stilbenes and Postoperative-Complications

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

The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility.

Topics: Aged; Antineoplastic Agents, Phytogenic; Caspase 3; Combined Modality Therapy; Double-Blind Method; Female; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pilot Projects; Placebos; Postoperative Complications; Resveratrol; Stilbenes; Titanium

The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway.

Topics: Administration, Oral; Aging; Animals; Biological Availability; Cognitive Dysfunction; Cytokines; Dose-Response Relationship, Drug; Emulsions; Hippocampus; Inflammation; Inflammation Mediators; Male; Microglia; Postoperative Complications; Rats, Wistar; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. Here we have used a variety of administration routes and combinations of AMPK activators to test this hypothesis. Topical administration of a resveratrol-based cream inhibited acute mechanical hypersensitivity evoked by incision and blocked the development of hyperalgesic priming. We also observed that systemic administration of metformin dose-dependently inhibited incision-evoked mechanical hypersensitivity and hyperalgesic priming. Interestingly, low doses of systemic metformin and local resveratrol that had no acute effect were able to mitigate development of hyperalgesic priming. Combined treatment with doses of systemic metformin and local resveratrol that were not effective on their own enhanced the acute efficacy of the individual AMPK activators for post-surgical mechanical pain alleviation and blocked the development of hyperalgesic priming. Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti-nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting.

Topics: AMP-Activated Protein Kinases; Analgesics; Animals; Cells, Cultured; Ganglia, Spinal; Hyperalgesia; Male; Metformin; Mice, Inbred ICR; Neurons; Pain; Pain Threshold; Postoperative Complications; Resveratrol; Signal Transduction; Stilbenes

Intra-abdominal adhesions are a very common complication following abdominal surgery. Our previous studies have demonstrated that the inhibition of inflammation at the sites of peritoneal injury can prevent the formation of intra-abdominal adhesions. Resveratrol is a natural extract with a broad range of anti-inflammatory effects. Therefore, we propose that resveratrol can reduce the formation of intra-abdominal adhesions after surgery. The aim of this study was to investigate the effect of resveratrol on intra-abdominal adhesion prevention in a rat model with surgery-induced peritoneal adhesions.. The cecum wall and its opposite parietal peritoneum were abraded following laparotomy to induce intra-abdominal adhesion formation. Varying doses of resveratrol were administered to the animals. On the eighth day after surgery, the adhesion score was assessed using a visual scoring system. Picrosirius red staining and a hydroxyproline assay were used to assess the amount of collagen deposition in the adhesion tissues. The levels of serum interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and transforming growth factor beta-1 (TGF-β1) were determined by an enzyme-linked immunosorbent assay (ELISA). Western blotting was performed to determine the protein expression of TGF-β1, fibrinogen, and α-smooth muscle actin (α-SMA) in rat peritoneal adhesion tissue. Real-time RT-PCR was performed to quantify the mRNA expression of TGF-β1, fibrinogen, and α-SMA.. Resveratrol significantly reduced intra-abdominal adhesion formation and fibrin deposition in the rat model. Furthermore, resveratrol significantly reduced the serum levels of IL-6, TNF-α, and TGF-β1. The protein and mRNA expression of TGF-β1, fibrinogen, and α-SMA in the rat peritoneum and adhesion tissues were also down-regulated due to resveratrol intervention.. Resveratrol can effectively prevent the formation of postoperative intra-abdominal adhesions in a rat model. This effect may be related to the suppression of inflammatory cytokine expression in the injured peritoneum by resveratrol. This study suggests that resveratrol may be a new and effective anti-adhesive agent that is worthy of further study and has potential application value.

Topics: Abdomen; Actins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Collagen; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Fibrinogen; Interleukin-6; Male; Peritoneum; Postoperative Complications; Rats, Sprague-Dawley; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Tissue Adhesions; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Adhesion formation is one of the most important problems occuring after pelvic surgery in the majority of women. The aim of this experimental study was to investigate the effects of the antioxidant resveratrol (3,5,4'-o-trihydroxystilbene) on adhesion formation in a rat uterine horn adhesion model.. Thirty Wistar-Albino female rats were randomly divided into three groups with equal numbers. In Group A, 5.9 mg/kg/day resveratrol was applied by the orogastric route for 10 days before and 20 days after surgery. In Group B, resveratrol was given only for 20 days after surgery. In the control group, no drug was applied before or after surgery. A uterine serosal injury was created using a standard technique after laparotomy in all rats. All animals were sacrificed 3 weeks after surgery and intrapelvic adhesions determined macroscopically and microscopically.. Adhesion formation, total adhesion score and the severity of adhesions were all significantly lower in both resveratrol treatment groups than in the control group (p < 0.05). Notably, the severity of adhesions was much less in Group A in which the rats received resveratrol before and after surgical operation.. This study suggests that 5 ± 1 mg/kg/day perioperative resveratrol administration is an effective strategy for the prevention of postoperative peritoneal adhesion formation after pelvic surgery in a rat model.

Topics: Animals; Antioxidants; Disease Models, Animal; Female; Postoperative Complications; Rats; Rats, Wistar; Resveratrol; Stilbenes; Tissue Adhesions; Uterine Diseases; Uterus

Our aim was to investigate the anti-adhesion potential of resveratrol, a phytoestrogen naturally found in wine, in a rat uterine horn model.. Lesions were created by laparotomy in the uterine horn of 70 rats, randomized before the operation into seven groups consisting of ten animals each: (1) control group, no adjuvant therapy; (2) intraperitoneal (IP) application of the resveratrol dilution vehicle, 10 mg/kg, before closing the laparotomy; (3) subcutaneous (SC) injection of dilution vehicle, 10 mg/kg, 30 min before the operation; (4) IP application of resveratrol, 10 mg/kg, before closing the laparotomy; (5) SC injection of resveratrol, 10 mg/kg, 30 min before the operation; (6) IP application of resveratrol, 10 mg/kg, before closing the laparotomy and continued SC daily for 5 days; and (7) SC injection of resveratrol, 10 mg/kg, 30 min before the operation and continued SC daily for 5 days. On the 14th postoperative day adhesion scores were determined. Levels of thiobarbituric acid-reactive substances and total antioxidant capacity (TAC) were also measured.. In animals treated with repeated SC resveratrol, adhesions were graded as significantly less severe than in the vehicle control group or the groups treated with resveratrol IP or IP plus SC. TAC of control group rats was significantly lower than that of animals treated with repeated SC resveratrol.. Repeated SC resveratrol significantly reduces adhesion formation.

Topics: Animals; Antioxidants; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Postoperative Complications; Rats; Rats, Wistar; Resveratrol; Stilbenes; Thiobarbituric Acid Reactive Substances; Tissue Adhesions

Topics: Blastomycosis; Hypersensitivity; Postoperative Complications; Probability; Stilbamidines; Stilbenes