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      Comment on “Polydeoxyribonucleotide Exerts Therapeutic Effect by Increasing VEGF and Inhibiting Inflammatory Cytokines in Ischemic Colitis Rats”

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          Abstract

          We read and highly appreciated the interesting article by Kim et al. [1], focusing on the potential therapeutic effects of polydeoxyribonucleotide (PDRN) as an ischemic colitis medical treatment. The colon is particularly susceptible to hypoperfusion and critical low-flow state precipitate to an often innate preexisting less developed microvasculature [2]. As a compensatory mechanism, in the first stage of the colonic hypoxic state, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) are induced, and they paracrinally act to preserve tissue from ischemic damage. By attempting to counteract the hypoxic condition, activation of adenosine A2A receptors (A2AR) occurs in a cooperative fashion with hypoxia, modulating the anti-inflammatory pathway and stimulating VEGF release [3]. PDRN, a specific ligand of A2AR, further enhances the VEGF expression, triggering a downregulation of inflammatory cytokines and an inhibition of both intrinsic and extrinsic apoptotic machineries [4–5]. Moreover, PDRN acts with a “salvage pathway” through the cell internalization of PDRN-derived purine and pyrimidine, mostly where de novo synthesis of DNA is severely impaired by ischemic condition, allowing a rapid tissue recovery [6]. This bioactive natural compound turns out to have relevant therapeutic effects in a range of pathological conditions, for its tissue repairing, anti-ischemic, and anti-inflammatory properties [6]. In Kim et al. [1], the authors documented a PDRN ability in increasing VEGF expression, reducing the histological damage, downregulating anti-inflammatory responses, and modulating apoptosis through the interaction with adenosine A2AR. In this regard, the effects of PDRN in the experimental model of ischemic colitis are abolished using DMPX, a specific adenosine A2AR antagonist. This observation minimizes the involvement of the “salvage pathway” in the mechanism of action of PDRN in ischemic colitis. Furthermore, considering the involvement of VEGF in the activation of adenosine A2AR, we believe it could be advantageous to demonstrate the effect of PDRN on neoangiogenesis and microvessel density, which may result in an augmented oxygen supply and a subsequent balance of the apoptotic mechanism [3]. To date, one of the most important ongoing clinical PDRN applications is wound healing, in which it increases reepithelialization and tissue granulation, increases the production of VEGF and blood vessels, and reduces the infiltration of inflammatory cells and scar size [7, 8]. Furthermore, it has also been used to reduce neuropathic pain and brain damage, to heal tendon injuries, to contrast the effect of estrogen deficiency-induced osteoporosis, and with intratracheal instillation to reduce lung inflammation and injury [9]. In conclusion, we believe that the data of Kim et al. [1] are remarkable, and considering the safe profile of PDRN also in humans, it could be useful to attempt a clinical randomized trial to verify the properties of this promising compound.

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          Ischemic colitis: clinical practice in diagnosis and treatment.

          Ischemic colitis is the most common form of ischemic injury of the gastrointestinal tract and can present either as an occlusive or a non-occlusive form. It accounts for 1 in 1000 hospitalizations but its incidence is underestimated because it often has a mild and transient nature. The etiology of ischemic colitis is multifactorial and the clinical presentation variable. The diagnosis is based on a combination of clinical suspicion, radiographic, endoscopic and histological findings. Therapy and outcome depends on the severity of the disease. Most cases of the non-gangrenous form are transient and resolve spontaneously without complications. On the other hand, high morbidity and mortality and urgent operative intervention are the hallmarks of gangrenous ischemic colitis.
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            Pharmacological Activity and Clinical Use of PDRN

            PDRN is a proprietary and registered drug that possesses several activities: tissue repairing, anti-ischemic, and anti-inflammatory. These therapeutic properties suggest its use in regenerative medicine and in diabetic foot ulcers. PDRN holds a mixture of deoxyribonucleotides with molecular weights ranging between 50 and 1,500 KDa, it is derived from a controlled purification and sterilization process of Oncorhynchus mykiss (Salmon Trout) or Oncorhynchus keta (Chum Salmon) sperm DNA. The procedure guarantees the absence of active protein and peptides that may cause immune reactions. In vitro and in vivo experiments have suggested that PDRN most relevant mechanism of action is the engagement of adenosine A2A receptors. Besides engaging the A2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A2A receptors is a unique property of PDRN and seems to be linked to DNA origin, molecular weight and manufacturing process. In this context, PDRN represents a new advancement in the pharmacotherapy. In fact adenosine and dipyridamole are non-selective activators of adenosine receptors and they may cause unwanted side effects; while regadenoson, the only other A2A receptor agonist available, has been approved by the FDA as a pharmacological stress agent in myocardial perfusion imaging. Finally, defibrotide, another drug composed by a mixture of oligonucleotides, has different molecular weight, a DNA of different origin and does not share the same wound healing stimulating effects of PDRN. The present review analyses the more relevant experimental and clinical evidences carried out to characterize PDRN therapeutic effects.
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              Polydeoxyribonucleotide administration improves the intra-testicular vascularization in rat experimental varicocele.

              To study the effect of PDRN on angiogenesis in a model of varicocele in rats. After the creation of experimental varicocele, rats were randomized to one of the four treatments: vehicle, PDRN, DMPX, and PDRN plus DMPX. Twenty-one days after randomization, all animals were euthanized and the left testis was harvested. Academic hospital. Male Sprague-Dawley rats were used. A clamp was passed behind the left renal vein distally to the spermatic vein insertion. A silk ligature was placed around the left renal vein at this site and was tied over the top of a probe. The latter was then withdrawn and the vein was allowed to expand. In shams, a suture was placed but it was not tied. To assess testicular microvascular density using CD34 immunostaining. Microvascular density in the varicocele plus PDRN group was significantly higher than in other groups. PDRN could represent a novel therapeutic strategy for varicocele treatment in subfertile patients, improving the innate pathophysiologic mechanism of neoangiogenesis, through compensatory oxygen and metabolite supply to tubular and extratubular testicular compartments. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2023
                3 July 2023
                : 2023
                : 9803930
                Affiliations
                Department of Human Pathology of Adult and Childhood “Gaetano Barresi”, Unit of Pediatric Surgery, University of Messina, Messina, Italy
                Author notes

                Academic Editor: Anna Chiarini

                Author information
                https://orcid.org/0000-0002-7629-7782
                https://orcid.org/0000-0003-0276-9211
                https://orcid.org/0000-0003-4262-2433
                https://orcid.org/0000-0002-7616-5480
                Article
                10.1155/2023/9803930
                10332923
                055a2626-7ad7-461f-bab4-ce5280b24e17
                Copyright © 2023 Donatella Di Fabrizio et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 April 2021
                : 3 April 2021
                Categories
                Letter to the Editor

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