Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

Multifunctional alginate/polydeoxyribonucleotide hydrogels for promoting diabetic wound healing.

A multifunctional alginate/PDRN hydrogel system by ionic crosslinking and the Schiff base reaction between oxidized alginate (OA) and PDRN was developed in the present study. Biocompatibility assessment of the PDRN-loaded OA hydrogels showed a significant enhancement in cell viability in human dermal fibroblast (HDF) cells. In addition, hydrogels showed migratory, anti-inflammatory, intracellular reactive oxygen species scavenging, and anti-apoptotic activities. In vivo studies using a streptozotocin-induced diabetic Wister rat model indicated that OA-4PDRN had the highest percentage of wound closure (96.1 ± 2.6 %) at day 14 compared to the control (79.0 ± 2.3 %) group. This was accompanied by up-regulation of vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-ß) accompanied by down-regulation of pro-inflammatory markers (IL-6, IL-1ß). Following histopathological observations, PDRN-loaded OA hydrogel ensured tissue safety and induced wound healing with granular tissue formation, collagen deposition, re-epithelialization, and regeneration of blood vessels and hair follicles. The downregulation of inflammatory cytokines (CD68) and expression of angiogenesis-related cytokines (CD31) in wound sites revealed the suppression of inflammation and increased angiogenesis, ensuring skin tissue regeneration in diabetic wound healing. In conclusion, the findings suggest that PDRN-loaded OA hydrogel has enormous therapeutic potential as a diabetic wound dressing.

Analysis of Skin Regeneration and Barrier-Improvement Efficacy of Polydeoxyribonucleotide Isolated from Panax Ginseng (C.A. Mey.) Adventitious Root.

Polydeoxyribonucleotide (PDRN) has the ability to regenerate skin cells and improve the skin barrier and wound healing. This study investigated the possibility of replacing animal-derived PDRN with plant-derived PDRN. To test this, the adventitious roots of Korean ginseng (Panax ginseng C.A. Meyer), which is commonly used to treat various diseases, were suspension-cultivated through tissue culture; subsequently, PDRN was purified using microfluidization, an ultra-high-pressure physical grinding method. The results showed that purified Panax PDRN was effective in healing skin wounds and enhancing the skin barrier. Panax PDRN promoted the proliferation of keratinocytes and fibroblasts by increasing the expression of fibronectin, filaggrin, Ki-67, Bcl-2, inhibin beta A, and Cyclin D1. It also acted as an agonist of the adenosine A2A receptor and induced the phosphorylation of focal adhesion kinase, adenosine triphosphate-dependent tyrosine kinase, and mitogen-activated protein kinase. This activated signal transduction, thereby regenerating skin cells and strengthening the barrier. These results were not only observed in skin cells but also in an artificial skin model (KeraSkinTM). The use of plant-derived PDRN instead of animal-derived PDRN can promote animal welfare and environmental sustainability. Furthermore, Panax PDRN can potentially be a new plant-derived PDRN (PhytoPDRN) that may be utilized in the treatment of various skin diseases.

Effect of polydeoxyribonucleotide on early bone formation in lateral bone augmentation with immediate implant placement: an experimental in vivo study.

This study investigated early bone formation using collagenated biphasic calcium phosphate (CBCP) with or without polynucleotide (PDRN). Third (P3) or fourth (P4) premolars of six male beagle dogs were extracted and 5-mm-high dehiscence defects were created, followed by 3D-printed implant placement. The buccal bone defects were grafted with (i) CBCP and collagen membrane or (ii) CBCP soaked in polydeoxyribonucleotide (CBCP/PDRN) and collagen membrane. Samples of the experimental sites were harvested at 2- and 6-weeks post-surgery. The specimens were evaluated with radiologic and histomorphometric analysis. No significant differences were found between the CBCP and CBCP/PDRN groups in the micro-CT analysis at 2 or 6 weeks. No significant differences were observed in bone-to-implant contact (BIC) or bone area fraction occupancy (BAFO) in buccal augmented and lingual non-augmented areas. In the qualitative analysis, the new bone (NB) area and NB proportion in buccal augmented areas showed significantly higher values in the CBCP/PDRN group than in the CBCP group at 2 and 6 weeks. Peri-implant buccal dehiscence defects with immediate 3D-printed implant placement were corrected using a collagen membrane and CBCP or CBCP/PDRN. PDRN might have the potential to facilitate early bone formation with sufficient stability over time in dehiscence defects.

Development and characterization of polydeoxyribonucleotide (PDRN) loaded chitosan polyplex: In vitro and in vivo evaluation of wound healing activity.

Polydeoxyribonucleotide (PDRN) is an accelerated diabetic wound healing therapy with promising abilities to promote cell growth, angiogenesis, collagen synthesis, and reduce inflammation where its sustainable delivery and release behavior is critical to ensure effective wound healing properties. Therefore, a nanopolyplex was developed here, by encapsulating PDRN with chitosan to affirm its delivery systematically. The physicochemical characterization revealed its successful encapsulation which facilitates the gradual release of PDRN. In vitro studies of the polyplex demonstrated no cytotoxicity and enhanced cell proliferation and migration properties with high antimicrobial activities. In vivo, wound healing studies in Wistar rats dorsal skin defect model induced with diabetes mellitus affirm the highest wound healing activity and wound closure rate by chitosan/PDRN polyplex treatment. Considerably high histopathological changes such as epithelialization, collagen deposition, blood vessels, and hair follicle formation were observed under the polyplex treatment. The immunohistochemical analysis for platelet endothelial cell adhesion molecule (CD31) and cluster of differentiation (CD68) revealed the ability of polyplex to increase CD31 expression and decrease CD68 expression thereby promoting the wound healing process. Collectively, these results suggest that significantly accelerated, high-quality wound healing effects could be obtained by the developed chitosan/PDRN polyplex and thus it could be introduced as a potential therapeutic product for diabetic wound healing.

Polydeoxyribonucleotide and Shock Wave Therapy Sequence Efficacy in Regenerating Immobilized Rabbit Calf Muscles.

This study primarily aimed to investigate the combined effects of polydeoxyribonucleotide (PDRN) and extracorporeal shock wave therapy (ESWT) sequences on the regenerative processes in atrophied animal muscles. Thirty male New Zealand rabbits, aged 12 weeks, were divided into five groups: normal saline (Group 1), PDRN (Group 2), ESWT (Group 3), PDRN injection before ESWT (Group 4), and PDRN injection after ESWT (Group 5). After 2 weeks of cast immobilization, the respective treatments were administered to the atrophied calf muscles. Radial ESWT was performed twice weekly. Calf circumference, tibial nerve compound muscle action potential (CMAP), and gastrocnemius (GCM) muscle thickness after 2 weeks of treatment were evaluated. Histological and immunohistochemical staining, as well as Western blot analysis, were conducted 2 weeks post-treatment. Staining intensity and extent were assessed using semi-quantitative scores. Groups 4 and 5 demonstrated significantly greater calf muscle circumference, GCM muscle thickness, tibial nerve CMAP, and GCM muscle fiber cross-sectional area (type I, type II, and total) than the remaining three groups (p < 0.05), while they did not differ significantly in these parameters. Groups 2 and 3 showed higher values for all the mentioned parameters than Group 1 (p < 0.05). Group 4 had the greatest ratio of vascular endothelial growth factor (VEGF) to platelet endothelial cell adhesion molecule-1 (PECAM-1) in the GCM muscle fibers compared to the other four groups (p < 0.05). Western blot analysis revealed significantly higher expression of angiogenesis cytokines in Groups 4 and 5 than in the other groups (p < 0.05). The combination of ESWT and PDRN injection demonstrated superior regenerative efficacy for atrophied calf muscle tissue in rabbit models compared to these techniques alone or saline. In particular, administering ESWT after PDRN injection yielded the most favorable outcomes in specific parameters.

Targeting Adenosine Signalling in Knee Chondropathy: The Combined Action of Polydeoxyribonucleotide and Pulsed Electromagnetic Fields: A Current Concept Review.

Chondropathy of the knee is one of the most frequent degenerative cartilage pathologies with advancing age. Scientific research has, in recent years, advanced new therapies that target adenosine A2 receptors, which play a significant role in human health against many disease states by activating different protective effects against cell sufferance and damage. Among these, it has been observed that intra-articular injections of polydeoxyribonucleotides (PDRN) and Pulsed Electromagnetic Fields (PEMF) can stimulate the adenosine signal, with significant regenerative and healing effects. This review aims to depict the role and therapeutic modulation of A2A receptors in knee chondropathy. Sixty articles aimed at providing data for our study were included in this review. The present paper highlights how intra-articular injections of PDRN create beneficial effects by reducing pain and improving functional clinical scores, thanks to their anti-inflammatory action and the important healing and regenerating power of the stimulation of cell growth, production of collagen, and the extracellular matrix. PEMF therapy is a valid option in the conservative treatment of different articular pathologies, including early OA, patellofemoral pain syndrome, spontaneous osteonecrosis of the knee (SONK), and in athletes. PEMF could also be used as a supporting therapy after an arthroscopic knee procedure total knee arthroplasty to reduce the post-operative inflammatory state. The proposal of new therapeutic approaches capable of targeting the adenosine signal, such as the intra-articular injection of PDRN and the use of PEMF, has shown excellent beneficial results compared to conventional treatments. These are presented as an extra weapon in the fight against knee chondropathy.

Efficacy of Polydeoxyribonucleotide in Promoting the Healing of Diabetic Wounds in a Murine Model of Streptozotocin-Induced Diabetes: A Pilot Experiment.

We assessed the efficacy of polydeoxyribonucleotide (PDRN) in accelerating the healing of diabetic wounds in a murine model of streptozotocin (STZ)-induced diabetes. After the creation of diabetic wounds, the mice of the PDRN SC, PDRN IP and PBS groups received a subcutaneous, an intra-peritoneal injection of PDRN and a subcutaneous injection of PBS, respectively. After euthanasia, time-dependent changes in the wound diameter and histologic scores were measured and vascular endothelial growth factor (VEGF), transforming growth factor-ß1 (TGF-ß1) and collagen types I and III were assessed for their expression levels. The PDRN SC and the PDRN IP groups showed a significantly smaller diameter of diabetic wounds, significantly higher histologic scores, a significantly greater expression of VEGF, a significantly lower expression of TGF-ß1 and a significantly greater expression of collagen types I and III as compared with the PBS group (p < 0.05 or 0.0001). In conclusion, PDRN might be effective in promoting the healing of diabetic wounds in a murine model of STZ-induced diabetes.

Involvement of Hypoxia-Inducible Factor 1-α in Experimental Testicular Ischemia and Reperfusion: Effects of Polydeoxyribonucleotide and Selenium.

Polydeoxyribonucleotide (PDRN) is an agonist of the A2A adenosine receptor derived from salmon trout sperm. Selenium (Se) is a trace element normally present in the diet. We aimed to investigate the long-term role of PDRN and Se, alone or in association, after ischemia-reperfusion (I/R) in rats. The animals underwent 1 h testicular ischemia followed by 30 days of reperfusion or a sham I/R and were treated with PDRN or Se alone or in association for 30 days. I/R significantly increased hypoxia-inducible factor 1-α (HIF-1α) in Leydig cells, malondialdehyde (MDA), phosphorylated extracellular signal-regulated kinases 1/2 (pErk 1/2), and apoptosis decreased testis weight, glutathione (GSH), testosterone, nuclear factor erythroid 2-related factor 2 (Nrf2), induced testicular structural changes, and eliminated HIF-1α spermatozoa positivity. The treatment with either PDRN or Se significantly decreased MDA, apoptosis, and HIF-1α positivity of Leydig cells, increased testis weight, GSH, testosterone, and Nrf2, and improved the structural organization of the testes. PDRN and Se association showed a higher protective effect on all biochemical, structural, and immunohistochemical parameters. Our data suggest that HIF-1α could play important roles in late testis I/R and that this transcriptional factor could be modulated by PDRN and Se association, which, together with surgery, could be considered a tool to improve varicocele-induced damages.

Combination Therapy of Polydeoxyribonucleotide and Microcurrent in Muscle Regeneration on Cast-Induced Muscle Atrophy in Rabbit.

Background: The aim of this study was to evaluate how polydeoxyribonucleotide (PDRN) and microcurrent therapy (MT) functioned synergistically in a cast-immobilized rabbit model with an atrophied calf muscle. Methods: At the age of 12 weeks, 32 male New Zealand rabbits were enrolled in four groups. After 2 weeks of cast-immobilization, 4 procedures were performed on atrophied calf muscle [weekly two injections normal saline 0.2 ml injection group 1 (G1-NS), weekly two injections 0.2 ml PDRN injection group 2 (G2-PDRN), MT group 3 (G3-MT), and 0.2 ml PDRN injection with MT group 4 (G4-PDRN+MT)]. For 2 weeks, MT was used for 60 minutes each day. The calf circumference (CC), the thickness of gastrocnemius muscle (TGCM), and the tibial nerve compound muscle action potential (CMAP) were evaluated using ultrasound before and after 2 weeks of treatment. Proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor, and platelet endothelial cell adhesion molecule-1 (PECAM-1) of GCM fibers (type I, type II, and total) were measured. Statistical analyses were performed using ANOVA. Results: The mean atrophic alterations of right CC, CMAP, and TGCM (medial/lateral) were substantially lower in G4-PDRN+MT than in the G1-NS, G2-PDRN, and G3-MT, respectively (p < 0.05). Furthermore, mean CSAs (type I, type II, and total) of medial and lateral GCM muscle fibers in G4-PDRN+MT were significantly higher when compared to other three groups (p < 0.05). In terms of the PCNA-, VEGF-, and PECAM-1-positive cell ratio of medial and lateral GCM muscle fibers, G4-PDRN+MT was considerably higher than G1-NS, G2-PDRN, and G3-MT (p < 0.05). Conclusions: On the atrophied calf muscle of the rabbit model, PDRN injection combined with MT was more effective than PDRN injection alone, MT alone, and normal saline injection separately.

Effect of Polydeoxyribonucleotide (PDRN) Treatment on Corneal Wound Healing in Zebrafish (Danio rerio).

This study aimed to develop a corneal epithelial injury model in zebrafish (Danio rerio) and investigate the effectiveness of polydeoxyribonucleotide (PDRN) treatment on in vivo corneal epithelial regeneration and wound healing. Chemical injury to zebrafish cornea was produced by placing a small cotton swab containing 3% acetic acid solution. PDRN treatment was performed by immersing corneal-injured zebrafish in water containing PDRN (2 mg/mL) for 10 min at 0, 24, 48, and 72 h post-injury (hpi). The level of corneal healing was evaluated by fluorescein staining, histological examination, transcriptional profiling, and immunoblotting techniques. Fluorescein staining results demonstrate that PDRN treatment significantly (p < 0.05) reduced the wounded area of the zebrafish eye at 48 and 72 hpi, suggesting that PDRN may accelerate the corneal re-epithelialization. Histopathological evaluation revealed that injured corneal epithelial cells were re-organized at 72 hpi upon PDRN treatment with increased goblet cell density and size. Moreover, transcriptional analysis results demonstrate that PDRN treatment induced the mRNA expression of adora2ab (6.3-fold), pax6a (7.8-fold), pax6b (29.3-fold), klf4 (7.3-fold), and muc2.1 (5.0-fold) after the first treatment. Besides, tnf-α (2.0-fold) and heat-shock proteins (hsp70; 2.8-fold and hsp90ab1; 1.6-fold) have modulated the gene expression following the PDRN treatment. Immunoblotting results convincingly confirmed the modulation of Mmp-9, Hsp70, and Tnf-α expression levels upon PDRN treatment. Overall, our corneal injury model in zebrafish allows for understanding the morphological and molecular events of corneal epithelial healing, and ophthalmic responses for PDRN treatment following acid injury in zebrafish.

A stitch in time saves nine: timely use of N-acetyl cysteine (NAC) for chemotherapy-induced veno-occlusive disease (VOD)-is it a cost-effective alternative?

Chemotherapy-induced veno-occlusive disease (VOD) is a rare liver dysfunction seen among pediatric cancer patients which could lead to severe morbidity and mortality. Defibrotide is the commonly used antidote in the management of both stem cell transplant and chemotherapy-associated VOD along with liver supportive measures. Defibrotide is costly and generally not accessible to majority of patients treated at resource poor settings. In this report, we describe the successful management of chemotherapy-induced VOD with timely administration of N-acetyl cysteine.

Regeneration of Chronic Rotator Cuff Tear in a Rabbit Model: Synergetic Benefits of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells, Polydeoxyribonucleotides, and Microcurrent Therapy.

Objective: To investigate synergic therapeutic effects of combined injection of intralesional mesenchymal stem cells derived from human umbilical cord blood (UCB-MSCs) and polydeoxyribonucleotide (PDRN) combined with microcurrent therapy (MIC) on full thickness rotator cuff tendon tear (FTRCTT) in rabbit models. Methods: Thirty-two rabbit models were assigned to 4 different groups. FTRCTT in the supraspinatus tendon was created. After 6 weeks, 4 types of procedures (0.2 mL normal saline injection, group 1 (G1-NS); 0.2 mL SC injection, group 2 (G2-MSC); 0.2 mL SC and weekly four injections of 0.2 mL PDRN with sham MIC, group 3 (G3-MSC+PDRN+sham MIC); and 0.2 mL SC and weekly four injections of 0.2 mL PDRN with MIC for four weeks, group 4 (G4-MSC+PDRN+MIC)) were performed in FTRCTT. Gross morphologic and histological changes of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (PECAM-1) and motion analysis were performed. Results: There was a significant difference in gross morphologic changes between baseline and week 4 posttreatment in group 4 compared to the other three groups (p = 0.01). In groups 3 and 4, all parameters of histochemical and motion analysis have been found to be significantly greater than the ones in groups 1 and 2 (p < 0.05). In group 4, PCNA-, VEGF-, and PECAM-1-stained cells, as well as walking distance, were significantly greater than the ones in group 3 (p < 0.05). Conclusion: The treatment with UCB-MSCs and PDRN combined with MIC might be the most effective in rabbit models' traumatic FRTCTT.

Effectiveness of defibrotide in the prevention of hepatic venooclusive disease among adult patients receiving allogeneic hematopoietic cell transplantation: A retrospective single center experience.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most life-threatening early complications following hematopoietic cell transplantation (HCT). Due to the high mortality rate of severe VOD/SOS accompanied with multiorgan failure, there is a great interest in preventive strategies. The efficacy of defibrotide (DF) on the prevention of VOD/SOS has been clearly shown in high-risk pediatric patients, but evidence-based data on adults is scarce. In this report, we aimed to assess the impact of DF on the incidence of VOD/SOS in our center by posttransplant day 30 among patients who were treated with allogeneic HCT (allo-HCT). The study included a total of 56 patiens (28 males, 28 females). The median age of the study cohort was 43 (20-68). The daily dose of DF was 10 mg/kg and 25 mg/kg in 53 (94.6 %) and 3 (5.3 %) patients, respectively. Patients also recieved oral ursodeoxycolic acid (UDCA) 250 mg three-times daily started with conditioning until D + 90. Twenty-three (41.1 %) patients had at least one major EBMT-defined risk factor for development of VOD/SOS. One patient who belonged to a very high-risk group (with at least two major risk factors) developed very-severe VOD/SOS at posttransplant D + 20 and died as a result of multiorgan failure. The cumulative incidence of VOD/SOS at D + 30 was 1.9 %. Our findings indicate that 10 mg/kg daily intravenous DF combined with UDCA is quite effective in prevention of VOD/SOS in patients who underwent first allo-HSCT.

Defibrotide combined with triple therapy including posttransplant cyclophosphamide, low dose rabbit anti-t-lymphocyte globulin and cyclosporine is effective in prevention of graft versus host disease after allogeneic peripheral blood stem cell transplantation for hematologic malignancies.

Endothelial dysfunction and damage play important roles in the pathophysiology of graft versus host disease (GvHD) and hepatic venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS). Preliminary evidence suggests that defibrotide (DF) may decrease the risk of GvHD. We speculated that DF prophylaxis may have a synergistic effect with other immunosupressive agents by decreasing the incidence of GvHD and retrospectively evaluated the impact of a DF prophylaxis on the development of GvHD. Thirty-eight adult patients with various hematological neoplasms who underwent peripheral blood allogeneic hematopoietic stem cell transplantation from all donor types were included. All patients received DF for prevention of VOD/SOS. GvHD prophylaxis included rabbit anti-T lymphocyte globulin (rATLG), posttransplant cyclophosphamide (PTCy) and cyclosporine (CsA). The median follow-up of the surviving patients was 484 (365-814) days. The cumulative incidence of grade III-IV acute GvHD and moderate/severe chronic GvHD requiring systemic immunosupression at 1 year were 20.6 % and 5.3 %, respectively. Non-relapse mortality, GvHD-relapse-free survival, and overall survival of the study cohort at 1-year were 21.1 %, 44.7 % and 57.9 %, respectively. Our preliminary results suggest that DF may act as a global endothelial protectant and decrease the risk of GvHD in combination with rATLG, PTCy and CsA.

The importance of endothelial protection: the emerging role of defibrotide in reversing endothelial injury and its sequelae.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potentially life-threatening complication of hematopoietic cell transplantation (HCT), results from prolonged sinusoidal endothelial cell activation and profound endothelial cell damage, with sequelae. Defibrotide, the only drug approved in the United States and Europe for treating VOD/SOS post-HCT, has European Commission orphan drug designation for preventing graft-versus-host disease (GvHD), associated with endothelial dysfunction. This endothelial cell protector and stabilizing agent restores thrombo-fibrinolytic balance and preserves endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, anti-oxidative, and anti-adhesive activity. Defibrotide also preserves endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulating p38 mitogen-activated protein kinase (MAPK) and histone deacetylases (HDACs) is key to defibrotide's endothelial protective effects; phosphatidylinositol 3-kinase/Akt (PI3K/AKT) potentially links defibrotide interaction with the endothelial cell membrane and downstream effects. Despite defibrotide's being most extensively studied in VOD/SOS, emerging preclinical and clinical data support defibrotide for treating or preventing other conditions driven by endothelial cell activation, dysfunction, and/or damage, such as GvHD, transplant-associated thrombotic microangiopathy, or chimeric antigen receptor T-cell (CAR-T) therapy-associated neurotoxicity, underpinned by cytokine release syndrome and endotheliitis. Further preclinical and clinical studies will explore defibrotide's potential utility in a broader range of disorders resulting from endothelial cell activation and dysfunction.

Amelioration of alcohol­induced gastric mucosa damage by oral administration of food­polydeoxyribonucleotides.

Gastritis refers to inflammation caused by injury to the gastric epithelium, which is usually due to excessive alcohol consumption and prolonged use of nonsteroidal anti­inflammatory drugs. Millions of individuals worldwide suffer from this disease. However, the lack of safe and promising treatments makes it urgent to explore and develop leads from natural resources. Therefore, food as medicine may be the best approach for the treatment of these disorders. The present study described the protective effects of food­polydeoxyribonucleotides (f­PDRNs) in a rat model of gastric mucosal injury induced by HCl­EtOH. Administration of f­PDRN was performed with low­PRF002 (26 mg/kg/day), medium­PRF002 (52 mg/kg/day) and high­PRF002 (78 mg/kg/day) on the day of autopsy. The site of damage to the mucous membrane was also analysed. In addition, an increase in gastric juice pH, total acidity of gastric juice and decrease in gastric juice secretion were confirmed, and gastric juice secretion­related factors corresponding to the administration of f­PDRN were analysed. Administration of f­PDRN reduced the mRNA expression of histamine H2 receptor, muscarinic acetylcholine receptor M3, cholecystokinin 2 receptor and H+/K+ ATPase related to gastric acid secretion and downregulation of histamine, myeloperoxidase and cyclic adenosine monophosphate. In addition, it was histologically confirmed that the loss of epithelial cells and the distortion of the mucosa were recovered in the group in which f­PDRN was administered compared to the model group with gastric mucosa damage. In summary, the present study suggested that f­PDRN has therapeutic potential and may have beneficial effects if taken regularly as a food supplement.

PDRN, a natural bioactive compound, blunts inflammation and positively reprograms healing genes in an "in vitro" model of oral mucositis.

Oral mucositis is a side effect hard to treat following high dose chemotherapy or radiotherapy. Adenosine A2A receptor stimulation blocks NF-κB and boosts the Wnt/ß-catenin signaling, thus blunting inflammation and triggering growth factor codifying genes. Polydeoxyribonucleotide (PDRN) is a registered drug that activates the A2A receptor. Therefore, the aim of this study was to evaluate PDRN effects in an "in vitro" model of oral mucositis induced by prompting an inflammatory phenotype in human gingival fibroblasts (GF) and human oral mucosal epithelial cells (EC). GF and EC were stimulated with LPS (2 µg/ml) alone or in combination with i) PDRN (100 µg/ml); ii) PDRN plus ZM241385 (1 µM) as an A2AR antagonist; iii) CGS21680 (1 µM) as an A2AR agonist. LPS boosted NF-κB, TNF-α and IL-6 expression, decreased IL-10 levels and downregulated both Wnt/ß-catenin, VEGF and EGF expression. PDRN reverted the LPS-induced phenotype as well as CGS21680. Co-incubation with ZM241385 abolished PDRN effects, thus confirming A2A receptor involvement in PDRN mechanism of action. These results suggest that PDRN efficacy may be due to a "dual mode" of action: NF-κB inhibition and Wnt/ß-catenin signaling activation. However, these interesting findings need to be confirmed by animal and clinical studies.

Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide.

Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap-derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

Applications of Marine Organism-Derived Polydeoxyribonucleotide: Its Potential in Biomedical Engineering.

Polydeoxyribonucleotides (PDRNs) are a family of DNA-derived drugs with a molecular weight ranging from 50 to 1500 kDa, which are mainly extracted from the sperm cells of salmon trout or chum salmon. Many pre-clinical and clinical studies have demonstrated the wound healing and anti-inflammatory properties of PDRN, which are mediated by the activation of adenosine A2A receptor and salvage pathways, in addition to promoting osteoblast activity, collagen synthesis, and angiogenesis. In fact, PDRN is already marketed due to its therapeutic properties against various wound healing- and inflammation-related diseases. Therefore, this review assessed the most recent trends in marine organism-derived PDRN using the Google Scholar search engine. Further, we summarized the current applications and pharmacological properties of PDRN to serve as a reference for the development of novel PDRN-based technologies.