stilbenes and Wounds-and-Injuries

Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO.. Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.

Topics: Adaptive Immunity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthroplasty, Replacement, Hip; Blast Injuries; Brain Injuries, Traumatic; Burns; Cell Differentiation; Cytokines; Humans; Hypoxia; Immunosuppressive Agents; Inflammation; Janus Kinase Inhibitors; Macrophages; Mast Cells; Mesenchymal Stem Cells; Myositis Ossificans; Ossification, Heterotopic; Postoperative Complications; Pyrazoles; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Signal Transduction; Sirolimus; Spinal Cord Injuries; Stilbenes; Wounds and Injuries

Resveratrol, a natural polyphenolic compound of grape and red wine, owns potential anti-inflammatory effects, which results in the reduction of cytokines overproduction, the inhibition of neutrophil activity, and the alteration of adhesion molecules expression. Resveratrol also possesses antioxidant, anti-coagulation and anti-aging properties, and it may control of cell cycle and apoptosis. Resveratrol has been shown to reduce organ damage following traumatic and shock-like states. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the activation of estrogen receptor, the regulation of the sirtuin 1/nuclear factor-kappa B and mitogen-activated protein kinases/hemeoxygenase-1 pathway, and the mediation of proinflammatory cytokines and reactive oxygen species formation and reaction. In the recent studies, resveratrol attenuates hepatocyte injury and improves cardiac contractility due to reduction of proinflammatory mediator expression and ameliorates hypoxia-induced liver and kidney mitochondrial dysfunction following trauma and hemorrhagic injuries. Moreover, through anti-inflammatory effects and antioxidant properties, the resveratrol is believed to protect organ function in trauma-hemorrhagic injury. In this review, the organ-protective and anti-inflammatory effects of resveratrol in trauma-hemorrhagic injury will be discussed.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Humans; Resveratrol; Shock, Hemorrhagic; Sirtuin 1; Stilbenes; Wounds and Injuries

Polydatin is a glucoside of resveratrol with lots of functional properties in the central nervous system, such as anti-edema, anti-oxidation and anti-inflammation. The purpose of this study was to evaluate the effects of polydatin on traumatic spinal cord injury (SCI) and explore the relative mechanisms. SCI models were established using the weight-drop method in rats, additionally, single polydatin administration (20, 40 mg/kg body weight) remarkably improved motor function of SCI rat, along with decreased nitric oxide (NO) generation and inflammatory factor (IL-1β, IL-6 and TNF-α) production in spinal cord tissues. Similar to the results of in vivo experiments, the inflammatory response was aggravated with the intervention of lipopolysaccharide (LPS) in BV2 microglia. However, polydatin treatment (1, 2 and 4 μM) inhibited iNOS expression, decreased NLRP3 inflammasome activation, which subsequently relieved microglial inflammation. Above all, our data indicated that polydatin possessed neuroprotective effects in SCI rats, possibly by suppressing iNOS expression and NLRP3 inflammasome activation in microglia.

Topics: Animals; Behavior, Animal; Cell Line; Drugs, Chinese Herbal; Glucosides; Humans; Inflammasomes; Inflammation Mediators; Male; Microglia; Neuroprotection; Nitric Oxide; Nitric Oxide Synthase Type II; NLR Family, Pyrin Domain-Containing 3 Protein; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Stilbenes; Wounds and Injuries

The purpose of this arm of the study was to investigate the impact of medication on healing times of the various wound types, including acute wounds and leg ulcers. A prospective longitudinal study design was used, with de-identified data collected using an electronic mobile wound care database system. Three main categories of data were collected, including patients' demographics, wounds types and treatment characteristics. For acute wounds, there was a total of 1732 patients with 2089 acute wounds. The average healing time was about 35 days. The only significant association was with chemotherapy, which increased healing time by 21 days (P = 0·048). There were non-significant trends towards reduced healing times with antibiotics (0·5 days; P = 0·853), anticoagulants (1·7 days, P = 0·673) and corticosteroids (4·98 days, P = 0·303). Non-steroidal anti-inflammatory drugs (NSAIDs) were associated with a non-significant increase in healing time (2·17 days, P = 0·707). For leg ulcers, there was a total of 264 patients with 370 leg ulcers. We only examined the impact of antibiotics, anticoagulants, corticosteroids and NSAIDs on healing times as they had an adequate number of wounds to analyse. The average healing times of leg ulcers were found to be 73 days. None of the classes of medications had any significant impact on healing time. Both anticoagulants and NSAIDs increased healing time by (22·5 days, P = 0·08) and (12·5 days, P = 0·03), respectively. On the other hand, antibiotics and corticosteroids decreased healing times non-significantly by (9·1 days, P = 0·33) and (21·6 days, P = 0·84), respectively.

Topics: Adrenal Cortex Hormones; Anti-Infective Agents, Local; Anticoagulants; Humans; Longitudinal Studies; Occlusive Dressings; Prospective Studies; Stilbenes; Surgical Wound Infection; Time Factors; Wound Healing; Wounds and Injuries

Heterotopic ossification (HO) involves formation of endochondral bone at non-skeletal sites, is prevalent in severely wounded service members, and causes significant complications and delayed rehabilitation. As common prophylactic treatments such as anti-inflammatory drugs and irradiation cannot be used after multi-system combat trauma, there is an urgent need for new remedies. Previously, we showed that the retinoic acid receptor γ agonist Palovarotene inhibited subcutaneous and intramuscular HO in mice, but those models do not mimic complex combat injury. Thus, we tested Palovarotene in our validated rat trauma-induced HO model that involves blast-related limb injury, femoral fracture, quadriceps crush injury, amputation and infection with methicillin-resistant Staphylococcus aureus from combat wound infections. Palovarotene was given orally for 14days at 1mg/kg/day starting on post-operative day (POD) 1 or POD-5, and HO amount, wound dehiscence and related processes were monitored for up to 84days post injury. Compared to vehicle-control animals, Palovarotene significantly decreased HO by 50 to 60% regardless of when the treatment started and if infection was present. Histological analyses showed that Palovarotene reduced ectopic chondrogenesis, osteogenesis and angiogenesis forming at the injury site over time, while fibrotic tissue was often present in place of ectopic bone. Custom gene array data verified that while expression of key chondrogenic and osteogenic genes was decreased within soft tissues of residual limb in Palovarotene-treated rats, expression of cartilage catabolic genes was increased, including matrix metalloproteinase-9. Importantly, Palovarotene seemed to exert moderate inhibitory effects on wound healing, raising potential safety concerns related to dosing and timing. Our data show for the first time that Palovarotene significantly inhibits HO triggered by blast injury and associated complications, strongly indicating that it may prevent HO in patients at high risk such as those sustaining combat injuries and other forms of blast trauma.

Topics: Animals; Blast Injuries; Chondrogenesis; Disease Models, Animal; Gene Expression Regulation; Male; Ossification, Heterotopic; Osteogenesis; Pyrazoles; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Stilbenes; Wound Healing; Wounds and Injuries

Resveratrol (RSV) has been shown to inhibit the inflammatory reaction and ameliorate the organ damage resulting from trauma-hemorrhage (TH). However, the effects of RSV on the metabolomic profiles under these conditions remain unclear. The aim of this study was to determine the metabolomic profiles of plasma in TH rats and to evaluate the therapeutic effects of RSV using high-performance liquid chromatography-mass spectrometry. Thirty male Sprague-Dawley rats were divided into sham operation (n = 10), sham-operation plus RSV treatment (n = 10), TH (n = 10), and TH plus RSV treatment (n = 10) groups. Plasma samples were obtained at 24 h after surgery. Electrospray ionization-tandem mass spectrometry was used to characterize the plasma metabolomes. The systemic analyses of plasma metabolomes and their targets were determined using a number of computational approaches, including principal component analysis, partial least squares discriminant analysis, and heat map analysis. Using these methods, the effects of RSV on the metabolomic profiles in animals that underwent trauma-hemorrhagic injury were determined. These approaches allowed a clear discrimination of the pathophysiological characteristics among the groups. The results demonstrate RSV treatment significantly reduced the metabolic derangements caused by TH. Compared with the sham-operated rats, the plasma levels of carnitine in the TH rats were relatively lower, but the levels of acetylcarnitine and butyrylcarnitine were higher, suggesting that RSV ameliorated the deranged carnitine metabolism in TH rats. There was a statistically significant increase in carnitine. In addition, RSV treatment reduced ketoacidosis and protein degradation, as evidenced by the attenuation of the elevated plasma branched-chain amino acid levels in the TH rats. Our study showed that the alterations of the metabolomic profiles in the rats subjected to trauma-hemorrhagic shock were attenuated by RSV treatment. In view of the metabolomic evidence, we conclude that RSV exerts beneficial effects in trauma-hemorrhagic shock injury and that these effects are partially mediated by improving energy metabolism and reducing protein degradation.

Topics: Animals; Carnitine; Drug Evaluation, Preclinical; Male; Metabolome; Metabolomics; Rats, Sprague-Dawley; Resveratrol; Shock, Hemorrhagic; Stilbenes; Vasodilator Agents; Wounds and Injuries

Resveratrol has been shown to have protective effects for patients in shock-like states, and Akt (protein kinase B) is known to play a role in pro-inflammatory events in response to injury. The aim of this study is to determine whether resveratrol provides cardioprotection mediated via an Akt-dependent pathway in trauma-hemorrhaged animals.. Male Sprague-Dawley rats underwent trauma-hemorrhage and resuscitation. A single dose of resveratrol (30 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or vehicle was administered intravenously during the resuscitation. Two hours after either the trauma-hemorrhage or sham operation, the cardiac output, the positive maximal pressure increase of the left ventricle (+dP/dt(max)), and the negative maximal pressure decrease of the left ventricle (-dP/dt(max)) were measured. Cardiac myeloperoxidase (MPO) activity, interleukin (IL)-6, and intercellular adhesion molecule (ICAM)-1 levels, Akt activity, and apoptosis were measured. One-way ANOVA and Tukey's test were used for statistical analysis.. Cardiac output and ± dP/dt(max) decreased significantly after trauma-hemorrhage. Administration of resveratrol significantly improved these cardiac function parameters. Trauma-hemorrhage increased cardiac MPO activity, IL-6 levels, and ICAM-1 levels, and these parameters were significantly improved in the resveratrol-treated rats subjected to trauma-hemorrhage. Although trauma-hemorrhage decreased cardiac Akt phosphorylation (p-Akt), resveratrol treatment following trauma-hemorrhage prevented the same decrease in cardiac p-Akt. The increase in cardiac apoptosis was attenuated in rats that received resveratrol. Co-administration of wortmannin prevented the beneficial effects of resveratrol on the attenuation of pro-inflammatory responses and cardiac injury after trauma-hemorrhage.. Resveratrol attenuates cardiac injury following trauma-hemorrhage, which is, at least in part, due to its anti-inflammatory effects via Akt-dependent pathways.

Topics: Androstadienes; Animals; Apoptosis; Cardiac Output; Cardiotonic Agents; Heart; Hemorrhage; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Models, Animal; Myocardium; Peroxidase; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Resveratrol; Signal Transduction; Stilbenes; Ventricular Function, Left; Wortmannin; Wounds and Injuries

Mitochondria play a critical role in metabolic homeostasis of a cell. Our recent studies, based on the reported interrelationship between c-Myc and Sirt1 (mammalian orthologue of yeast sir2 [silent information regulator 2]) expression and their role in mitochondrial biogenesis and function, demonstrated a significant downregulation of Sirt1 protein expression and an upregulation of c-Myc following trauma-hemorrhage (T-H). Activators of Sirt1 are known to improve mitochondrial function and the naturally occurring polyphenol resveratrol (RSV) has been shown to significantly increase Sirt1 activity by increasing its affinity to both NAD+ and the acetylated substrate. In this study we tested the salutary effect of RSV following T-H and its influence on Sirt1 expression. Rats were subjected to T-H or sham operation. RSV (8 mg/kg body weight, intravenously) or vehicle was administered 10 min after the onset of resuscitation, and the rats were killed 2 h following resuscitation. Sirtinol, a Sirt1 inhibitor, was administered 5 min prior to RSV administration. Cardiac contractility (±dP/dt) was measured and heart tissue was tested for Sirt1, Pgc-1α, c-Myc, cytosolic cytochrome C expression and ATP level. Left ventricular function, after T-H, was improved (P < 0.05) following RSV treatment, with significantly elevated expression of Sirt1 (P < 0.05) and Pgc-1α (P < 0.05), and decreased c-Myc (P < 0.05). We also observed significantly higher cardiac ATP content, declined cytosolic cytochrome C and decreased plasma tumor necrosis factor-α in the T-H-RSV group. The salutary effect due to RSV was abolished by sirtinol, indicating a Sirt1-mediated effect. We conclude that RSV may be a useful adjunct to resuscitation fluid following T-H.

Topics: Animals; Benzamides; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Hemorrhage; Male; Myocardial Contraction; Naphthols; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Stilbenes; Wounds and Injuries

Oxyresveratrol is a potent antioxidant and free-radical scavenger found in mulberry wood (Morus alba L.) with demonstrated protective effects against cerebral ischemia. We analyzed the neuroprotective ability of oxyresveratrol using an in vitro model of stretch-induced trauma in co-cultures of neurons and glia, or by exposing cultures to high levels of glutamate. Cultures were treated with 25 μM, 50 μM or 100 μM oxyresveratrol at the time of injury. Trauma produced marked neuronal death when measured 24 h post-injury, and oxyresveratrol significantly inhibited this death. Microscopic examination of glia suggested signs of toxicity in cultures treated with 100 μM oxyresveratrol, as demonstrated by elevated S-100B protein release and a high proportion of cells with condensed nuclei. Cultures exposed to glutamate (100 μM) for 24 h exhibited ~ 37% neuronal loss, which was not inhibited by oxyresveratrol. These results show that the two pathologies of high glutamate exposure and trauma are differentially affected by oxyresveratrol treatment in vitro. Further studies using oxyresveratrol in trauma models are warranted, as toxicity to glia could be beneficial by inhibiting reactive gliosis, which often occurs after trauma.

Topics: Animals; Antioxidants; Brain Ischemia; Cell Death; Cells, Cultured; Cerebral Cortex; Coculture Techniques; Free Radical Scavengers; Glutamic Acid; Mice; Nerve Growth Factors; Neuroglia; Neurons; Neuroprotective Agents; Plant Extracts; Rats; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Stilbenes; Wounds and Injuries

Resveratrol protects against organ injury caused by trauma-hemorrhage, although the mechanism remains unknown. We have previously shown that it exerts protective effects in the liver via estrogen receptors and their signaling. Thus, we set out to determine whether resveratrol-mediated estrogen receptor-dependent p38 mitogen-activated protein kinase (MAPK)/heme oxygenase 1 activation protects the intestine after trauma-hemorrhage. To study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure, ~ 40 mmHg for 90 min) followed by fluid resuscitation. Animals were pretreated with an estrogen receptor antagonist (ICI 182,780), a specific p38 MAPK inhibitor (SB-203580), or a heme oxygenase enzyme antagonist (chromium-mesoporphyrin) 30 min before vehicle or resveratrol (30 mg/kg) administration, followed by resuscitation, and were killed 2 h thereafter. Intestinal water content, myeloperoxidase activity, and TNF-α, IL-6, intercellular adhesion molecule 1, cytokine-induced neutrophil chemoattractant (CINC) 1, and CINC-3 levels and edema of the lung were measured. Mean arterial blood pressure, cardiac output, positive maximal pressure of left ventricular increase (+dP/dtmax), and negative maximal pressure of left ventricular decrease (-dP/dtmax) were also determined. Intestinal p38 MAPK activity and heme oxygenase 1 expression were also determined. Trauma-hemorrhage led to an increase in intestinal water content, myeloperoxidase activity, and TNF-α, IL-6, intercellular adhesion molecule 1, CINC-1, and CINC-3 levels. This was accompanied by a decrease in intestinal p38 MAPK activity. Administration of resveratrol improved all of the above parameters. Resveratrol treatment also increased intestinal heme oxygenase 1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Administration of ICI 182,780, SB-203850, or chromium-mesoporphyrin with resveratrol abolished the resveratrol-mediated improvement of the above parameters. Resveratrol administration also attenuated trauma-hemorrhage-induced cardiac dysfunction and edema of the lung. These results suggest that estrogen receptor-dependent upregulation of the p38 MAPK/heme oxygenase 1 pathway plays a critical role in mediating the salutary effects of resveratrol on shock-induced intestinal injury.

Topics: Animals; Chemokine CXCL1; Chemokine CXCL2; Heme Oxygenase-1; Intercellular Adhesion Molecule-1; Interleukin-6; Intestinal Mucosa; Intestines; Male; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Resveratrol; Shock, Hemorrhagic; Stilbenes; Tumor Necrosis Factor-alpha; Wounds and Injuries

Astringinin can attenuate organ injury following trauma-hemorrhage, the mechanism remains unknown. Protein kinase B/hemeoxygenase-1 (Akt/HO-1) pathway exerts potent anti-inflammatory effects in various tissues. The aim of this study is to elucidate whether Akt/HO-1 plays any role in astringinin-mediated attenuation of hepatic injury following trauma-hemorrhage. For study this, male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 35-40 mmHg for 90 min) followed by fluid resuscitation. A single dose of astringinin (0.3 mg/kg body weight) with or without a PI3K inhibitor (wortmannin) or a HO antagonist (chromium-mesoporphyrin) was administered during resuscitation. Various parameters were measured at 24 h post-resuscitation. Results showed that trauma-hemorrhage increased plasma aspartate and alanine aminotransferases (AST and ALT) concentrations and hepatic myeloperoxidase activity, cytokine induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1, and interleukin-6 levels. These parameters were significantly improved in the astringinin-treated rats subjected to trauma-hemorrhage. Astringinin treatment also increased hepatic Akt activation and HO-1 expression as compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of wortmannin or chromium-mesoporphyrin abolished the astringinin-induced beneficial effects on post-resuscitation pro-inflammatory responses and hepatic injury. These findings collectively suggest that the salutary effects of astringinin administration on attenuation of hepatic injury after trauma-hemorrhage are likely mediated via Akt dependent HO-1 up-regulation.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemokine CXCL1; Chemokine CXCL2; Heme Oxygenase-1; Hemorrhage; Intercellular Adhesion Molecule-1; Interleukin-6; Liver; Male; Peroxidase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Stilbenes; Wounds and Injuries

Although studies have demonstrated that resveratrol administration following adverse circulatory conditions is known to be protective, the mechanism by which resveratrol produces the salutary effects remains unknown. We hypothesized that resveratrol administration in males following trauma-hemorrhage decreases cytokine production and protects against lung injury. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min, then resuscitation). A single dose of resveratrol (30 mg/kg of body weight) or vehicle was administered intravenously during resuscitation. Twenty-four hours thereafter, tissue myeloperoxidase activity (a marker of neutrophil sequestration), cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule (ICAM)-1, and interleukin (IL)-6 levels in the lung and protein concentrations in bronchoalveolar lavage fluid were measured (n = 6 rats/group). One-way ANOVA and Tukey's test were used for statistical analysis. Trauma-hemorrhage increased lung myeloperoxidase activity, CINC-1, CINC-3, ICAM-1, and IL-6 levels and protein concentrations in bronchoalveolar lavage fluid. These parameters were significantly improved in the resveratrol-treated rats subjected to trauma-hemorrhage. The salutary effects of resveratrol administration on attenuation of lung injury following trauma-hemorrhage are likely due to reduction of pro-inflammatory mediators.

Topics: Animals; Cytokines; Hemorrhage; Intercellular Adhesion Molecule-1; Male; Peroxidase; Pneumonia; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Wounds and Injuries