Ischemia and reperfusion (I/R) causes a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to the ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, and inflammatory responses to cell death. In normal conditions, ROS mediate important beneficial responses. When their production is prolonged or elevated, harmful events are observed with peculiar cellular changes. In particular, during I/R, ROS stimulate tissue inflammation and induce NLRP3 inflammasome activation. The mechanisms underlying the activation of NLRP3 are several and not completely elucidated. It was recently shown that NLRP3 might sense directly the presence of ROS produced by normal or malfunctioning mitochondria or indirectly by other activators of NLRP3. Aim of the present review is to describe the current knowledge on the role of NLRP3 in some organs (brain, heart, kidney, and testis) after I/R injury, with particular regard to the role played by ROS in its activation. Furthermore, as no specific therapy for the prevention or treatment of the high mortality and morbidity associated with I/R is available, the state of the art of the development of novel therapeutic approaches is illustrated.

Background-We investigated whether electrical stimulation (STIM) of efferent vagus nerves may suppress nuclear factor (NF)-B activation and the inflammatory cascade in hemorrhagic (Hem) shock. Methods and Results-Rats were subjected to bilateral cervical vagotomy (VGX) or sham surgical procedures.

Twenty-four months of treatment with genistein has positive effects on BMD in osteopenic postmenopausal women. ClinicalTrials.gov registration number: NCT00355953.

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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 (db1/ db1) and their normal littermates (db1/1m). Animals were treated daily for 12 days with PDRN (8 mg/kg/ip) or its vehicle (100 mL 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 (vehicle51.0 AE 0.2 n-fold vs. b-actin; PDRN51.5 AE 0.09 n-fold vs. b-actin) and protein wound content on day 6 (vehicle50.3 AE 0.07 pg/wound; PDRN50.9 AE 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.

After 3 yr of treatment, genistein exhibited a promising safety profile with positive effects on bone formation in a cohort of osteopenic, postmenopausal women.

The effects of recombinant human erythropoietin (rHuEPO) in diabetes-related healing defects were investigated by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJm ؉/؉ Lept db mice (db ϩ /db ϩ ) and their normoglycemic littermates (db ϩ/ϩ m). Animals were treated with rHuEPO (400 units/kg in 100 l s.c.) or its vehicle alone (100 l). Mice were killed on different days (3, 6, and 12 days after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, for monitoring angiogenesis by CD31 expression, and for evaluating histological changes. Furthermore, we evaluated wound-breaking strength at day 12. At day 6, rHuEPO injection in diabetic mice resulted in an increase in VEGF mRNA expression (vehicle ‫؍‬ 0.33 ؎ 0.1 relative amount of mRNA; rHuEPO ‫؍‬ 0.9 ؎ 0.09 relative amount of mRNA; P < 0.05) and protein wound content (vehicle ‫؍‬ 23 ؎ 5 pg/wound; rHuEPO ‫؍‬ 92 ؎ 12 pg/wound; P < 0.05) and caused a marked increase in CD31 gene expression (vehicle ‫؍‬ 0.18 ؎ 0.05 relative amount of mRNA; rHuEPO ‫؍‬ 0.98 ؎ 0.21 relative amount of mRNA; P < 0.05) and protein synthesis. Furthermore, rHuEPO injection improved the impaired wound healing and, at day 12, increased the wound-breaking strength in diabetic mice (vehicle ‫؍‬ 12 ؎ 2 g/mm; rHuEPO 21 ؎ 5 g/mm; P < 0.05). Erythropoietin may have a potential application in diabetes-related wound disorders.

Our study suggests that rHuEPO may be an effective therapeutic approach to improve clinical outcomes after thermal injury.