Background— We investigated whether electrical stimulation (STIM) of efferent vagus nerves may suppress nuclear factor (NF)-κB activation and the inflammatory cascade in hemorrhagic (Hem) shock. Methods and Results— Rats were subjected to bilateral cervical vagotomy (VGX) or sham surgical procedures. Hem shock was induced by intermittent withdrawing of blood until mean arterial pressure stabilized within the range of 35 to 40 mm Hg. Application of constant voltage pulses to the caudal vagus ends (STIM; 5 V, 2 ms, 1 Hz for 12 minutes, 5 minutes after mean arterial pressure stabilization) increased survival time (VGX+Hem+Sham STIM=38±3 minutes; VGX+Hem+STIM >180 minutes), reverted the marked hypotension (VGX+Hem+Sham STIM=33±3 mm Hg; VGX+Hem+STIM=66±5 mm Hg), inhibited IκBα liver loss, and blunted the augmented NF-κB activity, decreased hepatic tumor necrosis factor (TNF)-α mRNA (VGX+Hem+Sham STIM=1.42±0.5 amount of TNF-α m-RNA; VGX+Hem+STIM=0.51±0.2 amount of TNF-α mRNA), and reduced plasma TNF-α (VGX+Hem+Sham STIM=190±24 pg/mL; VGX+Hem+STIM=87±15 pg/mL). Chlorisondamine, a nicotinic receptor antagonist, abated the effects of vagal stimulation. Conclusions— Our results show a parasympathetic inhibition of NF-κB by which the brain opposes NF-κB activation in the liver and modulates the inflammatory response during acute hypovolemic hemorrhagic shock.

Observational studies and small trials of short duration suggest that the isoflavone phytoestrogen genistein reduces bone loss, but the evidence is not definitive. To assess the effects of genistein on bone metabolism in osteopenic postmenopausal women. Randomized, double-blind, placebo-controlled trial. 3 university medical centers in Italy. 389 postmenopausal women with a bone mineral density (BMD) less than 0.795 g/cm² at the femoral neck and no significant comorbid conditions. After a 4-week stabilization period during which participants received a low-soy, reduced-fat diet, participants were randomly assigned to receive placebo (n = 191) or 54 mg of genistein (n = 198) daily for 24 months. Both the genistein and placebo tablets contained calcium and vitamin D. The primary outcome was BMD at the anteroposterior lumbar spine and femoral neck at 24 months. Secondary outcomes were serum levels of bone-specific alkaline phosphatase and insulin-like growth factor I, urinary excretion of pyridinoline and deoxypyridinoline, and endometrial thickness. Data on adverse events were also collected. At 24 months, BMD had increased in genistein recipients and decreased in placebo recipients at the anteroposterior lumbar spine (change, 0.049 g/cm² [95% CI, 0.035 to 0.059] vs. −0.053 g/cm² [CI, −0.058 to −0.035]; difference, 0.10 g/cm² [CI, 0.08 to 0.12]; P < 0.001) and the femoral neck (change, 0.035 g/cm² [CI, 0.025 to 0.042] vs. −0.037 g/cm² [CI, −0.044 to −0.027]; difference, 0.062 g/cm² [CI, 0.049 to 0.073]; P < 0.001). Genistein statistically significantly decreased urinary excretion of pyridinoline and deoxypyridinoline, increased levels of bone-specific alkaline phosphatase and insulin-like growth factor I, and did not change endometrial thickness compared with placebo. More genistein recipients than placebo recipients experienced gastrointestinal side effects (19% vs. 8%; P = 0.002) and discontinued the study. The study did not measure fractures and had limited power to evaluate adverse effects. Twenty-four months of treatment with genistein has positive effects on BMD in osteopenic postmenopausal women. ClinicalTrials.gov registration number: NCT00355953.

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 A_2A receptors. Besides engaging the A_2A receptor, PDRN offers nucleosides and nucleotides for the so called “salvage pathway.” The binding to adenosine A_2A 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 A_2A 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.

Healing of diabetic wounds still remains a critical medical problem. Polydeoxyribonucleotide (PDRN), a compound having a mixture of deoxyribonucleotide polymers, stimulates the A2 purinergic receptor with no toxic or adverse effect. We studied the effects of PDRN in diabetes‐related healing defect using an incisional skin‐wound model produced on the back of female diabetic mice (db+/db+) and their normal littermates (db+/+m). Animals were treated daily for 12 days with PDRN (8 mg/kg/ip) or its vehicle (100 μL 0.9%NaCl). Mice were killed 3, 6, and 12 days after skin injury to measure vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, to assay angiogenesis and tissue remodeling through histological evaluation, and to study CD31, Angiopoietin‐1 and Transglutaminase‐II. Furthermore, we measured wound breaking strength at day 12. PDRN injection in diabetic mice resulted in an increased VEGF message (vehicle=1.0±0.2 n‐fold vs. β‐actin; PDRN=1.5±0.09 n‐fold vs. β‐actin) and protein wound content on day 6 (vehicle=0.3±0.07 pg/wound; PDRN=0.9±0.1 pg/wound). PDRN injection improved the impaired wound healing and increased the wound‐breaking strength in diabetic mice. PDRN also caused a marked increase in CD31 immunostaining and induced Transglutaminase‐II and Angiopoietin‐1 expression. Furthermore, the concomitant administration of 3,7‐dimethyl‐1‐propargilxanthine, a selective adenosine A2A receptor antagonist, abolished PDRN positive effects on healing. However, 3,7‐dimethyl‐1‐propargilxanthine alone did not affect wound healing in both diabetic mice and normal littermates. These results suggest that PDRN might be useful in wound disorders associated with diabetes.

Context: This study was performed to evaluate the effects of genistein on metabolic and cardiovascular risk factors in Caucasian postmenopausal subjects with metabolic syndrome (MetS). Objective: Our objective was to assess the effects of genistein on surrogate endpoints associated with diabetes and cardiovascular disease. Design and Setting: This was a randomized, double-blind, placebo-controlled trial at 3 university medical centers in Italy. Patients: Patients included 120 postmenopausal women with MetS according to modified Third Report of the National Cholesterol Education Program (NCEP), Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria. Intervention: After a 4-week stabilization period, postmenopausal women with MetS were randomly assigned to receive placebo (n = 60) or 54 mg genistein daily (n = 60) for 1 year. Main Outcome Measures: The primary outcome was homeostasis model assessment for insulin resistance (HOMA-IR) at 1 year. Secondary outcomes were fasting glucose, fasting insulin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, visfatin, adiponectin, and homocysteine levels. Data on adverse events were also recorded. Results: At 1 year in genistein recipients, fasting glucose, fasting insulin, and HOMA-IR (mean from 4.5 to 2.7; P < .001) decreased and were unchanged in placebo recipients. Genistein statistically increased HDL-C (mean from 46.4 to 56.8 mg/dL) and adiponectin and decreased total cholesterol, LDL-C (mean from 108.8 to 78.7 mg/dL), triglycerides, visfatin, and homocysteine (mean from 14.3 to 11.7 μmol/L) blood levels. Systolic and diastolic blood pressure was also reduced in genistein recipients. Genistein recipients neither experienced more side adverse effects than placebo nor discontinued the study. Conclusion: One year of treatment with genistein improves surrogate endpoints associated with risk for diabetes and cardiovascular disease in postmenopausal women with MetS.