to protect themselves against ischemic stress and to preserve cardiac function. Although initially seen as two completely separate responses, recent works have highlighted the intertwined crosstalk between apoptosis and autophagy. Numerous researches have tried to unveil the mechanisms and the molecular players involved in this phenomenon and have identified in high-mobility group box 1 (HMGB1), a highly conserved non-histone nuclear protein with important roles in the heart, one of the major regulator. Thus, the aim of this mini review is to discuss how HMGB1 regulates these two responses in ischemic heart diseases. Indeed, a detailed understanding of the crosstalk between apoptosis and autophagy in these pathologies and how HMGB1 regulates them would be of tremendous help in developing novel therapeutic approaches aimed to promote cardiomyocyte survival and to diminish tissue injury following MI.
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http://dx.doi.org/10.1530/VB-19-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439920PMC
August 2019

Taking Advantage of Plant Defense Mechanisms to Promote Human Health. The Plant Immune System. First of Two Parts.

Endocr Metab Immune Disord Drug Targets 2020 Aug 31. Epub 2020 Aug 31.

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, School of Medicine, University of Bari, Bari. Italy.

Background: Despite the evidence that plants do not possess sessile cells, they are able to mount a vigorous immune response against invaders or under stressful conditions. Mechanisms of action: Plants are endowed with pattern recognition receptors (PPRs) which perceive damage-associated molecular patterns and microbe-associated molecular patterns or pathogen-associated molecular patterns (PAMPs), respectively. PPR activation leads to either the initiation of PAMP-triggered immunity (PTI) (early response) or the effectortriggered immunity (ETI). Both PTI and ETI contribute to plant systemic acquired resistance as also an expression of immunological memory or trained immunity. Plant immune receptors: PTI is initiated by activation of both receptor-like kinases and receptor-like proteins, while ETI depends on nucleotide-binding leucine-rich-repeat protein receptors for microbe recognition. Peptides involved in plant defenses: Plant chloroplasts contribute to both PTI and ETI through production of peptides which act as hormones or phytocytokines. Salicylic acid, jasmonic acid and ethylene are the major compounds involved in plant defense.

Specific Aims: The interaction between plant receptors and/or their products and bacterial components will be discussed. Also emphasis will be placed on plant microbiome for its contribution to plant immune response. Finally, the mutual interplay between insects and plants will also be illustrated.

Conclusion: A better knowledge on plant immunity may pave the way for the exploitation of plant derivatives in the field of agriculture and medicine, as well.
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http://dx.doi.org/10.2174/1871530320999200831224302DOI Listing
August 2020

Platelets: Angels and demons dancing on the immune stage. Nutrition conducts the orchestra.

Endocr Metab Immune Disord Drug Targets 2020 Sep 1. Epub 2020 Sep 1.

Departement of Basic Medical Sciences, Neuroscience and Sensory Organs, School of Medicine, University of Bari "Aldo Moro", Bari. Italy.

Background: Platelets are cellular fragments derived from bone-marrow megacaryocytes and they are mostly involved in haemostasis and coagulation. However, according to recent data, platelets are able to perform novel immune functions. In fact, they possess a receptorial armamentarium on their membrane for interacting with innate and adaptive immune cells. In addition, platelets also secrete granules which contain cytokines and chemokines for activating and recruiting even distant immune cells.

Objectives: The participation of platelets in inflammatory processes will be discussed also in view of their dual role in terms of triggering or resolving inflammation. Involvement of platelets in disease will be illustrated, pointing to their versatile function to either up- or down-regulate pathological mechanisms. Finally, despite the availability of some anti-platelet agents, such as aspirin, dietary manipulation of platelet function is currently investigated. In this regard, special emphasis will be placed on dietary omega-3 polyunsaturated fatty acids (PUFAs) and polyphenol effects on platelets.

Conclusion: Platelets play a dual role in inflammatory-immune-mediated diseases either activating or deactivating immune cells. Diet based on substances, such as omega-3 PUFAs and polyphenols, may act as a modulator of platelet function, even if more clinical trials are needed to corroborate such a contention.
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http://dx.doi.org/10.2174/1871530320666200901183119DOI Listing
September 2020

Kappa-light Chain Amyloid Overlapping Hypertrophic Cardiomyopathy With Myocardial Noncompaction.

Circ Cardiovasc Imaging 2020 07 1;13(7):e010379. Epub 2020 Jul 1.

Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences (A.F., M.A., C.C.), Sapienza University, Rome.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010379DOI Listing
July 2020

Antioxidant modulation of sirtuin 3 during acute inflammatory pain: The ROS control.

Pharmacol Res 2020 07 11;157:104851. Epub 2020 May 11.

Institute of Research for Food Safety & Health (IRC-FSH), Department of Health Sciences, University "Magna Graecia" of Catanzaro, 88201 Catanzaro, Italy. Electronic address:

Oxidative stress induced post-translational protein modifications are associated with the development of inflammatory hypersensitivities. At least 90% of cellular reactive oxygen species (ROS) are produced in the mitochondria, where the mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), is located. MnSOD's ability to reduce ROS is enhanced by the mitochondrial NAD-dependent deacetylase sirtuin (SIRT3). SIRT3 can reduce ROS levels by deacetylating MnSOD and enhancing its ability to neutralize ROS or by enhancing the transcription of MnSOD and other oxidative stress-responsive genes. SIRT3 can be post-translationally modified through carbonylation which results in loss of activity. The contribution of post-translational SIRT3 modifications in central sensitization is largely unexplored. Our results reveal that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with natural and synthetic antioxidants, prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD, and blocked the development of thermal hyperalgesia. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization.
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http://dx.doi.org/10.1016/j.phrs.2020.104851DOI Listing
July 2020

Fabry cardiomyopathy: Gb3-induced auto-reactive panmyocarditis requiring heart transplantation.

ESC Heart Fail 2020 06 29;7(3):1331-1337. Epub 2020 Apr 29.

Cardiothoracic Surgery, Udine University Hospital, Rome, Italy.

Resistance to enzyme replacement therapy (ERT) is a major therapeutic challenge in Fabry disease (FD). Recent reports attribute to immune-mediated inflammation a main role in promoting disease progression and resistance to ERT. Aim of the study is to report a Gb3-induced auto-reactive panmyocarditis causing inefficacy of ERT and severe electrical instability, which required cardiac transplantation. Examining the explanted heart from a 57-year-old man with FD cardiomyopathy (CM) on 3-year ERT presenting incoming ventricular fibrillation, we documented a severe virus-negative myocarditis extended to cardiomyocytes, intramural coronary vessels, conduction tissue, and subepicardial ganglia. Serology was positive for anti-Gb3, anti-heart, and anti-myosin antibodies. In vitro Gb3 stimulation of patient's peripheral blood mononuclear cells (PBMC) induced high amount production of inflammatory cytokine IL1-β, IL-6, IL-8, and TNF-α. PBMC were stained using the monoclonal antibodies CD3-V500, CD4-V450, CD8-APCcy7, CD45RO-PerCPcy5.5 and CD27-FITC from BD Biosciences and CD56-PC7 from Bekman Coulter. The phenotypic analysis of PBMC showed a lower frequency of CD8 (9.2%) vs. 19.3% and NKT cells (1.6% vs. 2.4%) in Fabry patient respect to healthy donor, suggesting a possible homing to peripheral tissues. A Gb3-induced auto-reactive myocarditis is suggested as a possible cause of FDCM progression and ERT resistance. Immune-mediated inflammation of systemic Fabry cells may coexist and be controlled by implemental immunosuppressive therapy.
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http://dx.doi.org/10.1002/ehf2.12723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261584PMC
June 2020

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity.

Cancers (Basel) 2020 Mar 17;12(3). Epub 2020 Mar 17.

Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Experimental Immunology Laboratory, Via dei Monti di Creta 104, 00167 Rome, Italy.

Cancer treatment has made significant progress in the cure of different types of tumors. Nevertheless, its clinical use is limited by unwanted cardiotoxicity. Aside from the conventional chemotherapy approaches, even the most newly developed, i.e., molecularly targeted therapy and immunotherapy, exhibit a similar frequency and severity of toxicities that range from subclinical ventricular dysfunction to severe cardiomyopathy and, ultimately, congestive heart failure. Specific mechanisms leading to cardiotoxicity still remain to be elucidated. For instance, oxidative stress and DNA damage are considered key players in mediating cardiotoxicity in different treatments. microRNAs (miRNAs) act as key regulators in cell proliferation, cell death, apoptosis, and cell differentiation. Their dysregulation has been associated with adverse cardiac remodeling and toxicity. This review provides an overview of the cardiotoxicity induced by different oncologic treatments and potential miRNAs involved in this effect that could be used as possible therapeutic targets.
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http://dx.doi.org/10.3390/cancers12030704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140035PMC
March 2020

Cardiac Repair: The Intricate Crosstalk between the Epicardium and the Myocardium.

Curr Stem Cell Res Ther 2020 ;15(8):661-673

Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, Rome and San Raffaele Open University, Rome, Italy.

Background: Substantial evidences support the hypothesis that the epicardium has a role in cardiac repair and regeneration in part providing, by epithelial to mesenchymal transition (EMT), progenitor cells that differentiate into cardiac cell types and in part releasing paracrine factors that contribute to cardiac repair. Besides cell contribution, a significant paracrine communication occurs between the epicardium and the myocardium that improves the whole regenerative response. Signaling pathways underlying this communication are multiple as well as soluble factors involved in cardiac repair and secreted both by myocardial and epicardial cells. Most recently, extracellular vesicles, i.e. exosomes, that accumulate in the pericardial fluid (PF) and are able to transport bioactive molecules (cytosolic proteins, mRNAs, miRNAs and other non-coding RNAs), have been also identified as potential mediators of epicardial-mediated repair following myocardial injury.

Conclusion: This mini-review provides an overview of the epicardial-myocardial signaling in regulating cardiac repair in ischemic heart diseases. Indeed, a detailed understanding of the crosstalk between myocardial and epicardial cells and how paracrine mechanisms are involved in the context of ischemic heart diseases would be of tremendous help in developing novel therapeutic approaches to promote cardiomyocytes survival and heart regeneration following myocardial infarction (MI).
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http://dx.doi.org/10.2174/1574888X15666200219105448DOI Listing
January 2020

Recent Advances on the Anti-Inflammatory and Antioxidant Properties of Red Grape Polyphenols: In Vitro and In Vivo Studies.

Antioxidants (Basel) 2019 Dec 31;9(1). Epub 2019 Dec 31.

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, School of Medicine, University of Bari, 70124 Bari, Italy.

In this review, special emphasis will be placed on red grape polyphenols for their antioxidant and anti-inflammatory activities. Therefore, their capacity to inhibit major pathways responsible for activation of oxidative systems and expression and release of proinflammatory cytokines and chemokines will be discussed. Furthermore, regulation of immune cells by polyphenols will be illustrated with special reference to the activation of T regulatory cells which support a tolerogenic pathway at intestinal level. Additionally, the effects of red grape polyphenols will be analyzed in obesity, as a low-grade systemic inflammation. Also, possible modifications of inflammatory bowel disease biomarkers and clinical course have been studied upon polyphenol administration, either in animal models or in clinical trials. Moreover, the ability of polyphenols to cross the blood-brain barrier has been exploited to investigate their neuroprotective properties. In cancer, polyphenols seem to exert several beneficial effects, even if conflicting data are reported about their influence on T regulatory cells. Finally, the effects of polyphenols have been evaluated in experimental models of allergy and autoimmune diseases. Conclusively, red grape polyphenols are endowed with a great antioxidant and anti-inflammatory potential but some issues, such as polyphenol bioavailability, activity of metabolites, and interaction with microbiota, deserve deeper studies.
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http://dx.doi.org/10.3390/antiox9010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022464PMC
December 2019

Heart Failure From Gouty Myocarditis: A Case Report.

Ann Intern Med 2020 03 3;172(5):363-365. Epub 2019 Dec 3.

Sapienza University and IRCCS L. Spallanzani, Rome, Italy (A.F., C.C.).

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http://dx.doi.org/10.7326/L19-0486DOI Listing
March 2020

Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies.

JCI Insight 2019 11 14;4(22). Epub 2019 Nov 14.

School of Cardiovascular Medicine and Sciences, King's College London BHF Centre for Research Excellence, London, United Kingdom.

Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.
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http://dx.doi.org/10.1172/jci.insight.126315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948859PMC
November 2019

Primary aldosteronism-associated cardiomyopathy: Clinical-pathologic impact of aldosterone normalization.

Int J Cardiol 2019 10 20;292:141-147. Epub 2019 Jun 20.

Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, La Sapienza University, Italy; Cellular and Molecular Cardiology Lab, IRCCS L. Spallanzani, Rome, Italy.

Background: Primary aldosteronism (PA) causes a cardiomyopathy (CM) which substrate and evolution after aldosterone normalization are unreported.

Methods: Four male patients with aldosterone-secreting adrenal adenoma and cardiomyopathy (PACM, group A) were evaluated with 2D-echo, Magnetic Resonance (CMR), coronary angiography and left ventricular endomyocardial biopsy. Biopsy samples were processed for histology, electron microscopy, immunohistochemistry, and Western Blot analysis of myocardial aldosterone receptors and aquaporin 1 and 4. Results were compared with endomyocardial samples from 5 patients with hypertensive cardiomyopathy of equivalent severity and normal plasma aldosterone (group B) and surgical samples from 5 controls (group C). One PACM patient was re-examined with CMR and endomyocardial biopsy 12 months after adrenalectomy with aldosterone and cardiac normalization.

Results: Coronary arteries were normal in all. Group A showed prominent myocardial hypertrophy and fibrosis, with water accumulation in the cytosol and organelles of cardiomyocytes and microvascular smooth muscle cells, associated to reduced myofibril concentration and 2.8-fold increase in myocardial aldosterone receptors and aquaporin 1. At CMR, LGE areas were diffusely present. After aldosterone normalization, cardiomyocyte diameter reduced with disappearance of intracellular vacuoles, recovery of electron-density of cytosol and cell organelles, and myofibrillar content, persisting fibrosis and down-regulation of aldosterone receptors and aquaporin 1 channels. At CMR, myocardial mass reduced with recovery of cardiac contractility. LGE signal remained unchanged.

Conclusion: PACM is a reversible entity characterized by over-expression of aldosterone receptors and aquaporin 1. It induces a reversible intracellular water overloading causing impaired cardiomyocyte relaxation, contraction and ultrastructural integrity.
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http://dx.doi.org/10.1016/j.ijcard.2019.06.055DOI Listing
October 2019

Polyphenol Effects on Splenic Cytokine Response in Post-Weaning Contactin 1-Overexpressing Transgenic Mice.

Molecules 2019 Jun 12;24(12). Epub 2019 Jun 12.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, 70124 Bari, Italy.

Background: In mice, postnatal immune development has previously been investigated, and evidence of a delayed maturation of the adaptive immune response has been detected.

Methods: In this study, the effects of red grape polyphenol oral administration on the murine immune response were explored using pregnant mice (TAG/F3 transgenic and wild type (wt) mice) as the animal model. The study was performed during pregnancy as well as during lactation until postnatal day 8. Suckling pups from polyphenol-administered dams as well as day 30 post-weaning pups (dietary-administered with polyphenols) were used. Polyphenol effects were evaluated, measuring splenic cytokine secretion.

Results: Phorbol myristate acetate-activated splenocytes underwent the highest cytokine production at day 30 in both wt and TAG/F3 mice. In the latter, release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α was found to be higher than in the wt counterpart. In this context, polyphenols exerted modulating activities on day 30 TAG/F3 mice, inducing release of interleukin (IL)-10 in hetero mice while abrogating release of IL-2, IFN-γ, TNF-α, IL-6, and IL-4 in homo and hetero mice.

Conclusion: Polyphenols are able to prevent the development of an inflammatory/allergic profile in postnatal TAG/F3 mice.
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http://dx.doi.org/10.3390/molecules24122205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631041PMC
June 2019

HMGB1 and repair: focus on the heart.

Pharmacol Ther 2019 04 6;196:160-182. Epub 2018 Dec 6.

Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Pisana, Rome, Italy; San Raffaele Open University, Rome, Italy. Electronic address:

High-mobility group box 1 (HMGB1) is one of the most abundant proteins in eukaryotes and the best characterized damage-associated molecular pattern (DAMP). The biological activities of HMGB1 depend on its subcellular location, context and post-translational modifications. Inside the nucleus, HMGB1 is engaged in many DNA events such as DNA repair, transcription regulation and genome stability; in the cytoplasm, its main function is to regulate the autophagic flux while in the extracellular environment, it possesses more complicated functions and it is involved in a large variety of different processes such as inflammation, migration, invasion, proliferation, differentiation and tissue regeneration. Due to this pleiotropy, the role of HMGB1 has been vastly investigated in various pathological diseases and a large number of studies have explored its function in cardiovascular pathologies. However, in this contest, the precise mechanism of action of HMGB1 and its therapeutic potential are still very controversial since is debated whether HMGB1 is involved in tissue damage or plays a role in tissue repair and regeneration. The main focus of this review is to provide an overview of the effects of HMGB1 in different ischemic heart diseases and to discuss its functions in these pathological conditions.
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http://dx.doi.org/10.1016/j.pharmthera.2018.12.005DOI Listing
April 2019

Immune-Mediated Myocarditis in Fabry Disease Cardiomyopathy.

J Am Heart Assoc 2018 09;7(17):e009052

1 Department of Cardiovascular Nephrologic, Anesthetic and Geriatric Sciences La Sapienza University of Rome Italy.

Background Glycosphingolipid accumulation in Fabry cells generates a proinflammatory response that may influence disease evolution and responsiveness to enzyme replacement therapy. This study evaluated incidence, mechanism, and impact of myocarditis in Fabry disease cardiomyopathy ( FDCM ). Methods and Results Myocarditis, defined as CD 3 T lymphocytes >7/mm associated with necrosis of glycolipid-laden myocardiocytes, was retrospectively evaluated in endomyocardial biopsies from 78 patients with FDCM : 13 with maximal wall thickness (MWT) <11 mm (group 1), 17 with MWT 11 to 15 mm (group 2), 30 with MWT 16 to 20 mm (group 3), and 18 with MWT >20 mm (group 4). Myocarditis was investigated by polymerase chain reaction for cardiotropic viruses, by serum antiheart and antimyosin antibodies, and by cardiac magnetic resonance. Myocarditis was recognized at histology in 48 of 78 patients with FDCM (38% of group 1, 41% of group 2, 66% of group 3, and 72% of group 4). Myocarditis was characterized by positive antiheart and antimyosin antibodies and negative polymerase chain reaction for viral genomes. CD 3 cells/mm correlated with myocyte necrosis, antimyosin autoantibody titer, and MWT ( P<0.001, r=0.79; P<0.001, r=0.84; P<0.001, r=0.61, respectively). Cardiac magnetic resonance showed myocardial edema in 24 of 78 patients (31%): 0% of group 1, 23% of group 2, 37% of group 3, and 50% of group 4. Conclusions Myocarditis is detectable at histology in up to 56% of patients with FDCM . It is immune mediated and correlates with disease severity. It can be disclosed by antiheart/antimyosin autoantibodies and in the advanced phase by cardiac magnetic resonance. It may contribute to progression of FDCM and resistance to enzyme replacement therapy.
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http://dx.doi.org/10.1161/JAHA.118.009052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201436PMC
September 2018

Effects of Polyphenol Administration to European Farmed Sea Bass ( L.): Special Focus on Hepatopancreas Morphology.

Endocr Metab Immune Disord Drug Targets 2019 ;19(4):526-533

Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy.

Background And Objective: Hepatopancreas is an accessory organ associated with the liver in some fish, even including sea bass (Dicentrharcus labrax L.). Hepatopancreas contains an exocrine portion but until now its function has poorly been investigated.

Methods: Here, European farmed sea bass have been treated with a feed enriched in polyphenols extracted from seeds of red grape (Nero di Troia cultivar) at two different doses (100 and 200 mg/kg, respectively) from day 273 to day 323. In fish samples, hepatopancreas area sizes have been measured to evaluate the effects of this dietary regimen on its morphology.

Results: Quite interestingly, in treated fish area sizes of hepatopancreas were higher than those detected in untreated fish. Two hundred mg dose of polyphenols was more effective than that of 100 mg/kg polyphenols. Finally, hepatic polyphenol concentration was diminished in fish receiving 100 mg dose polyphenols and normalized with 200 mg dose in comparison to untreated fish. This evidence suggests the utilization of polyphenols for liver function, even including hepatopancreas development.

Conclusion: Our data suggest an expansion of hepatopancreas induced by polyphenol administration that is also associated with less mortality in farmed fish.
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http://dx.doi.org/10.2174/1871530318666181009111214DOI Listing
January 2020

Antimicrobial Peptides: Phylogenic Sources and Biological Activities. First of Two Parts.

Curr Pharm Des 2018 ;24(10):1043-1053

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, School of Medicine, Bari, Italy.

Antimicrobial peptides (AMPs) are phylogenetically ancient substances released by living organisms for self protection against a broad variety of microbes. Moreover, AMPs are endowed with immune modulatory activities, linking innate and adaptive immunity together. Lantibiotics are AMPs of bacterial origin currently investigated for the generation of a new class of anti-infective compounds, owing to the phenomenon of antibiotic resistance against a broad variety of bacteria. Also, plants and marine AMPs are screened as novel drugs against human pathogens. Human AMPs encompass defensins and cathelicidins produced by various cell types mostly at mucosal sites. Besides their antimicrobial activity, both AMPs have been shown to trigger either inflammatory or anti-inflammatory pathways. Food-derived AMPs are mostly represented by lactoferrin and lysozyme both present in secretions, e.g., milk, and appear to be very exploitable for the generation of functional foods. Finally, the role of natural products ingested with food or administered as supplements on induction and production of AMPs will be discussed.
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http://dx.doi.org/10.2174/1381612824666180403123736DOI Listing
October 2019

Antimicrobial Peptides in Human Disease: Therapeutic Approaches. Second of Two Parts.

Curr Pharm Des 2018 ;24(10):1148-1156

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, School of Medicine, Bari, Italy.

Antimicrobial Peptides (AMPs) are produced by a variety of human immune and non immune cells in health and disease. In virtue of their antimicrobial activity, AMPs have been exploited in human disease and here this aspect will extensively be described. AMPs in comparison to antibiotics possess a larger spectrum of antimicrobial activity without inducing microbial resistance. Therefore, their use in the course of antibiotic-resistant infections is justified. AMP activity in early life, in the airways, in the oral and gastro-enteric system, in the skin and in the female reproductive tract, respectively, will be elucidated. In addition, the use of AMPs in sepsis will be discussed due to the frequency of this pathological condition characterized by multiple organ dysfunctions. Finally, the evidence that AMPs represent valid substitutes of antibiotics will be provided and a series of novel substances able to reinforce the innate immune response in different clinical settings will be discussed.
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http://dx.doi.org/10.2174/1381612824666180327155230DOI Listing
October 2019

Novel α-Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical-Pathologic Correlation.

J Am Heart Assoc 2018 02 10;7(4). Epub 2018 Feb 10.

Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and GeriatricSciences, Sapienza University, Rome, Italy.

Background: Mutations of α-actin gene (ACTC1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.

Methods And Results: In an Italian family of 7 subjects, 4 aged 10 (II-1), 14 (II-2), 43 (I-4) and 46 years (I-5), presenting abnormal ECG changes, dyspnea and palpitation (II-2, I-4, and I-5), and recurrent cerebral ischemic attack (I-5), underwent 2-dimensional echo, cardiac magnetic resonance, Holter monitoring, and next-generation sequencing gene analysis. Patients II-2 and I-5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age-related prolongation of QRS duration. Two-dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I-4, I-5, and II-2 a progressive LV hypertrophy up to 22-mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next-generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC.

Conclusions: Novel p.(Ala21Val) mutation of ACTC1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.
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http://dx.doi.org/10.1161/JAHA.117.008068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850207PMC
February 2018

Molecular mechanisms of cardioprotective effects mediated by transplanted cardiac ckit cells through the activation of an inflammatory hypoxia-dependent reparative response.

Oncotarget 2018 Jan 6;9(1):937-957. Epub 2017 Dec 6.

IRCCS San Raffaele Pisana, Rome, Italy.

The regenerative effects of cardiac ckit stem cells (ckitCSCs) in acute myocardial infarction (MI) have been studied extensively, but how these cells exert a protective effect on cardiomyocytes is not well known. Growing evidences suggest that in adult stem cells injury triggers inflammatory signaling pathways which control tissue repair and regeneration. Aim of the present study was to determine the mechanisms underlying the cardioprotective effects of ckitCSCs following transplantation in a murine model of MI. Following isolation and expansion, cardiac ckitCSCs were subjected to normoxic and hypoxic conditions and assessed at different time points. These cells adapted to hypoxia as showed by the activation of HIF-1α and the expression of a number of genes, such as VEGF, GLUT1, EPO, HKII and, importantly, of alarmin receptors, such as RAGE, P2X7R, TLR2 and TLR4. Activation of these receptors determined an NFkB-dependent inflammatory and reparative gene response (IRR). Importantly, hypoxic ckitCSCs increased the secretion of the survival growth factors IGF-1 and HGF. To verify whether activation of the IRR in a hypoxic microenvironment could exert a beneficial effect , autologous ckitCSCs were transplanted into mouse heart following MI. Interestingly, transplantation of ckitCSCs lowered apoptotic rates and induced autophagy in the peri-infarct area; further, it reduced hypertrophy and fibrosis and, most importantly, improved cardiac function. ckitCSCs are able to adapt to a hypoxic environment and activate an inflammatory and reparative response that could account, at least in part, for a protective effect on stressed cardiomyocytes following transplantation in the infarcted heart.
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http://dx.doi.org/10.18632/oncotarget.22946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787525PMC
January 2018

Corrigendum to "Immune Profile of Obese People and In Vitro Effects of Red Grape Polyphenols on Peripheral Blood Mononuclear Cells".

Oxid Med Cell Longev 2017;2017:4589705. Epub 2017 Aug 20.

Department of Biomedical Sciences and Human Oncology, Section of Clinical Oncology, University of Bari, 70124 Bari, Italy.

[This corrects the article DOI: 10.1155/2017/9210862.].
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http://dx.doi.org/10.1155/2017/4589705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585667PMC
August 2017

In Vitro Effects of Nickel on Healthy Non-Allergic Peripheral Blood Mononuclear Cells. The Role of Red Grape Polyphenols.

Endocr Metab Immune Disord Drug Targets 2017 ;17(2):166-173

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, P.zza Giulio Cesare 11, 70124 Bari. Italy.

Background: Nickel (Ni) is widely distributed in the environment and continuous exposure to this metal may lead to pathological manifestations, such as the human allergic contact dermatitis.

Methods: The in vitro effects of Ni on human healthy non allergic peripheral blood mononuclear cells (PBMCs) in the absence or presence of red grape polyphenols have been evaluated. In the culture supernatants, levels of cytokines have been determined by ELISA, while nitric oxide (NO) concentration has been evaluated by a colorimetric procedure.

Results: Ni per se did not affect release of interferon-γ, interleukin (IL)-4 and IL-10. Instead, this metal dramatically reduced production of IL-17 which was restored by the supplementation of polyphenols. Finally, while Ni significantly increased generation of NO, polyphenols reduced production of this compound.

Conclusion: Taken together, all these data may indicate a preventative role of polyphenols against Ni exposure in non allergic to Ni individuals, also confirming the immunomodulating role of these natural products. The interaction Ni/polyphenols/lipopolysaccharides will also be discussed.
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http://dx.doi.org/10.2174/1871530317666170713145350DOI Listing
June 2018

Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications.

Front Immunol 2017 9;8:677. Epub 2017 Jun 9.

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy.

It is well known that cocoa and dark chocolate possess polyphenols as major constituents whose dietary consumption has been associated to beneficial effects. In fact, cocoa and dark chocolate polyphenols exert antioxidant and anti-inflammatory activities switching on some important signaling pathways such as toll-like receptor 4/nuclear factor κB/signal transducer and activator of transcription. In particular, cocoa polyphenols induce release of nitric oxide (NO) through activation of endothelial NO synthase which, in turn, accounts for vasodilation and cardioprotective effects. In the light of the above described properties, a number of clinical trials based on the consumption of cocoa and dark chocolate have been conducted in healthy subjects as well as in different categories of patients, such as those affected by cardiovascular, neurological, intestinal, and metabolic pathologies. Even if data are not always concordant, modifications of biomarkers of disease are frequently associated to improvement of clinical manifestations. Quite interestingly, following cocoa and dark chocolate ingestion, cocoa polyphenols also modulate intestinal microbiota, thus leading to the growth of bacteria that trigger a tolerogenic anti-inflammatory pathway in the host. Finally, many evidences encourage the consumption of cocoa and dark chocolate by aged people for the recovery of the neurovascular unit.
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http://dx.doi.org/10.3389/fimmu.2017.00677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465250PMC
June 2017

Immune Profile of Obese People and In Vitro Effects of Red Grape Polyphenols on Peripheral Blood Mononuclear Cells.

Oxid Med Cell Longev 2017 24;2017:9210862. Epub 2017 Jan 24.

Department of Biomedical Sciences and Human Oncology, Section of Clinical Oncology, University of Bari, 70124 Bari, Italy.

The in vitro ability of polyphenols, extracted from red grape, to modulate peripheral blood mononuclear cell responses has been evaluated in 20 obese (Ob) people. With regard to cytokine release in response to phorbol myristate acetate (PMA), levels of interleukin-2 (IL-2), interferon- (IFN-), IL-4, IL-10, and IL-17 were higher in the Ob than in healthy (H) subjects. , IL-21 concentrations were detected only in H people but they were undetectable in the Ob counterpart. In general terms, levels of IL-1, IL-6, IL-8, and tumor necrosis factor- were higher in Ob people when compared to H controls. On the other hand, polyphenols did not modify IFN-, IL-4, and IL-17 levels. However, an increase in IL-2 was observed in H individuals, whereas its levels were decreased in the Ob counterpart. Polyphenols significantly increased IL-10 release from H donors, whereas a trend to increase was observed in Ob people. In addition, polyphenols were able to significantly increase levels of H IL-21, while this was not the case in Ob people. Since IL-21 is an inducer of Th17 cells, it is likely that polyphenols may suppress the sources of this cytokine production of IL-10. Accordingly, polyphenols decreased IL-1 and IL-6 release in comparison to H controls.
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http://dx.doi.org/10.1155/2017/9210862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294383PMC
March 2017

Hypoxia and Inflammation in Prostate Cancer Progression. Cross-talk with Androgen and Estrogen Receptors and Cancer Stem Cells.

Endocr Metab Immune Disord Drug Targets 2016 ;16(4):235-248

Consortium MEBIC, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy.

Tumors are complex tissues in which transformed cells communicate with the surrounding microenvironment and evolve traits promoting their own survival and malignancy. Hypoxia and inflammation are constant characteristics of prostate tumor microenvironment influencing both cancer stem cells and differentiated tumor cells. HIFs and NF-kB are the key regulators of the transcriptional response to hypoxic and inflammatory stresses, respectively, and a crosstalk between HIFs and NF-kB pathways has been widely documented. Similarly, androgen and estrogen signaling, that play important roles in the growth and function of normal prostate gland, when deregulated, have a significant part in the acquisition of hallmarks of malignant diseases. Moreover, androgen and estrogen receptors have been shown to intersect with the HIF/NF-kB signaling in prostate cancer. Aim of this review is to present the current knowledge regarding the crucial role, in prostate cancer progression, of a molecular network linking hypoxia, pro-inflammatory response and steroid receptors.
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http://dx.doi.org/10.2174/1871530316666161130160144DOI Listing
August 2017

Cigarette Smoke-mediated Perturbations of the Immune Response: A New Therapeutic Approach with Natural Compounds.

Endocr Metab Immune Disord Drug Targets 2016 ;16(3):158-167

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, Policlinico, Piazza Giulio Cesare 11, 70124, Bari,. Italy.

Cigarette smoke (CS) accounts for the outcome of several pathologies, even including lung cancer, cardiovascular disease and chronic obstructive pulmonary disease (COPD). Under healthy conditions, lung immune system becomes tolerant in response to various external stimuli. CS exposure alters the pulmonary immune equilibrium, thus leading to a condition of hyper activation of the local innate and adaptive immunity. COPD is one of the major complications of chronic CS exposure where a pro-inflammatory profile of the pulmonary and systemic immunity is predominant. In this review, alternative treatments with natural products to mitigate CS-mediated pulmonary inflammation are proposed. In particular, polyphenols, a class of natural compounds largely present in fruits and vegetables, have been shown to act as anti-inflammatory agents. Accordingly, recent experimental and clinical evidences support polyphenol-mediated potential health benefits in smokers. For instance, pomegranate juice is able to attenuate the damage provoked by CS on cultured human alveolar macrophages. In addition, maqui beery extract has been proven to normalize H2O2 and interleukin-6 levels in exhaled breath condensate in healthy smokers. However, some limitations of alternative treatments are represented by a better knowledge of the mechanism(s) of action exerted by polyphenols and by the lack of animal models of COPD. In any case, the potential targets of polyphenols in the course of COPD will be outlined with special reference to the activation of T regulatory cells as well as to the inhibition of the polymorphonuclear cell and monocyte respiratory burst and of the NF-κB pathway, respectively.
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http://dx.doi.org/10.2174/1872214810666160927123447DOI Listing
August 2017

Morphometrical and Morphological Alterations of Human Leukocytes Exposed to 1.8 GHz Electromagnetic Radiations: In Vitro Protective Effects Induced by Polyphenols.

Endocr Metab Immune Disord Drug Targets 2016 ;16(3):189-196

Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari, Bari, Italy, P. zza Giulio Cesare, 11 70124 Bari,. Italy.

Background: Our recent findings have demonstrated that electromagnetic radiations (EMR) (1.8 GHz radiofrequency) are able to in vitro induce morphometrical and morphological modifications of human leukocytes from normal donors.

Methods: In view of the evidence that polyphenols exert many beneficial effects on plants, animals and humans, leukocytes from human peripheral blood were pre-treated for 1 h with two polyphenol preparations from red grape before EMR exposure (1.8 GHz).

Results: Our data will show that polyphenol pre-treatment reverts to normality the morphology of irradiated leukocytes in comparison to irradiated cells only. Conversely, leukocyte morphometry seems to be not affected by this treatment.

Conclusion: Here, we demonstrate that polyphenols are also able to normalize leukocyte morphology per se altered before as well as after irradiation. Finally, a working hypothesis aimed at clarifying the protective mechanisms exerted by polyphenols on irradiated leukocytes will be illustrated.
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http://dx.doi.org/10.2174/1871530316666161003153024DOI Listing
August 2017