The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Francesco Squadrito - One of the best experts on this subject based on the ideXlab platform.
-
Targeting Adenosine Receptor by Polydeoxyribonucleotide: An Effective Therapeutic Strategy to Induce White-to-Brown Adipose Differentiation and to Curb Obesity
'MDPI AG', 2021Co-Authors: Federica Mannino, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Violetta Squadrito, Domenico Antonio Giorgi, Igor Pirrotta, Francesco SquadritoAbstract:Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of Polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario
-
Polydeoxyribonucleotide, an Adenosine-A2A Receptor Agonist, Preserves Blood Testis Barrier from Cadmium-Induced Injury.
Frontiers in Pharmacology, 2017Co-Authors: Francesco Squadrito, Domenico Puzzolo, Antonio Micali, Natasha Irrera, Antonina Pisani, Herbert Marini, Mariagrazia Rinaldi, Lorenzini C, A. Valenti, Rosaria LauràAbstract:Cadmium (Cd) impairs blood-testis barrier (BTB). Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system. We investigated the effects of PDRN on the morphological and functional changes induced by Cd in mice testes. Adult Swiss mice were divided into four groups: controls administered with 0.9% NaCl (1 ml/kg, i.p., daily) or with PDRN (8 mg/kg, i.p. daily), animals challenged with Cd chloride (CdCl2) (2 mg/kg i.p, daily) and animals challenged with CdCl2 (2 mg/kg i.p., daily) and treated with PDRN (8 mg/kg i.p., daily). Experiments lasted 14 days. Testes were processed for biochemical, structural and ultrastructural evaluation and hormones were assayed in serum. CdCl2 increased pERK 1/2 expression and Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels; it decreased testosterone (TE) and inhibin-B levels and induced structural damages in extratubular compartment and in seminiferous epithelium, with ultrastructural features of BTB disruption. Many TUNEL-positive germ cells were present. CdCl2 increased tubular TGF-β3 immunoreactivity and reduced claudin-11, occludin and N-cadherin immunoreactivity. PDRN administration reduced pERK 1/2 expression, FSH and LH levels; it increased TE and inhibin-B levels, ameliorated germinal epithelium changes and protected BTB ultrastructure. Few TUNEL-positive germ cells were present and the extratubular compartment was preserved. Furthermore, PDRN decreased TGF-β3 immunoreactivity and enhanced claudin-11, occludin and N-cadherin immunoreactivity. We demonstrate a protective effect of PDRN on Cd-induced damages of BTB and suggest that PDRN may play an important role against Cd, particularly against its harmful effects on gametogenesis.
-
adenosine receptor stimulation by Polydeoxyribonucleotide improves tissue repair and symptomology in experimental colitis
Frontiers in Pharmacology, 2016Co-Authors: Giovanni Pallio, Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Gabriele Pizzino, Federica Galfo, Giovanni Squadrito, Socrate Pallio, Giuseppe Anastasi, Giuseppina CutroneoAbstract:Activation of the adenosine receptor pathway has been demonstrated to be effective in improving tissue remodelling and blunting the inflammatory response. Active colitis is characterized by an intense inflammatory reaction resulting in extensive tissue damage. Symptomatic improvement requires both control of the inflammatory process and repair and remodelling of damaged tissues. We investigated the ability of an A2A receptor agonist, Polydeoxyribonucleotide (PDRN), to restore tissue structural integrity in two experimental colitis models using male Sprague-Dawley rats. In the first model, colitis was induced with a single intra-colonic instillation of dinitro-benzene-sulfonic acid (DNBS), 25mg diluted in 0.8ml 50% ethanol. After 6 hrs, animals were randomized to receive either PDRN (8mg/kg/i.p.), or PDRN + the A2A antagonist (DMPX; 10mg/kg/i.p.), or vehicle (0.8 ml saline solution) daily. In the second model, dextran sodium sulphate (DSS) was dissolved in drinking water at a concentration of 8%. Control animals received standard drinking water. After 24 hrs animals were randomized to receive PDRN or PDRN+DMPX as described above. Rats were sacrificed 7 days after receiving DNBS or 5 days after DSS. In both experimental models of colitis, PDRN ameliorated the clinical symptoms and weight loss associated with disease as well as promoted the histological repair of damaged tissues. Moreover, PDRN reduced expression of inflammatory cytokines, myeloperoxydase activity, and malondialdheyde. All these effects were abolished by the concomitant administration of the A2a antagonist DMPX. Our study suggests that PDRN may represent a promising treatment for improving tissue repair during inflammatory bowel diseases.
-
Polydeoxyribonucleotide an adenosine a2a receptor agonist preserves blood testis barrier from cadmium induced injury
Italian journal of anatomy and embryology, 2016Co-Authors: Domenico Puzzolo, Francesco Squadrito, Antonio Micali, Natasha Irrera, Antonina Pisani, Herbert Marini, Mariagrazia Rinaldi, Rosaria Laurà, Alba Arco, Domenica AltavillaAbstract:Cadmium (Cd) impairs the blood-testis barrier (BTB) with changes of its junctional complexes [1]. Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system [2]. We investigated the effects of PDRN on the morphological and functional Cd-induced changes in mice testes. Swiss mice were divided into four groups: control animals treated with 0.9% NaCl (1 ml/kg, i.p., daily); control animals treated with PDRN (8 mg/kg, i.p. daily), animals challenged with Cd chloride (CdCl2) (2 mg/kg i.p, daily) and animals challenged with CdCl2 and treated with PDRN. The experiments lasted 14 days. At the end of experiment, the testes were processed for biochemical, structural and ultrastructural evaluation. CdCl2 increased pERK 1/2 expression and Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels, decreased testosterone (TE) and inhibin-B levels and induced structural damages in the extratubular compartment and in the seminiferous epithelium, with ultrastructural features of BTB disruption. Many TUNEL-positive germ cells were present in the peripheral parts of the tubules. CdCl2 increased also tubular TGF-β3 immunoreactivity and reduced claudin-11, occludin and N-cadherin immunoreactivity. PDRN administration reduced pERK 1/2 expression, FSH and LH levels, increased TE and inhibin-B levels, ameliorated germinal epithelium changes and protected BTB ultrastructure. Only few TUNEL-positive germ cells were present and the extratubular compartment was preserved, showing only a mild edema. Furthermore PDRN decreased TGF-β3 immunoreactivity and enhanced claudin-11, occludin and N-cadherin immunoreactivity. We demonstrate, for the first time, a protective effect of PDRN on Cd-induced BTB damages in mice testes. We suggest that the A2A agonist may play an important role against environmental Cd, and in particular against its harmful effects on gametogenesis.
-
the effect of pdrn an adenosine receptor a2a agonist on the healing of chronic diabetic foot ulcers results of a clinical trial
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Francesco Squadrito, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Giovanni De Caridi, Salvatore Corrao, Carmelo Sterrantino, Antonino SaittaAbstract:Context: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. Objective: The aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. Design and Setting: This randomized, double-blind, placebo-controlled trial, involved two medical centers in Italy. Intervention: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2) were randomly assigned to receive placebo (n = 106) or PDRN (n = 110). The treatments (PDRN and placebo) were performed 3 days a week for 8 weeks by intramuscular and perilesional route. Main Outcome Measures: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the reepithelialization of wound surface (as percentage of the original area). Results: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete heali...
Alessandra Bitto - One of the best experts on this subject based on the ideXlab platform.
-
Targeting Adenosine Receptor by Polydeoxyribonucleotide: An Effective Therapeutic Strategy to Induce White-to-Brown Adipose Differentiation and to Curb Obesity
'MDPI AG', 2021Co-Authors: Federica Mannino, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Violetta Squadrito, Domenico Antonio Giorgi, Igor Pirrotta, Francesco SquadritoAbstract:Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of Polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario
-
Neuroprotective Effects of Polydeoxyribonucleotide in a Murine Model of Cadmium Toxicity
'Hindawi Limited', 2018Co-Authors: Herbert R. Marini, Domenico Puzzolo, Antonio Micali, Elena Bianca Adamo, Natasha Irrera, Antonina Pisani, Giovanni Pallio, Vincenzo Trichilo, Consuelo Malta, Alessandra BittoAbstract:Cadmium (Cd) is a harmful heavy metal, which causes severe brain damage and neurotoxic effects. Polydeoxyribonucleotide (PDRN) stimulates adenosine A2A receptor, thus contrasting several deleterious mechanisms in course of tissue damages. We aimed to investigate the possible neuroprotective effect of PDRN in a murine model of Cd-induced brain toxicity. Male C57 BL/6J mice were treated as follows: vehicle (0.9% NaCl, 1 ml/kg/day), PDRN (8 mg/kg/day), CdCl2 (2 mg/kg/day), and CdCl2 + PDRN. Animals were tested with the Morris water maze test to assess spatial memory and learning. After 14 days of treatment, brains were processed to evaluate the presence of edema in the cerebral tissue, the expression of mammalian target of rapamycin kinase (mTOR) and brain-derived neurotrophic factor (BDNF), and the morphological behavior of the hippocampal structures. After CdCl2 administration, the escape latency was high, protein expression of BDNF was significantly decreased if compared to controls, mTOR levels were higher than normal controls, and brain edema and neuronal damages were evident. The coadministration of CdCl2 and PDRN significantly diminished the escape latency, increased BDNF levels, and decreased protein expression of mTOR. Furthermore, brain edema was reduced and the structural organization and the number of neurons, particularly in the CA1 and CA3 hippocampal areas, were improved. In conclusion, a functional, biochemical, and morphological protective effect of PDRN against Cd induced toxicity was demonstrated in mouse brain
-
adenosine receptor stimulation by Polydeoxyribonucleotide improves tissue repair and symptomology in experimental colitis
Frontiers in Pharmacology, 2016Co-Authors: Giovanni Pallio, Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Gabriele Pizzino, Federica Galfo, Giovanni Squadrito, Socrate Pallio, Giuseppe Anastasi, Giuseppina CutroneoAbstract:Activation of the adenosine receptor pathway has been demonstrated to be effective in improving tissue remodelling and blunting the inflammatory response. Active colitis is characterized by an intense inflammatory reaction resulting in extensive tissue damage. Symptomatic improvement requires both control of the inflammatory process and repair and remodelling of damaged tissues. We investigated the ability of an A2A receptor agonist, Polydeoxyribonucleotide (PDRN), to restore tissue structural integrity in two experimental colitis models using male Sprague-Dawley rats. In the first model, colitis was induced with a single intra-colonic instillation of dinitro-benzene-sulfonic acid (DNBS), 25mg diluted in 0.8ml 50% ethanol. After 6 hrs, animals were randomized to receive either PDRN (8mg/kg/i.p.), or PDRN + the A2A antagonist (DMPX; 10mg/kg/i.p.), or vehicle (0.8 ml saline solution) daily. In the second model, dextran sodium sulphate (DSS) was dissolved in drinking water at a concentration of 8%. Control animals received standard drinking water. After 24 hrs animals were randomized to receive PDRN or PDRN+DMPX as described above. Rats were sacrificed 7 days after receiving DNBS or 5 days after DSS. In both experimental models of colitis, PDRN ameliorated the clinical symptoms and weight loss associated with disease as well as promoted the histological repair of damaged tissues. Moreover, PDRN reduced expression of inflammatory cytokines, myeloperoxydase activity, and malondialdheyde. All these effects were abolished by the concomitant administration of the A2a antagonist DMPX. Our study suggests that PDRN may represent a promising treatment for improving tissue repair during inflammatory bowel diseases.
-
the effect of pdrn an adenosine receptor a2a agonist on the healing of chronic diabetic foot ulcers results of a clinical trial
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Francesco Squadrito, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Giovanni De Caridi, Salvatore Corrao, Carmelo Sterrantino, Antonino SaittaAbstract:Context: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. Objective: The aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. Design and Setting: This randomized, double-blind, placebo-controlled trial, involved two medical centers in Italy. Intervention: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2) were randomly assigned to receive placebo (n = 106) or PDRN (n = 110). The treatments (PDRN and placebo) were performed 3 days a week for 8 weeks by intramuscular and perilesional route. Main Outcome Measures: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the reepithelialization of wound surface (as percentage of the original area). Results: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete heali...
-
Polydeoxyribonucleotide restores blood flow in an experimental model of ischemic skin flaps
Journal of Vascular Surgery, 2012Co-Authors: Francesca Polito, Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Mariarosaria Galeano, Margherita Calo, Herbert Marini, Domenica AltavillaAbstract:Background Ischemia is a major factor contributing to failure of skin flap surgery, which is routinely used for coverage of wounds to prevent infection and to restore form and function. An emerging concept is that adenosine A 2A receptors can improve tissue oxygenation by stimulating angiogenesis, likely through vascular endothelial growth factor (VEGF). This study assessed the ability of Polydeoxyribonucleotide (PDRN) to restore blood flow and improve wound healing, acting through the A 2A receptor, in a rat model of ischemic skin flaps. Methods The H-shaped double-flap model was used in male Sprague-Dawley rats. After surgical procedures, the animals were randomized to receive intraperitoneal PDRN (8 mg/kg) or vehicle (NaCl 0.9%). Rats were euthanized 3, 5, and 10 days after skin injury, after the evaluation of skin perfusion by laser Doppler. The wounds underwent histologic analysis and were measured for VEGF messenger RNA and protein expression, hypoxia inducible factor-1-α (HIF-1α), and inducible nitric oxide synthase (iNOS) protein expression, and nitrite content. Results Blood flow markedly increased in blood flow in ischemic flaps treated with PDRN, with a complete recovery starting from day 5 (ischemic flap + vehicle, 1.80 ± 0.25; ischemic flap + PDRN, 2.46 ± 0.25; P P P P Conclusions These results suggest that PDRN restores blood flow and tissue architecture, probably by modulating HIF-1α and VEGF expression, and may be an effective therapeutic approach in improving healing of ischemic skin flaps.
Domenica Altavilla - One of the best experts on this subject based on the ideXlab platform.
-
Targeting Adenosine Receptor by Polydeoxyribonucleotide: An Effective Therapeutic Strategy to Induce White-to-Brown Adipose Differentiation and to Curb Obesity
'MDPI AG', 2021Co-Authors: Federica Mannino, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Violetta Squadrito, Domenico Antonio Giorgi, Igor Pirrotta, Francesco SquadritoAbstract:Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of Polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario
-
Polydeoxyribonucleotide an adenosine a2a receptor agonist preserves blood testis barrier from cadmium induced injury
Italian journal of anatomy and embryology, 2016Co-Authors: Domenico Puzzolo, Francesco Squadrito, Antonio Micali, Natasha Irrera, Antonina Pisani, Herbert Marini, Mariagrazia Rinaldi, Rosaria Laurà, Alba Arco, Domenica AltavillaAbstract:Cadmium (Cd) impairs the blood-testis barrier (BTB) with changes of its junctional complexes [1]. Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system [2]. We investigated the effects of PDRN on the morphological and functional Cd-induced changes in mice testes. Swiss mice were divided into four groups: control animals treated with 0.9% NaCl (1 ml/kg, i.p., daily); control animals treated with PDRN (8 mg/kg, i.p. daily), animals challenged with Cd chloride (CdCl2) (2 mg/kg i.p, daily) and animals challenged with CdCl2 and treated with PDRN. The experiments lasted 14 days. At the end of experiment, the testes were processed for biochemical, structural and ultrastructural evaluation. CdCl2 increased pERK 1/2 expression and Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels, decreased testosterone (TE) and inhibin-B levels and induced structural damages in the extratubular compartment and in the seminiferous epithelium, with ultrastructural features of BTB disruption. Many TUNEL-positive germ cells were present in the peripheral parts of the tubules. CdCl2 increased also tubular TGF-β3 immunoreactivity and reduced claudin-11, occludin and N-cadherin immunoreactivity. PDRN administration reduced pERK 1/2 expression, FSH and LH levels, increased TE and inhibin-B levels, ameliorated germinal epithelium changes and protected BTB ultrastructure. Only few TUNEL-positive germ cells were present and the extratubular compartment was preserved, showing only a mild edema. Furthermore PDRN decreased TGF-β3 immunoreactivity and enhanced claudin-11, occludin and N-cadherin immunoreactivity. We demonstrate, for the first time, a protective effect of PDRN on Cd-induced BTB damages in mice testes. We suggest that the A2A agonist may play an important role against environmental Cd, and in particular against its harmful effects on gametogenesis.
-
the effect of pdrn an adenosine receptor a2a agonist on the healing of chronic diabetic foot ulcers results of a clinical trial
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Francesco Squadrito, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Giovanni De Caridi, Salvatore Corrao, Carmelo Sterrantino, Antonino SaittaAbstract:Context: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. Objective: The aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. Design and Setting: This randomized, double-blind, placebo-controlled trial, involved two medical centers in Italy. Intervention: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2) were randomly assigned to receive placebo (n = 106) or PDRN (n = 110). The treatments (PDRN and placebo) were performed 3 days a week for 8 weeks by intramuscular and perilesional route. Main Outcome Measures: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the reepithelialization of wound surface (as percentage of the original area). Results: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete heali...
-
Polydeoxyribonucleotide restores blood flow in an experimental model of ischemic skin flaps
Journal of Vascular Surgery, 2012Co-Authors: Francesca Polito, Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Mariarosaria Galeano, Margherita Calo, Herbert Marini, Domenica AltavillaAbstract:Background Ischemia is a major factor contributing to failure of skin flap surgery, which is routinely used for coverage of wounds to prevent infection and to restore form and function. An emerging concept is that adenosine A 2A receptors can improve tissue oxygenation by stimulating angiogenesis, likely through vascular endothelial growth factor (VEGF). This study assessed the ability of Polydeoxyribonucleotide (PDRN) to restore blood flow and improve wound healing, acting through the A 2A receptor, in a rat model of ischemic skin flaps. Methods The H-shaped double-flap model was used in male Sprague-Dawley rats. After surgical procedures, the animals were randomized to receive intraperitoneal PDRN (8 mg/kg) or vehicle (NaCl 0.9%). Rats were euthanized 3, 5, and 10 days after skin injury, after the evaluation of skin perfusion by laser Doppler. The wounds underwent histologic analysis and were measured for VEGF messenger RNA and protein expression, hypoxia inducible factor-1-α (HIF-1α), and inducible nitric oxide synthase (iNOS) protein expression, and nitrite content. Results Blood flow markedly increased in blood flow in ischemic flaps treated with PDRN, with a complete recovery starting from day 5 (ischemic flap + vehicle, 1.80 ± 0.25; ischemic flap + PDRN, 2.46 ± 0.25; P P P P Conclusions These results suggest that PDRN restores blood flow and tissue architecture, probably by modulating HIF-1α and VEGF expression, and may be an effective therapeutic approach in improving healing of ischemic skin flaps.
-
Polydeoxyribonucleotide pdrn restores blood flow in an experimental model of peripheral artery occlusive disease
Journal of Vascular Surgery, 2008Co-Authors: Alessandra Bitto, Francesca Polito, Domenica Altavilla, Letteria Minutoli, Alba Migliorato, Francesco SquadritoAbstract:Objective This study investigated whether Polydeoxyribonucleotide (PDRN) may be efficacious in the treatment of peripheral artery occlusive diseases, which are a major cause of morbidity in Western countries and still lack standardized treatment. Methods We investigated the effects of PDRN, a mixture of deoxyribonucleotides, in an experimental model of hind limb ischemia (HLI) in rats to stimulate vascular endothelial growth factor (VEGF)-A production and to avoid critical ischemia. The femoral artery was excised to induce HLI. Sham-operated on rats (sham HLI) were used as controls. Animals were treated daily with intraperitoneal PDRN (8 mg/kg) or its vehicle. Animals were euthanized at day 7, 14, and 21 after the evaluation of blood flow by laser Doppler. Dissected muscles were used to measure VEGF-A messenger RNA (mRNA) and protein expression, to evaluate edema, and to assess histologic damage. Results Administration of PDRN dramatically increased VEGF mRNA throughout the study (day 14: HLI, 7 ± 2.2 n-fold/β-actin; HLI + PDRN, 13.3 ± 3.8 n-fold/β-actin; P P P 2A receptor antagonist, abolished the positive effects of PDRN, confirming that PDRN acts through this receptor. Conclusion These results led us to hypothesize a role for PDRN in treating peripheral artery occlusive diseases.
Natasha Irrera - One of the best experts on this subject based on the ideXlab platform.
-
Neuroprotective Effects of Polydeoxyribonucleotide in a Murine Model of Cadmium Toxicity
'Hindawi Limited', 2018Co-Authors: Herbert R. Marini, Domenico Puzzolo, Antonio Micali, Elena Bianca Adamo, Natasha Irrera, Antonina Pisani, Giovanni Pallio, Vincenzo Trichilo, Consuelo Malta, Alessandra BittoAbstract:Cadmium (Cd) is a harmful heavy metal, which causes severe brain damage and neurotoxic effects. Polydeoxyribonucleotide (PDRN) stimulates adenosine A2A receptor, thus contrasting several deleterious mechanisms in course of tissue damages. We aimed to investigate the possible neuroprotective effect of PDRN in a murine model of Cd-induced brain toxicity. Male C57 BL/6J mice were treated as follows: vehicle (0.9% NaCl, 1 ml/kg/day), PDRN (8 mg/kg/day), CdCl2 (2 mg/kg/day), and CdCl2 + PDRN. Animals were tested with the Morris water maze test to assess spatial memory and learning. After 14 days of treatment, brains were processed to evaluate the presence of edema in the cerebral tissue, the expression of mammalian target of rapamycin kinase (mTOR) and brain-derived neurotrophic factor (BDNF), and the morphological behavior of the hippocampal structures. After CdCl2 administration, the escape latency was high, protein expression of BDNF was significantly decreased if compared to controls, mTOR levels were higher than normal controls, and brain edema and neuronal damages were evident. The coadministration of CdCl2 and PDRN significantly diminished the escape latency, increased BDNF levels, and decreased protein expression of mTOR. Furthermore, brain edema was reduced and the structural organization and the number of neurons, particularly in the CA1 and CA3 hippocampal areas, were improved. In conclusion, a functional, biochemical, and morphological protective effect of PDRN against Cd induced toxicity was demonstrated in mouse brain
-
Polydeoxyribonucleotide, an Adenosine-A2A Receptor Agonist, Preserves Blood Testis Barrier from Cadmium-Induced Injury.
Frontiers in Pharmacology, 2017Co-Authors: Francesco Squadrito, Domenico Puzzolo, Antonio Micali, Natasha Irrera, Antonina Pisani, Herbert Marini, Mariagrazia Rinaldi, Lorenzini C, A. Valenti, Rosaria LauràAbstract:Cadmium (Cd) impairs blood-testis barrier (BTB). Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system. We investigated the effects of PDRN on the morphological and functional changes induced by Cd in mice testes. Adult Swiss mice were divided into four groups: controls administered with 0.9% NaCl (1 ml/kg, i.p., daily) or with PDRN (8 mg/kg, i.p. daily), animals challenged with Cd chloride (CdCl2) (2 mg/kg i.p, daily) and animals challenged with CdCl2 (2 mg/kg i.p., daily) and treated with PDRN (8 mg/kg i.p., daily). Experiments lasted 14 days. Testes were processed for biochemical, structural and ultrastructural evaluation and hormones were assayed in serum. CdCl2 increased pERK 1/2 expression and Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels; it decreased testosterone (TE) and inhibin-B levels and induced structural damages in extratubular compartment and in seminiferous epithelium, with ultrastructural features of BTB disruption. Many TUNEL-positive germ cells were present. CdCl2 increased tubular TGF-β3 immunoreactivity and reduced claudin-11, occludin and N-cadherin immunoreactivity. PDRN administration reduced pERK 1/2 expression, FSH and LH levels; it increased TE and inhibin-B levels, ameliorated germinal epithelium changes and protected BTB ultrastructure. Few TUNEL-positive germ cells were present and the extratubular compartment was preserved. Furthermore, PDRN decreased TGF-β3 immunoreactivity and enhanced claudin-11, occludin and N-cadherin immunoreactivity. We demonstrate a protective effect of PDRN on Cd-induced damages of BTB and suggest that PDRN may play an important role against Cd, particularly against its harmful effects on gametogenesis.
-
adenosine receptor stimulation by Polydeoxyribonucleotide improves tissue repair and symptomology in experimental colitis
Frontiers in Pharmacology, 2016Co-Authors: Giovanni Pallio, Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Gabriele Pizzino, Federica Galfo, Giovanni Squadrito, Socrate Pallio, Giuseppe Anastasi, Giuseppina CutroneoAbstract:Activation of the adenosine receptor pathway has been demonstrated to be effective in improving tissue remodelling and blunting the inflammatory response. Active colitis is characterized by an intense inflammatory reaction resulting in extensive tissue damage. Symptomatic improvement requires both control of the inflammatory process and repair and remodelling of damaged tissues. We investigated the ability of an A2A receptor agonist, Polydeoxyribonucleotide (PDRN), to restore tissue structural integrity in two experimental colitis models using male Sprague-Dawley rats. In the first model, colitis was induced with a single intra-colonic instillation of dinitro-benzene-sulfonic acid (DNBS), 25mg diluted in 0.8ml 50% ethanol. After 6 hrs, animals were randomized to receive either PDRN (8mg/kg/i.p.), or PDRN + the A2A antagonist (DMPX; 10mg/kg/i.p.), or vehicle (0.8 ml saline solution) daily. In the second model, dextran sodium sulphate (DSS) was dissolved in drinking water at a concentration of 8%. Control animals received standard drinking water. After 24 hrs animals were randomized to receive PDRN or PDRN+DMPX as described above. Rats were sacrificed 7 days after receiving DNBS or 5 days after DSS. In both experimental models of colitis, PDRN ameliorated the clinical symptoms and weight loss associated with disease as well as promoted the histological repair of damaged tissues. Moreover, PDRN reduced expression of inflammatory cytokines, myeloperoxydase activity, and malondialdheyde. All these effects were abolished by the concomitant administration of the A2a antagonist DMPX. Our study suggests that PDRN may represent a promising treatment for improving tissue repair during inflammatory bowel diseases.
-
Polydeoxyribonucleotide an adenosine a2a receptor agonist preserves blood testis barrier from cadmium induced injury
Italian journal of anatomy and embryology, 2016Co-Authors: Domenico Puzzolo, Francesco Squadrito, Antonio Micali, Natasha Irrera, Antonina Pisani, Herbert Marini, Mariagrazia Rinaldi, Rosaria Laurà, Alba Arco, Domenica AltavillaAbstract:Cadmium (Cd) impairs the blood-testis barrier (BTB) with changes of its junctional complexes [1]. Polydeoxyribonucleotide (PDRN), an adenosine A2A agonist, has positive effects on male reproductive system [2]. We investigated the effects of PDRN on the morphological and functional Cd-induced changes in mice testes. Swiss mice were divided into four groups: control animals treated with 0.9% NaCl (1 ml/kg, i.p., daily); control animals treated with PDRN (8 mg/kg, i.p. daily), animals challenged with Cd chloride (CdCl2) (2 mg/kg i.p, daily) and animals challenged with CdCl2 and treated with PDRN. The experiments lasted 14 days. At the end of experiment, the testes were processed for biochemical, structural and ultrastructural evaluation. CdCl2 increased pERK 1/2 expression and Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels, decreased testosterone (TE) and inhibin-B levels and induced structural damages in the extratubular compartment and in the seminiferous epithelium, with ultrastructural features of BTB disruption. Many TUNEL-positive germ cells were present in the peripheral parts of the tubules. CdCl2 increased also tubular TGF-β3 immunoreactivity and reduced claudin-11, occludin and N-cadherin immunoreactivity. PDRN administration reduced pERK 1/2 expression, FSH and LH levels, increased TE and inhibin-B levels, ameliorated germinal epithelium changes and protected BTB ultrastructure. Only few TUNEL-positive germ cells were present and the extratubular compartment was preserved, showing only a mild edema. Furthermore PDRN decreased TGF-β3 immunoreactivity and enhanced claudin-11, occludin and N-cadherin immunoreactivity. We demonstrate, for the first time, a protective effect of PDRN on Cd-induced BTB damages in mice testes. We suggest that the A2A agonist may play an important role against environmental Cd, and in particular against its harmful effects on gametogenesis.
-
Polydeoxyribonucleotide restores blood flow in an experimental model of ischemic skin flaps
Journal of Vascular Surgery, 2012Co-Authors: Francesca Polito, Alessandra Bitto, Francesco Squadrito, Natasha Irrera, Mariarosaria Galeano, Margherita Calo, Herbert Marini, Domenica AltavillaAbstract:Background Ischemia is a major factor contributing to failure of skin flap surgery, which is routinely used for coverage of wounds to prevent infection and to restore form and function. An emerging concept is that adenosine A 2A receptors can improve tissue oxygenation by stimulating angiogenesis, likely through vascular endothelial growth factor (VEGF). This study assessed the ability of Polydeoxyribonucleotide (PDRN) to restore blood flow and improve wound healing, acting through the A 2A receptor, in a rat model of ischemic skin flaps. Methods The H-shaped double-flap model was used in male Sprague-Dawley rats. After surgical procedures, the animals were randomized to receive intraperitoneal PDRN (8 mg/kg) or vehicle (NaCl 0.9%). Rats were euthanized 3, 5, and 10 days after skin injury, after the evaluation of skin perfusion by laser Doppler. The wounds underwent histologic analysis and were measured for VEGF messenger RNA and protein expression, hypoxia inducible factor-1-α (HIF-1α), and inducible nitric oxide synthase (iNOS) protein expression, and nitrite content. Results Blood flow markedly increased in blood flow in ischemic flaps treated with PDRN, with a complete recovery starting from day 5 (ischemic flap + vehicle, 1.80 ± 0.25; ischemic flap + PDRN, 2.46 ± 0.25; P P P P Conclusions These results suggest that PDRN restores blood flow and tissue architecture, probably by modulating HIF-1α and VEGF expression, and may be an effective therapeutic approach in improving healing of ischemic skin flaps.
Letteria Minutoli - One of the best experts on this subject based on the ideXlab platform.
-
Targeting Adenosine Receptor by Polydeoxyribonucleotide: An Effective Therapeutic Strategy to Induce White-to-Brown Adipose Differentiation and to Curb Obesity
'MDPI AG', 2021Co-Authors: Federica Mannino, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Violetta Squadrito, Domenico Antonio Giorgi, Igor Pirrotta, Francesco SquadritoAbstract:Obesity is a worldwide chronic metabolic disease characterized by an abnormal fat accumulation and represents one of the main risk factors for several diseases. White adipose tissue is the primary site for energy storage in the form of triglycerides, whereas brown adipose tissue does not store energy-providing lipids but rather dissipates it by producing heat. White-to-brown adipocyte trans-differentiation could represent a new target of anti-obesity strategies and result in fat reduction. Previous studies indicated that adenosine receptor activation induces trans-differentiation of white adipocytes to brown adipocytes. The aim of this study was to evaluate the effects of Polydeoxyribonucleotide (PDRN), an A2Ar receptor agonist, in an in vitro model of browning. Mouse 3T3-L1 pre-adipocytes were differentiated in mature adipocytes with specific culture media and then treated with PDRN (10 µg/mL), PDRN + ZM241385 (1 µM), CGS21680 (1 µM) and CGS + ZM241385 for 24 h. Cell viability was studied by MTT assay, and browning induction was evaluated by Oil Red O staining and by RT-qPCR to study gene expression of browning markers. PDRN, as well as CGS21680, reduced the accumulation of lipids, cell volume and lipid droplet size; increased the expression of UCP1, PRDM16 and DIO2, considered as browning markers; and reduced the expression of FASn and FABP4, considered as whitening markers. In addition, PDRN decreased leptin expression and enhanced adiponectin mRNA levels. All these effects were abrogated when PDRN was co-incubated with the A2Ar antagonist ZM241385. In conclusion, these results suggest that PDRN is able to induce the white-to-brown adipose differentiation through A2Ar stimulation. Since PDRN is a safe drug already available in the market for other therapeutic indications, its “anti-obesity” potential warrants investigation in a clinical scenario
-
the effect of pdrn an adenosine receptor a2a agonist on the healing of chronic diabetic foot ulcers results of a clinical trial
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Francesco Squadrito, Alessandra Bitto, Domenica Altavilla, Letteria Minutoli, Giovanni Pallio, Vincenzo Arcoraci, Giovanni De Caridi, Salvatore Corrao, Carmelo Sterrantino, Antonino SaittaAbstract:Context: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. Objective: The aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. Design and Setting: This randomized, double-blind, placebo-controlled trial, involved two medical centers in Italy. Intervention: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2) were randomly assigned to receive placebo (n = 106) or PDRN (n = 110). The treatments (PDRN and placebo) were performed 3 days a week for 8 weeks by intramuscular and perilesional route. Main Outcome Measures: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the reepithelialization of wound surface (as percentage of the original area). Results: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete heali...
-
Polydeoxyribonucleotide reduces cytokine production and the severity of collagen induced arthritis by stimulation of adenosine a2a receptor
Arthritis & Rheumatism, 2011Co-Authors: Alessandra Bitto, Francesca Polito, Antonio Micali, Natasha Irrera, Angela Dascola, Angela Avenoso, Giancarlo Nastasi, Giuseppe M Campo, G Bagnato, Letteria MinutoliAbstract:Objective Broad antiinflammatory effects following adenosine A(₂A) receptor stimulation have been demonstrated in acute inflammatory diseases, including arthritis. Polydeoxyribonucleotide (PDRN) activates the adenosine A(₂A) receptor. This study was undertaken to investigate the effects of PDRN in collagen-induced arthritis (CIA) in mice. Methods Arthritis was induced in DBA/1 mice by an intradermal injection of 100 μl of bovine type II collagen in Freund's complete adjuvant. Mice were immunized a second time 21 days later. Control animals received 100 μl of a saline solution. Animals with CIA were randomized to receive one of the following: vehicle (1 ml/kg); PDRN (8 mg/kg intraperitoneally daily); 3,7-dimethyl-propargylxanthine (DMPX), a specific adenosine A(₂A) receptor antagonist (0.1 mg/kg intraperitoneally daily); or PDRN plus DMPX. The treatment was initiated immediately after the second immunization and continued to day 45. Clinical evaluation of arthritis was performed throughout the study. On day 45, the animals were killed and the severity of arthritis was evaluated histologically. Cartilage expression and circulating levels of high mobility group box chromosomal protein 1 (HMGB-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-10 were investigated. Inflammatory cytokine production was also evaluated in stimulated human chondrocytes treated with PDRN. Results PDRN treatment significantly ameliorated clinical signs of arthritis, improved histologic damage, reduced the cartilage expression and circulating levels of HMGB-1, TNFα, and IL-6, and enhanced IL-10 expression. The concomitant administration of DMPX and PDRN ablated the PDRN-induced protective effect in experimental arthritis. PDRN also reduced cytokine production from stimulated human chondrocytes. Conclusion Our findings indicate that PDRN may represent a new alternative for the treatment of arthritis.
-
Polydeoxyribonucleotide reduces cytokine production and the severity of collagen induced arthritis by stimulation of adenosine a a receptor
Arthritis & Rheumatism, 2011Co-Authors: Alessandra Bitto, Francesca Polito, Antonio Micali, Natasha Irrera, Angela Dascola, Angela Avenoso, Giancarlo Nastasi, Giuseppe M Campo, G Bagnato, Letteria MinutoliAbstract:Objective Broad antiinflammatory effects following adenosine A(₂A) receptor stimulation have been demonstrated in acute inflammatory diseases, including arthritis. Polydeoxyribonucleotide (PDRN) activates the adenosine A(₂A) receptor. This study was undertaken to investigate the effects of PDRN in collagen-induced arthritis (CIA) in mice. Methods Arthritis was induced in DBA/1 mice by an intradermal injection of 100 μl of bovine type II collagen in Freund's complete adjuvant. Mice were immunized a second time 21 days later. Control animals received 100 μl of a saline solution. Animals with CIA were randomized to receive one of the following: vehicle (1 ml/kg); PDRN (8 mg/kg intraperitoneally daily); 3,7-dimethyl-propargylxanthine (DMPX), a specific adenosine A(₂A) receptor antagonist (0.1 mg/kg intraperitoneally daily); or PDRN plus DMPX. The treatment was initiated immediately after the second immunization and continued to day 45. Clinical evaluation of arthritis was performed throughout the study. On day 45, the animals were killed and the severity of arthritis was evaluated histologically. Cartilage expression and circulating levels of high mobility group box chromosomal protein 1 (HMGB-1), tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and IL-10 were investigated. Inflammatory cytokine production was also evaluated in stimulated human chondrocytes treated with PDRN. Results PDRN treatment significantly ameliorated clinical signs of arthritis, improved histologic damage, reduced the cartilage expression and circulating levels of HMGB-1, TNFα, and IL-6, and enhanced IL-10 expression. The concomitant administration of DMPX and PDRN ablated the PDRN-induced protective effect in experimental arthritis. PDRN also reduced cytokine production from stimulated human chondrocytes. Conclusion Our findings indicate that PDRN may represent a new alternative for the treatment of arthritis.
-
Polydeoxyribonucleotide pdrn restores blood flow in an experimental model of peripheral artery occlusive disease
Journal of Vascular Surgery, 2008Co-Authors: Alessandra Bitto, Francesca Polito, Domenica Altavilla, Letteria Minutoli, Alba Migliorato, Francesco SquadritoAbstract:Objective This study investigated whether Polydeoxyribonucleotide (PDRN) may be efficacious in the treatment of peripheral artery occlusive diseases, which are a major cause of morbidity in Western countries and still lack standardized treatment. Methods We investigated the effects of PDRN, a mixture of deoxyribonucleotides, in an experimental model of hind limb ischemia (HLI) in rats to stimulate vascular endothelial growth factor (VEGF)-A production and to avoid critical ischemia. The femoral artery was excised to induce HLI. Sham-operated on rats (sham HLI) were used as controls. Animals were treated daily with intraperitoneal PDRN (8 mg/kg) or its vehicle. Animals were euthanized at day 7, 14, and 21 after the evaluation of blood flow by laser Doppler. Dissected muscles were used to measure VEGF-A messenger RNA (mRNA) and protein expression, to evaluate edema, and to assess histologic damage. Results Administration of PDRN dramatically increased VEGF mRNA throughout the study (day 14: HLI, 7 ± 2.2 n-fold/β-actin; HLI + PDRN, 13.3 ± 3.8 n-fold/β-actin; P P P 2A receptor antagonist, abolished the positive effects of PDRN, confirming that PDRN acts through this receptor. Conclusion These results led us to hypothesize a role for PDRN in treating peripheral artery occlusive diseases.