κ-Opioid receptor activation attenuates osteoarthritis synovitis by regulating macrophage polarization through the NF-κB pathway.

Osteoarthritis (OA) is a prevalent and chronic joint disease that affects the aging population, causing pain and disability. Macrophages in synovium are important mediators of synovial inflammatory activity and pathological joint pain. Previous studies have demonstrated the significant involvement of κ-opioid receptor (KOR) in the regulation of pain and inflammation. Our study reveals a significant reduction in synovial KOR expression among patients and mice with OA. Here, we find that KOR activation effectively inhibits the expressions of the LPS-induced-inflammatory cytokines TNF-α and IL-6 by inhibiting macrophage M1 phenotype. Mechanistically, KOR activation effectively suppresses the proinflammatory factor secretion of macrophages by inhibiting the translocation of NF-κB into the nucleus. Our animal experiments reveal that activation of KOR effectively alleviates knee pain and prevents synovitis progression in OA mice. Consistently, KOR administration suppresses the expressions of M1 macrophage markers and the NF-κB pathway in the synovium of the knee. Collectively, our study suggests that targeting KOR may be a viable strategy for treating OA by inhibiting synovitis and improving joint pain in affected patients.

Effectiveness of single loading dose of dexmedetomidine combined with propofol for deep sedation of endoscopic retrograde cholangiopancreatography (ERCP) in elderly patients: a prospective randomized study.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced endoscopic procedure and requires deep sedation. Deep sedation with dexmedetomidine for the respiratory drive preserved has become popular in recent years. However, the use of dexmedetomidine in elderly patients is controversial because its adverse events are more common. The objective of this study was to investigate the effectiveness of a single loading dose of dexmedetomidine combined with propofol for deep sedation of ERCP in elderly patients. METHODS: In this prospective randomized trial, 49 elderly patients undergoing ERCP were randomly allocated to the dexmedetomidine (DEX) or propofol (PRO) groups. The single loading dose of dexmedetomidine was set at 0.5 µg/kg at the start of anesthesia induction and loading for 10 min. The primary outcome was the cumulative dose of propofol. Secondary outcomes included time to awake, the frequency of airway interventions, and hemodynamics. RESULTS: The intraoperative cumulative dose of propofol was lower in the DEX group (111.0 ± 12.6 µg/kg/min) than the PRO group (143.7 ± 23.4 µg/kg/min) (P < 0.001). There was no statistically significant difference in the time to awake between the two groups. The incidence of artificial airway interventions and hypotension in the PRO group (36%, 60%) were significantly higher than those in the DEX group (4.2%, 16.7%) (P = 0.011, P = 0.003, respectively). In addition, the occurrence of bradycardia increased significantly in the DEX group (58.3%) compared with the PRO group (12%) (P < 0.001). CONCLUSIONS: The single loading dose of dexmedetomidine combined with propofol can reduce propofol consumption and artificial airway intervention and provide better hemodynamic stability than propofol for deep sedation in elderly patients during ERCP. TRIAL REGISTRATION: www.chictr.org.cn (Registration number ChiCTR1900028069, Registration date 10/12/2019).

MAGL regulates synovial macrophage polarization vis inhibition of mitophagy in osteoarthritic pain.

Pain is the hallmark symptom of osteoarthritis (OA), and current analgesic treatments may be insufficient or have potentially adverse effects. The inhibition of Monoacylglycerol lipase (MAGL) produces anti­inflammatory and anti­nociceptive effects. However, the potential mechanism of MAGL in OA pain remains unclear. In the present study, the synovial tissues were removed from OA patients and mice. Immunohistochemical staining and western blotting were used to detect the expression of MAGL. M1 and M2 polarization markers were detected by flow cytometry and western blotting, and the mitophagy levels were detected by the immunofluorescence staining of mitochondrial autophagosomes with lysosomes and western blotting. The OA mice were intraperitoneally injected with MJN110 to inhibit MAGL once a day for a week. Mechanical and thermal pain thresholds were detected by electronic Von Frey and hot plate methods on days 0, 3, 7, 10, 14, 17, 21, and 28. The accumulation of MAGL in the synovial tissues of OA patients and mice promoted the polarization of macrophages towards an M1 phenotype. Pharmacological inhibition and siRNA knockdown of MAGL promoted polarization of M1 macrophages towards an M2 phenotype. MAGL inhibition increased the mechanical and thermal pain thresholds of OA mice and enhanced the mitophagy levels of M1 macrophages. In conclusion, in the present study, it was shown that MAGL regulated synovial macrophage polarization by inhibiting mitophagy in OA.

REPIN1 regulates iron metabolism and osteoblast apoptosis in osteoporosis.

Osteoporosis is not well treated due to the difficulty of finding commonalities between the various types of it. Iron homeostasis is a vital component in supporting biochemical functions, and iron overload is recognized as a common risk factor for osteoporosis. In this research, we found that there is indeed evidence of iron accumulation in the bone tissue of patients with osteoporosis and REPIN1, as an origin specific DNA binding protein, may play a key role in this process. We revealed that sh-Repin1 therapy can rescue bone loss in an iron-overload-induced osteoporosis mouse model. Knockdown of Repin1 can inhibit apoptosis and enhance the resistance of osteoblasts to iron overload toxicity. REPIN1 promoted apoptosis by regulating iron metabolism in osteoblasts. Mechanistically, knockdown of Repin1 decreased the expression of Lcn2, which ameliorated the toxic effects of intracellular iron overload. The anti-iron effect of lentivirus sh-Repin1 was partially reversed or replicated by changing LCN2 expression level via si-RNA or plasmid, which indirectly verified the key regulatory role of LCN2 as a downstream target. Furthermore, the levels of BCL2 and BAX, which play a key role in the mitochondrial apoptosis pathway, were affected. In summary, based on the results of clinical specimens, animal models and in vitro experiments, for the first time, we proved the key role of REPIN1 in iron metabolism-related osteoporosis.

Dexmedetomidine alleviates osteoarthritis inflammation and pain through the CB2 pathway in rats.

As a common joint disease, osteoarthritis (OA) is often associated with chronic pain. Synovial inflammation is correlated with OA progression and pain. Synovial inflammation can produce a series of destructive substances, such as inflammatory factors and pain mediators, which aggravate cartilage injury and further accelerate the progression of OA. Although many studies investigated the effects of synovial inflammation on the onset and progression of OA, there are limited reports regarding slowing the progression of OA and relieving pain by modulating synovial inflammation. Therefore, there is an urgent need to search for safe and effective drugs to alleviate synovial inflammation. Dexmedetomidine, a selective α2 agonist, has been shown to have anti-inflammatory and analgesic effects. However, its role and mechanism in OA remain unclear. Here, the effects and mechanisms of dexmedetomidine in OA synovial inflammation were investigated both in vivo and in vitro. We observed that dexmedetomidine stunted LPS-induced migration and invasion of FLSs and the expression of inflammatory factors by upregulating cannabinoid receptor type 2 (CB2) expression. Surprisingly, the application of AM630 (CB2 antagonist) reversed this therapeutic effect. The results of the animal experiments showed that dexmedetomidine reduced synovial inflammation and increased the pain threshold in an OA rat model. These preliminary results imply that dexmedetomidine may be an effective compound for OA treatment.

MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the α/ß hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA.

miR-34a overexpression protects against hippocampal neuron damage caused by ketamine-induced anesthesia in immature rats through the Notch-1/NF-κB signaling pathway.

OBJECTIVE: To investigate the protective effect of miR-34a overexpression on hippocampal neuron damage caused by ketamine-induced anesthesia in immature rats and the underlying mechanism. METHODS: A total of 48 male SD rats were divided into control group (CG, n=12), ketamine group (KG, n=12), negative control group (NCG, n=12), and intervention group (IG, n=12) by using the random number table method. Neurological function, cognitive function, pathological changes of brain tissues, inflammatory cytokines, as well as mRNA expression levels of Notch-1, NICD, RBP-JK, and Hes-1 in brain tissues were detected in the four groups. RESULTS: The scores of auricular, paw withdrawal, corneal reflex, and escape reflexes of IG were higher than those of KG and NCG (P<0.05). At day 3 after intervention, the escape latency, time of staying in the quadrants of original platform, and times of crossing the quadrants of original platform of IG were lower than those of KG and NCG (P<0.05). HE staining results revealed that the morphology and structure of a few neurons and glial cells in IG were changed, and the intercellular space was increased. The brain tissues of NCG demonstrated marked neuron damage with unclear structure; these changes were less significant for KG. The levels of TNF-α, IL-1ß, and IL-6 of IG were lower than those of KG and CG (P<0.05). CONCLUSIONS: miR-34a overexpression exhibited a potent protective effect on hippocampal neuron damage caused by ketamine-induced anesthesia in immature rats.

Sevoflurane protects against hepatic ischemia/reperfusion injury by modulating microRNA-200c regulation in mice.

This present study was aimed to investigate the molecular mechanisms involved in sevoflurane protection of hepatic ischemia-reperfusion (I/R) injury. Firstly, we investigated the protective effects of sevoflurane against hepatic I/R injury. Biochemical analysis results showed that sevoflurane preconditioning significantly protected against hepatic I/R injury by reducing liver enzymes and improving antioxidant defense markers. We also found that sevoflurane attenuates I/R-induced hepatic cell death, by TUNEL staining, DNA fragmentation ELISA and PARP activity determination. Next, In order to find the molecular mechanism of sevoflurane preconditioning in hepatic I/R injury, we poured our attention to microRNAs regulation. We focused on miR-200c, one of microRNAs which screened from the gene expression omnibus (GEO). Furthermore, a hydrogen peroxide (H2O2)-induced oxidative stress apoptosis model was also established to mimic hepatic I/R injury, the effects of MiR-200c was investigated. We observed that MiR-200c inhibition decreased the H2O2-induced apoptosis of hepatic AML-12 cells. And also, ZEB1 is found as a target gene of miR-200c and is involved in H2O2-induced apoptosis. On the other hand, the in vivo model was established to examine whether sevoflurane protect against hepatic IR injury by downregulating MiR-200c. Together with the biochemical tests and apoptosis detection, results showed that over-expression of miR-200c significantly inhibited the protect effect of sevoflurane in Hepatic IR injury. Summarizing, sevoflurane preconditioning seems to ameliorate hepatic I/R injury in mice, mediated by mechanisms that include microRNA 200c down regulation. However, further more studies need to be carried out to verify this point.

Effects of epidural anesthesia and postoperative epidural analgesia on immune function in esophageal carcinoma patients undergoing thoracic surgery.

Thoracic epidural anesthesia (TEA) has been demonstrated to significantly reduce stress and immune dysfunction in trauma patients. In esophageal carcinoma patients undergoing thoracic surgery, TEA combined with general anesthesia during surgery and subsequent postoperative patient-controlled epidural analgesia (PCEA) may improve plasma cortisol (Cor), interleukin (IL)-6 and IL-17 levels and helper T-cell differentiation. A total of 60 esophageal carcinoma patients undergoing thoracic surgery were randomly allocated into groups I, II, III and I (n=15 per group). During surgery, groups I and II received total intravenous general anesthesia (TIVA), whereas groups III and IV received combined TEA and TIVA. Postoperatively, groups I and III received postoperative patient-controlled intravenous analgesia (PCIA), while groups II and IV received PCEA. The Cor, IL-6, IFN-γ, IL-4 and IL-17 levels were measured in peripheral blood samples collected prior to anesthesia (T0), at 2 h after incision (T1), at 4 h postoperatively (T2), at 24 h postoperatively (T3) and at 48 h postoperatively (T4). The plasma Cor, IL-17 and IL-6 levels increased significantly at the beginning of the operation in groups I, II and III, while in group IV there were no significant differences during the entire period, concurrent with enhanced Th0 to Th2 shift, contributing to a Th2-dominant Th1/Th2 ratio. General anesthesia with TEA more efficiently inhibited the onset of the Th2-dominant status and decreased the plasma levels of Cor and IL-6 compared to general anesthesia alone and PCEA inhibited the Th2-dominant status more efficiently compared to PCIA. Therefore, general anesthesia combined with TEA and sole administration of PCEA were demonstrated to inhibit the stress response and minimize immune dysfunction, generating most pronounced results upon combination TEA/PCEA treatment.

Effects of different priming doses of fentanyl on fentanyl-induced cough: a double-blind, randomized, controlled study.

BACKGROUND: Fentanyl-induced cough is not an uncommon phenomenon during the induction of general anesthesia. A preliminary randomized controlled study was designed to observe the effects of different priming doses of fentanyl on fentanyl-induced cough during induction of anesthesia. METHODS: Four hundred patients were randomized into four groups (n = 100 for each). Group I received 5 ml saline 0.9% 1 min before administration of fentanyl 2.5 µg/kg; group II received pre-emptive fentanyl 0.5 µg/kg 1 min before administration of fentanyl 2 µg/kg; group III received pre-emptive fentanyl 1 µg/kg 1 min before administration of fentanyl 1.5 µg/kg; and group IV received pre-emptive fentanyl 1.5 µg/kg 1 min before administration of fentanyl 1 µg/kg. The severity of cough was graded as none (0), mild (1-2), moderate (3-4), or severe (5 or more episodes). We defined T1 and T2 as the 1 min periods after the first and second injections, respectively, and recorded the number of patients whose first cough happened in the T1 or T2 period. RESULTS: The incidences of fentanyl-induced cough were 68%, 5%, 40% and 64% in groups I, II, III and IV, respectively. The incidence of cough in group II was lower than those in groups III and IV in the T1 period. The incidences of cough in groups II, III and IV were lower than that in group I in the T2 period. CONCLUSIONS: In summary, a priming dose of fentanyl 0.5 µg/kg suppressed fentanyl-induced cough during induction of anesthesia in clinical practice. Fentanyl-induced cough was positively correlated with the dose of fentanyl.