Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma

Background: Remote precoditioning of trauma (RPCT) confers cardioprotective effects against myocardial ischemia/reperfusion injury, which are mediated by spinal opioid receptors. The aim of this study was to identify the roles of opioid receptor subtypes in the cardioprotective effect of RPCT and possible mechanisms. Methods: In this study, 192 Sprague-Dawley rats were allocated to 12 groups. Except for the sham group, rats in all groups were subjected to myocardial ischemia reperfusion. Rats in the ischemia precondition (IPC) group were treated with IPC. In the RPCT groups, an abdominal incision was made 15 min before inducing ischemia. The selective delta-, kappa-, and mu-opioid receptor antagonists were administered to groups of animals receiving RPCT, respectively. Data were collected for myocardial infarct size, intercellular adhesion molecule 1 (ICAM-1), plasma cardiac troponin I (cTnI) concentrations, activation of protein kinase C epsilon (PKCe) in myocardial cell membranes, and adenosine release in the spinal cord. Results: Compared with the control groups, infarct size, plasma concentrations of cTnI, and myocardial ICAM-1 expression were significantly lower, while adenosine release and PKCe activation were enhanced in the IPC and RPCT groups. Compared with the RPCT group, infarct size, plasma cTnI concentration, and myocardial ICAM-1 expression were greater and adenosine release and PKCe activation were reduced in the mu-opioid receptor antagonist plus RPCT group. Conclusions: The spinal mu-opioid receptor mediated the cardiac protective effect of RPCT. The mechanism may be enhanced by adenosine release in the spinal cord and PKCe activation in the myo­cardium, thereby inhibiting inflammation induced by ischemia/reperfusion injury

Comparison of Different Histone Deacetylase Inhibitors in Attenuating Inflammatory Pain in Rats

Histone deacetylase inhibitors (HDACIs), which interfere with the epigenetic process of histone acetylation, have shown analgesic effects in animal models of persistent pain. The HDAC family comprises 18 genes; however, the different effects of distinct classes of HDACIs on pain relief remain unclear. The aim of this study was to determine the efficacy of these HDACIs on attenuating thermal hyperalgesia in persistent inflammatory pain. Persistent inflammatory pain was induced by injecting Complete Freund’s Adjuvant (CFA) into the left hind paw of rats. Then, HDACIs targeting class I (entinostat (MS-275)) and class IIa (sodium butyrate, valproic acid (VPA), and 4-phenylbutyric acid (4-PBA)), or class II (suberoylanilide hydoxamic acid (SAHA), trichostatin A (TSA), and dacinostat (LAQ824)) were administered intraperitoneally once daily for 3 or 4 days. We found that the injection of SAHA once a day for 3 days significantly attenuated CFA-induced thermal hyperalgesia from day 4 and lasted 7 days. In comparison with SAHA, suppression of hyperalgesia by 4-PBA peaked on day 2, whereas that by MS-275 occurred on days 5 and 6. Fatigue was a serious side effect seen with MS-275. These findings will be beneficial for optimizing the selection of specific HDACIs in medical fields such as pain medicine and neuropsychiatry

Efficacy of Nalbuphine with Flurbiprofen on Multimodal Analgesia with Transverse Abdominis Plane Block in Elderly Patients Undergoing Open Gastrointestinal Surgery: A Randomized, Controlled, Double-Blinded Trial

Objective. To assess different doses of nalbuphine with flurbiprofen compared to sufentanil with flurbiprofen in multimodal analgesia efficacy for elderly patients undergoing gastrointestinal surgery with a transverse abdominis plane block (TAPB). Methods. 158 elderly patients scheduling for elective open gastrointestinal surgery under general anesthesia and TAPB were randomly assigned to four groups according to different doses of nalbuphine with flurbiprofen in postoperative intravenous analgesia (PCIA). Postoperative pain intensity, effective pressing numbers of PCIA, and adverse effects were recorded at 6, 12, 24, and 48 hours after surgery. Results. Postoperative pain intensity, effective pressing numbers, and the incidence of postoperative nausea and vomiting (PONV) were similar among the four groups after surgery, while the severity of PONV was decreased in Group L compared with Group S at 6, 12, and 48 h after surgery. No individual experienced pruritus, respiratory depression, or hypotension. Conclusions. Low dose of nalbuphine (15 μg·kg−1·ml−1) combined with flurbiprofen is superior for elderly patients undergoing elective open gastrointestinal surgery with TAPB in terms of the efficient postoperative analgesia and decreased severity of PONV. This trial is registered with NCT02984865

Perioperative Dexmedetomidine Fails to Improve Postoperative Analgesic Consumption and Postoperative Recovery in Patients Undergoing Lateral Thoracotomy for Thoracic Esophageal Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial

Objectives. Dexmedetomidine is widely used as an adjunct to general anesthesia. In this study, we evaluated the effects of perioperative dexmedetomidine infusion on postoperative analgesia in patients undergoing lateral thoracotomy for thoracic esophageal cancer. Methods. A total of 62 patients undergoing lateral thoracotomy for thoracic esophageal cancer were randomized to receive adjuvant therapy with either dexmedetomidine (0.5 μg/kg intravenous bolus injection for 10 min before induction of anesthesia, followed by continuous infusion of 0.2–0.4 μg/kg/h until the end of surgery, and 0.06 μg/kg/h for 5 days after surgery) or equal volumes of saline. Acute postoperative pain was treated with patient-controlled intravenous sufentanil and flurbiprofen axetil. The primary outcomes of this study were the numbers of analgesic requirements in the first postoperative 72 h. Results. Perioperative dexmedetomidine did not decrease the numbers of analgesic requirements in the first postoperative 72 h (dexmedetomidine group: 12.14 ± 4.76, saline group: 10.89 ± 5.66; p=0.367). Likewise, the groups did not differ with respect to total postoperative analgesic requirements, postoperative pain, perioperative inflammation, blood cell count, incidence of adverse events, surgical recovery (assessed at postoperative days 2 and 5 using the surgical recovery scale), length of hospital stay, hospital cost, incidence of chronic pain, or quality of life. Notably, dexmedetomidine had beneficial effects on decreasing intraoperative opioid consumption and improving postoperative sleep quality. Discussion. Perioperative dexmedetomidine has limited analgesic benefits in lateral thoracotomy for esophageal cancer when added to an opioid-based multimodal anesthetic regimen but can reduce opioid consumption

The combination of cinnamaldehyde and kaempferol ameliorates glucose and lipid metabolism disorders by enhancing lipid metabolism via AMPK activation

Nutrients in diets, especially functional foods, are beneficial in metabolism-related diseases, such as diabetes. Cinnamaldehyde (CA), a natural flavorant, inhibits glycolysis while enhancing glucose storage. Kaempferol (KP), a flavonol in edible plants, inhibits amino acid metabolism and gluconeogenesis. Whether the combination of CA and KP exerts stronger effects in diabetes needs further investigation. In this work, nontargeted metabolomics results confirmed the simultaneous obstruction of glucose and amino acid metabolism by CA and KP. The falling status of the energy supply, demonstrated by the increased ratio of adenosine monophosphate (AMP) /adenosine triphosphate (ATP), was sensed by AMP-activated protein kinase (AMPK). The activation of AMPK in turn enhanced lipolysis and inhibited fatty acid synthesis both in vivo and in vitro. In conclusion, this study indicated that the CA and KP combination ameliorated glucose and lipid metabolism disorders by enhancing lipid metabolism via the activation of AMPK

Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle-Induced Liver Injury

The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN-induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial-induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN-induced liver injury. Furthermore, UCN-induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3-MA, a well-established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN-induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle-induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial-elicited liver toxicity