Purpose:To investigate the effect of end-stage kidney disease (ESKD) factor on the sedative effects of ciprofol. Patients and Methods:Elective kidney transplant recipients aged 18-64 years, with a body mass index (BMI) of 18.5-24.0 kg/m2, Mallampati class I or II, interincisor distance ≥ 3.5 cm, and undergoing regular preoperative dialysis were enrolled. A matched control group with normal kidney function was included for comparison. The Dixon's up-and-down method was used to determine the median effective dose (ED50) of ciprofol required to suppress the response to I-gel insertion. Secondary outcomes included ciprofol consumption during anesthesia maintenance, recovery time, perioperative hemodynamic changes, and adverse events. The total dosage of ciprofol used for anesthesia maintenance was recorded, and average ciprofol consumption per unit time per body weight was calculated. Results:No statistically significant difference were observed in the ED50 or 95% confidence interval (CI) of ciprofol for suppressing the I-gel insertion response between the ESKD and control groups. Similarly, recovery time and mean ciprofol consumption during anesthesia maintenance were comparable between groups. Hemodynamic parameters remained stable throughout the perioperative period in both groups, with no significant intergroup differences. The incidence of adverse events, including hypotension, bradycardia, and respiratory depression, was also comparable between groups. Conclusion:ESKD appears to have no significant effect on the sedative efficacy, anesthetic consumption, recovery profile, or safety of ciprofol.

Abstract Background Patients with moyamoya disease frequently experience delayed postoperative recovery. The impact of different anesthetic techniques on recovery quality remains uncertain. This study compared the effects of propofol-based total intravenous anesthesia and sevoflurane-based inhalational anesthesia on postoperative recovery in these patients. Methods Seventy-six patients scheduled for elective revascularization surgery were randomized to either propofol TIVA or sevoflurane inhalational anesthesia. Anaesthesia in the propofol group was maintained by intravenous infusion of propofol. Anaesthesia in the sevoflurane group was maintained by inhalation of sevoflurane. The primary outcome was the Quality of Recovery-15 (QoR-15) score on postoperative days 1–3. Secondary outcomes included Postoperative nausea and vomiting, pain, sleep quality, delirium, postoperative complications, and length of hospital stay. Results Seventy-three patients were included in the analysis. No significant differences were observed in QoR-15 scores between the groups at any timepoint. The sevoflurane group required higher doses of norepinephrine, more intraoperative fluids, and produced greater urine output. Although extubation time was longer in the propofol group, these patients required fewer rescue antiemetics and reported better sleep quality on the first postoperative day. Conclusions Neither propofol nor sevoflurane anesthesia significantly influenced overall recovery quality. This study provides a conceptual framework and evidence-based support for individualized anesthesia management in vulnerable populations, such as patients with cerebrovascular diseases. Trial registration: This study was registered with the China Ethics Committee of Registering Clinical Trials, Sichuan, China (ChiCTR2400087467; date: July 29, 2024).

Purpose: As a novel benzodiazepine sedative, remimazolam has demonstrated favorable anesthetic properties. However, its clinical performance in patients undergoing renal allograft transplantation remains undetermined. This study aimed to evaluate the efficacy of remimazolam for anesthesia in patients undergoing renal allograft transplantation, with the incidence of hypotension during induction as the primary endpoint. Patients and Methods: Sixty patients scheduled for elective living-related renal transplantation were enrolled. The participants were randomly allocated into two groups (n=30 each): the propofol group (Group P) and the remimazolam group (Group R). Groups P and R received propofol and remimazolam, respectively, for anesthesia induction and maintenance. The patients' hemodynamic parameters, postoperative recovery outcomes, adverse reactions, and pharmacokinetic parameters of the sedative drugs were recorded and compared between groups. Results: Compared with propofol, remimazolam has a longer onset time, but provides better hemodynamic stability, more rapid metabolism, negligible injection pain, and no significant impact on hepatic or renal function. Conclusion: Despite its prolonged onset time, remimazolam provides better hemodynamic stability and less injection pain than propofol in patients undergoing allogeneic renal transplantation, with comparable recovery outcomes. Its rapid metabolism is evidenced by a prompt decline in plasma concentration following discontinuation.

Purpose:Prospective evidence on sex-based variability in the sedative potency of dexmedetomidine remains limited. This study aimed to estimate and compare the median effective dose (ED50) of dexmedetomidine for preoperative sedation in adult men and women undergoing elective upper limb surgery. Patients and Methods:In this prospective, single-center, assessor-blinded, dose-finding study, adult patients aged 18 to 60 years scheduled for upper limb surgery were allocated to male and female dexmedetomidine groups according to biological sex. Dexmedetomidine was administered intravenously over 15 minutes using a modified Dixon's up-and-down sequential method (initial dose 1.0 μg/kg; step size 0.05 μg/kg). Adequate sedation was defined as a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale score < 3 at 26 minutes from infusion start. The primary endpoint was the Dixon-derived ED50, with supportive analyses including probit regression, bootstrap validation, and multivariable logistic regression adjusted for baseline covariates. Secondary outcomes included sedation depth and adverse events. Results:Forty-six patients (23 per group) were enrolled. The Dixon-derived ED50 (95% confidence interval) was 1.26 μg/kg (1.17-1.35) in men and 1.28 μg/kg (1.17-1.38) in women, with overlapping confidence intervals. Probit regression and bootstrap-validated ED50 estimates were consistently similar between groups. In multivariable analysis, sex was not independently associated with adequate sedation (P = 0.275), whereas dexmedetomidine dose was a significant predictor. At 26 minutes, neither MOAA/S scores nor bispectral index (BIS) values differed significantly between sexes. Bradycardia occurred in 39.1% of males versus 34.8% of females, and hypertension in 13.0% versus 4.3%, respectively; all adverse events were transient and safely managed. Conclusion:No clinically meaningful sex-related difference was observed in dexmedetomidine ED50 under standardized preoperative conditions. These findings do not support routine sex-based dose adjustment for preoperative sedation in relatively healthy adults.

BACKGROUND:Bone cancer pain (BCP) remains a significant clinical challenge with poorly understood mechanisms. While Th17 and Treg cells have been implicated in pain pathways, their specific roles in BCP pathogenesis require further investigation. Salidroside (SAL), a natural compound with anti-inflammatory properties, shows potential for pain management but its mechanism in BCP is unclear. PURPOSE:This study aimed to investigate SAL's analgesic effects in BCP and elucidate its mechanism of action through the AMPK/SIRT1 pathway and Th17/Treg cell regulation. STUDY DESIGN:Experimental animal study using a well-established BCP mouse model with pharmacological interventions and cellular/molecular analyses. METHODS:C57BL/6 mice were used to establish a BCP model via tumor cell implantation. Behavioral tests assessed mechanical allodynia and thermal hyperalgesia. Flow cytometry analyzed spinal cord Th17/Treg populations, while Western blotting evaluated AMPK/SIRT1 pathway proteins. Pharmacological interventions included SAL administration, IL-17 neutralization, and AMPK/SIRT1 pathway modulation. RESULTS:SAL treatment significantly alleviated pain behaviors in BCP mice (p < 0.01). Cellular analyses revealed SAL restored Th17/Treg balance by reducing Th17 markers (IL-17, RORγt, p-STAT3) and increasing Treg markers (FOXP3, p-STAT5). SAL activated the AMPK/SIRT1 pathway, while pathway inhibitors reversed SAL's therapeutic effects, confirming the mechanism. CONCLUSION:SAL effectively alleviates BCP by modulating Th17/Treg cell differentiation through AMPK/SIRT1 pathway activation. These findings suggest SAL's potential as a novel immunomodulatory therapy for BCP management.

Background The TREM2 signaling pathway is activated in multiple pain conditions; nevertheless, its role in the regulation of bone cancer pain remains largely unexplored. The persistent pathological progression of bone cancer pain induces microglial overstimulation, leading to the exacerbation of spinal central inflammation. These results confound the neurobehavioral symptoms and obscure the underlying mechanisms. Thus, the precise mechanism by which TREM2 induces bone cancer pain (BCP) has yet to be clarified. Methods Lewis lung carcinoma cells (LLC) were administered into the femoral bone marrow cavity of adult male C57BL/6J mice. Nociceptive responses were assessed utilizing von Frey and Hargreaves methods. Biochemical analysis was utilized to assess mRNA expression levels of relevant proteins and inflammatory markers in the spinal cords of the subjects, while immunofluorescence analysis was used to assess alterations in the quantity of activated microglial cells. Results We found that the expression levels of TREM2/DAP12 genes were increased in the spinal cords of BCP mice and may influence microglial activity via activation of the PI3K/Akt signaling pathway. The intrathecal delivery of TREM2-shRNA, combined with the selective PI3K inhibitor LY2494002, significantly inhibited the overactivation of microglia in pathological states, reduced the secretion of inflammatory mediators, and consequently mitigated central neuroinflammation while reversing pain sensitization in BCP mice. Conversely, intrathecal overexpression of the TREM2 gene can also induce abnormal pain responses. Conclusion TREM2 may be the key gene involved in the hyperalgesia induced by excessive activation of spinal microglia under pathological conditions of bone cancer, which depends on the phosphorylation of the PI3K/Akt signaling axis.

Purpose:The current study aimed to compare the effects of norepinephrine and phenylephrine on tissue oxygenation and clinical outcomes in Moyamoya disease patients. Patients and Methods:Sixty patients scheduled for superficial temporal artery-middle cerebral artery bypass were randomly assigned to either the norepinephrine group or the phenylephrine group. Standard doses of norepinephrine or phenylephrine were infused during surgery to maintain blood pressure fluctuating within ± 10% of baseline values. Cerebral oxygenation, muscle oxygenation, cardiac output, and urine volume were recorded at several timepoints: Before preoxygenation, After intubation, Skin cutting, Superficial temporal artery exposing, Middle cerebral artery exposing, and End of the surgery. Additionally, blood samples were collected from the superior vena cava and radial artery for blood gas analysis, to assess central venous oxygen saturation, blood lactate and calculate oxygen extraction rate. Length of hospital stay, incidence of neurological complications during hospitalization and mortality within 90 days were also recorded. Results:Compared with phenylephrine group, the norepinephrine group exhibited significantly higher cerebral oxygenation, muscle oxygenation and cardiac output at Superficial temporal artery exposing, Middle cerebral artery exposing, and End of the surgery (P<0.05). No significant difference was observed between groups at any timepoints regarding urine output, central venous oxygen saturation, blood lactate levels, oxygen extraction rate. Length of hospital stay, incidence of neurological complications during hospitalization and 90-day mortality rate were comparable between groups. Conclusion:The use of norepinephrine, in contrast to phenylephrine, for managing hypotension during superficial temporal artery-middle cerebral artery bypass significantly enhances tissue oxygenation, which may be related to the effective maintenance of cardiac output by norepinephrine.

Transformed from p-phenylenediamines (PPDs) antioxidant, PPD-derived quinones (PPD-Qs) have recently been recognized as emerging contaminants due to their potential negative impacts on the environment and human health. While there have been measurements of airborne PPD-Qs, the size distribution of PPD-Qs and the impact of particle size on PPD transformation chemistry remain largely unknown. Here, through the measurements of atmospheric particles in three megacities in China (Beijing, Xi'an, and Hefei), we find that PPD-Qs are widely distributed in these cities. Further analysis of the size-fractioned particles in Hefei indicates that 48 % of PPD-Qs reside in coarse particles. Given that previous studies mainly focus on the measurement of PPD-Qs in fine particles, the previously reported PPD-Q concentrations and the corresponding human exposure dosages are likely to be significantly underestimated. Furthermore, the ratio of PPD-Q to PPD concentration (PPD-Q/PPD) for particles with size range of 0.056 - 0.1 μm is up to 3 times higher than that with size range of 10 - 18 μm, highlighting the key role of particle size in determining the atmospheric oxidation reactivity of PPDs. Model simulations reveal a size-dependent pattern for the estimated concentration of particulate PPD-Qs in human body. In addition, we also demonstrate that PPD-Qs can induce the formation of cellular reactive oxygen species, suggesting that they may pose risks to human health. Overall, our results emphasize the importance of considering the particle size effect when evaluating the reaction potential and exposure risk of airborne PPD-Qs.

High-flow nasal oxygen (HFNO) is increasingly used for preoxygenation and apneic oxygenation; however, its efficacy during anesthesia induction for frame-based stereoelectroencephalography (SEEG) remains uncertain. This study evaluated whether HFNO is non-inferior to facemask ventilation in maintaining oxygenation during anesthesia induction for frame-based SEEG. In this randomized, controlled, non-inferiority trial, adult patients with refractory epilepsy undergoing frame-based SEEG were randomized to either the HFNO or facemask group. The primary endpoint was the lowest peripheral oxygen saturation (SpO2). Secondary endpoints included arterial blood gas analyses, hemodynamic measures, airway adjuncts use, first-pass intubation success (FPS), time to secure the airway, anesthesiologist satisfaction, patient comfort, and perioperative complications. Among 46 patients, the median (interquartile range [IQR]) lowest SpO2 was 98 (97–99) https://www.chictr.org.cn/showproj.html?proj=119780 ).

N-(1,3-Dimethylbutyl)-N '-phenyl-p-phenylenediamine-quinone (6PPD-Q) has been detected in human body fluids, with uncertainty about the occurrence of other p-phenylenediamine quinones (PPD-Qs) and their potential toxicities. In this study, following detection of PPD-Qs in human blood and cerebrospinal fluid (CSF), we investigated their toxicities to the blood-brain barrier (BBB). After ethical approval and signed informed consent, 27 participants were enrolled, and 20 blood and 20 CSF samples were collected. High-performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-3Q-MS) was used to detect the PPD-Qs in the samples. Cell biology and molecular biology technologies were applied to investigate the toxicological effects and the mechanisms of PPD-Qs on the BBB model by using human cerebral microvascular endothelial cell line (hCMEC-D3). PPD-Qs were frequently detected in both extracts of serum and CSF samples, with 6PPD-Q, N-isopropyl-N '-phenyl-1,4-phenylenediamine-quinone (IPPD-Q), and N,N '-bis(1,4-dimethylpentyl)-p-phenylenediamine-quinone (77PD-Q) being the most abundant. 77PD-Q and IPPD-Q exhibited greater toxicity compared with 6PPD-Q. 6PPD-Q, IPPD-Q, and 77PD-Q led to endothelial-to-mesenchymal transition (EndMT) of cerebral microvascular endothelial cells by upregulating PAI-1, resulting in BBB dysfunction. However, atorvastatin reversed this process and reduced their toxicities.

Purpose: Ciprofol is a recently developed short-acting gamma-aminobutyric acid receptor agonist with a higher potency than that of propofol. As a new sedative drug, there are few clinical studies on ciprofol. We sought to examine the safety and efficacy of ciprofol use for general anesthesia in neurosurgical individuals undergoing neurosurgical surgery with intraoperative neurophysiological monitoring (IONM). Patients and Methods: This single-center, non-inferiority, single-blind, randomized controlled trial was conducted from September 13, 2022 to September 22, 2023. 120 patients undergoing elective microvascular decompression surgery (MVD) with IONM were randomly assigned to receive either ciprofol or propofol. The primary outcome of this study was the amplitude of intraoperative compound muscle action potential decline, and the secondary outcome included the indexes related to neurophysiological monitoring and anesthesia outcomes. Results: The mean values of the primary outcome in the ciprofol group and the propofol group were 64.7 +/- 44.1 and 53.4 +/- 35.4, respectively. Furthermore, the 95% confidence interval of the difference was - 25.78 to 3.12, with the upper limit of the difference being lower than the non-inferiority boundary of 6.6. Ciprofol could achieve non-inferior effectiveness in comparison with propofol in IONM of MVD. The result during anesthesia induction showed that the magnitude of the blood pressure drop and the incidence of injection pain in the ciprofol group were significantly lower than those in the propofol group (P< 0.05). The sedative drug and norepinephrine consumption in the ciprofol group was significantly lower than that in the propofol group (P< 0.05). Conclusion: Ciprofol is not inferior to propofol in the effectiveness and safety of IONM and the surgical outcome. Concurrently, ciprofol is more conducive to reducing injection pain and improving hemodynamic stability, which may be more suitable for IONM-related surgery, and has a broad application prospect.

This study investigates the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological approach to treating neuropathic pain (NP), a major challenge in clinical research. Conducted on male Sprague-Dawley rats with NP induced through chronic constriction injury of the sciatic nerve, the research assessed pain behaviors and the impact of rTMS on molecular interactions within the amygdala. Through a comprehensive analysis involving Mechanical Withdrawal Threshold (MWT), Thermal Withdrawal Latency (TWL), RNA transcriptome sequencing, RT-qPCR, Western blotting, immunofluorescence staining, and Co-Immunoprecipitation (Co-IP), the study focused on the expression and interaction of integrin αvβ3 and its receptor P2X7R. Findings reveal that rTMS significantly influences the expression of integrin αvβ3 in NP models, suggesting an inhibition of the NP-associated NLRP3 inflammatory pathway through the disruption of integrin αvβ3-P2X7R interactions. These outcomes highlight the potential of rTMS in alleviating NP by targeting molecular interactions within the amygdala, offering a promising therapeutic avenue for managing NP.

BackgroundIn this clinical trial, we evaluated the effects of transcutaneous electroacupoint stimulation (TEAS) on postoperative fatigue (POF) in Parkinson disease (PD) patients undergoing deep brain stimulation (DBS) surgery.MethodsA total 60 PD patients undergoing DBS surgery were enrolled. They were randomized to receive either electrical stimulation [alternative frequency 2/10 Hz, dense and disperse, intensity adjusted to the maximum tolerated by the participants (6-15 mAmp)] via surface electrodes (TEAS group) or surface electrodes only without electrical stimulation (Con group) at bilateral Zusanli and Sanyinjiao acupuncture points. All participants received their assigned intervention (TEAS or Con) during the 1st stage of surgery [(except during microelectrode recording (MER)] and the entire 2nd stage of surgery. Intraoperative anesthetic requirements were adjusted based on bispectral index (BIS) monitor. POF was assessed by Christensen fatigue scales (ChrFS), along with Quality of Recovery-15 (QoR-15) and mini-mental state examination (MMSE) postoperatively over a 7-day-period. We recorded the usage of rescue analgesics and anti-emetics.ResultsFifty-nine patients’ datasets were included for final analyses. Fewer patients in TEAS experienced severe POF (defined as ChrFS ≥6) at T3 than those in the Con group (TEAS vs. Con: 7 vs. 22, p<0.001). During the 1st stage of surgery, more patients in Con group required dexmedetomidine infusion (TEAS vs. Con: 2 vs. 6; P<0.01). Total dosages of propofol and remifanil during the 2nd stage of surgery were TEAS vs. Con: 374.7±61.2 vs 421.5±81.9; p<0.001 and 572.3±82.0 vs. 662±148.2; P<0.001, respectively. Postoperative rescue analgesics (TEAS vs. Con: 2 vs. 6; P<0.001) were used less in the TEAS group. TEAS patients reported better POF, MMSE and QoR15 scores than those in the Con group during most of the assessment period.ConclusionsIntraoperative TEAS decreased the severity of POF, reduced intraoperative anesthetic requirements and facilitated post-DBS recovery in this group of PD patients.

Objective: Frailty, representing the physiological reserve and tolerance of the body, serves as a crucial evaluation index of the overall status of the older adults. This study aimed to investigate the prevalence of preoperative frailty and its impact on postoperative outcomes among older adults with lumbar degenerative disease in China. Patients and Methods: In this prospective study, a total of 280 patients aged 60 and above, diagnosed with lumbar degenerative disease and scheduled for surgical intervention were enrolled. The prevalence of frailty pre-surgery was evaluated using the Tilburg Frailty Indicator (TFI) and the modified Frailty Index 11 (mFI-11). The primary outcome was postoperative complication within 30 days post-surgery. The secondary outcomes were the length of hospital stay, hospital costs, reoperation within 30 days post-surgery and unplanned readmission within 30 days post-discharge. Both univariable and multivariable logistic regression were employed to screen and identify the risk factors predisposing patients to postoperative complications. Results: A total of 272 older adults were included in the study ultimately. The frailty detection rates of TFI and mFI-11 were 15.8% (43/272) and 10.7% (29/272) respectively. Thirty-four patients (12.5%) encountered complications. Significantly elevated rates of complications, prolonged hospital stays, increased hospital costs, and heightened readmission rates were observed in the frail group compared to the non-frail group (P<0.05). Univariable analysis showed that the potential factors related to complications are TFI, mFI11 and albumin. Multivariable logistic regression revealed that TFI was an independent risk factor for postoperative complications (OR=5.371, 95% CI: 2.338-12.341, P < 0.001). Conclusion: Frailty was an independent predictor of postoperative complications in older adults undergoing lumbar fusion surgery. Frailty assessment should be performed in such patients to improve preoperative risk stratification and optimize perioperative management strategies.

Background The present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and duration of mexiletine in rats. Methods Nociceptive blockage was evaluated by the inhibition of response to skin pinpricks in rats via the cutaneous trunci muscle reflex (CTMR). After subcutaneous injection, the analgesic activities of mexiletine in the absence and presence of either dopamine or phenylephrine were assessed. Each injection was standardized into 0.6 ml with a mixture of drugs and saline. Results Subcutaneous injections of mexiletine successfully induced dose-dependent cutaneous analgesia in rats. The results revealed that rats injected with 1.8 μmol mexiletine exhibited 43.75% blockage (%MPE), while rats injected with 6.0 μmol mexiletine showed 100% blockage. Co-application of mexiletine (1.8 or 6.0 μmol) with dopamine (0.06, 0.60, or 6.00 μmol) elicited full sensory block (%MPE). Sensory blockage ranged from 81.25% to 95.83% in rats injected with mexiletine (1.8 μmol) and phenylephrine (0.0059 or 0.0295 μmol), and complete subcutaneous analgesia was observed in rats injected with mexiletine (1.8 μmol) and a higher concentration of phenylephrine (0.1473 μmol). Furthermore, mexiletine at 6.0 μmol completely blocked nociception when combined with any concentration of phenylephrine, while 0.1473 μmol phenylephrine alone exhibited 35.417% subcutaneous analgesia. The combined application of dopamine (0.06/0.6/6 μmol) and mexiletine (1.8/6 μmol) resulted in increased %MPE, complete block time, full recovery time, and AUCs compared to the combined application of phenylephrine (0.0059 and 0.1473 μmol) and mexiletine (1.8/6 μmol) ( p < 0.001). Conclusion Dopamine is superior to phenylephrine in improving sensory blockage and enhancing the duration of nociceptive blockage by mexiletine.

Conditioned pain modulation (CPM) is a quantitative estimation of the capacity for endogenous pain modulation. Reduced CPM enables chronic painful event development or exacerbates pre-existing pain symptoms. Emerging reports indicate that patients with trigeminal neuralgia (TN) have dysregulated endogenous pain modulation. Transauricular vagus nerve stimulation (taVNS) is known to alleviate both acute and chronic pain symptoms. Its role in modulation or management of TN remains unknown. Here, we evaluated the taVNS efficacy in modulating CPM among TN patients. Conclusions from this investigation may facilitate establishment of novel non-invasive adjunctive approaches to treating TN patients. All research work was conducted at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital). In all, we recruited 62 study participants, 31 TN patients and 31 healthy volunteers, for a 2-day experimental test. At the beginning of the experiment (Day 1), all subjects received 30 min of active taVNS. On Day 2, they received sham taVNS with the same duration and intensity. Meanwhile, technicians documented participant pressure pain thresholds (PPT) and CPM values at baseline, and at 15 and 30 min post-active or sham taVNS. A 30-min active taVNS exposure substantially elevated the PPT and CPM effect (P < 0.05) among TN patients, and we also observed a notable rise in the PPT and CPM effect (P < 0.05) among healthy controls. Additionally, there were no serious adverse events from the administered treatment. Exposure to 30 min of active taVNS strongly augmented the CPM effect and elevated the PPT among TN patients and healthy controls. These effects were not observed with sham stimulation. Despite the limitations inherent to survey studies, such as duration and compliance biases, we consider that taVNS is a promising, safe, and cost-effective therapy. In future investigations, we recommend assessment of long-term taVNS application and its effects on CPM and clinical pain. ChiCTR2300078673 ( www.Chictr.org.cn ).

Background:The role of nerve growth factor (NGF)/tyrosine kinase A receptor (TrKA) signaling, which is activated in a variety of pain states, in regulating membrane-associated delta-opioid receptor (mDOR) expression is poorly understood. The hypothesis was that elevated NGF in bone cancer tumors could upregulate mDOR expression in spinal cord neurons and that mDOR agonism might alleviate bone cancer pain. Methods:Bone cancer pain (BCP) was induced by inoculating Lewis lung carcinoma cells into the femoral marrow cavity of adult C57BL/6J mice of both sexes. Nociceptive behaviors were evaluated by the von Frey and Hargreaves tests. Protein expression in the spinal dorsal horn of animals was measured by biochemical analyses, and excitatory synaptic transmission was recorded in miniature excitatory synaptic currents. Results:The authors found that mDOR expression was increased in BCP mice (BCP vs. sham, mean +/- SD: 0.18 +/- 0.01 g vs. mean +/- SD: 0.13 +/- 0.01 g, n = 4, P < 0.001) and that administration of the DOR agonist deltorphin 2 (Del2) increased nociceptive thresholds (Del2 vs. vehicle, median [25th, 75th percentiles]: 1.00 [0.60, 1.40] g vs. median [25th, 75th percentiles]: 0.40 [0.16, 0.45] g, n = 10, P = 0.001) and reduced miniature excitatory synaptic current frequency in lamina II outer neurons (Del2 vs. baseline, mean +/- SD: 2.21 +/- 0.81 Hz vs. mean +/- SD: 2.43 +/- 0.90 Hz, n = 12, P < 0.001). Additionally, NGF expression was increased in BCP mice (BCP vs. sham, mean +/- SD: 0.36 +/- 0.03 vs. mean +/- SD: 0.16 +/- 0.02, n = 4, P < 0.001), and elevated NGF was associated with enhanced mDOR expression via TrKA signaling. Conclusions:Activation of mDOR produces analgesia that is dependent on the upregulation of the NGF/TrKA pathway by increasing mDOR levels under conditions of BCP in mice.

Bone cancer pain (BCP) is refractory to currently used analgesics. Recently, sirtuin 2 (SIRT2) was reported to play a vital role in neuropathic pain but its role in BCP remains unknown. It was hypothesized that spinal SIRT2 attenuates BCP by deacetylating FoxO3a and suppressing oxidative stress. The mouse model of BCP established by injecting tumor cells into the intramedullary space of the femur demonstrated that spinal SIRT2 and FoxO3a were downregulated in BCP development. Intrathecal administration of LV-SIRT2 reduced pain hypersensitivity (mechanical and thermal nociception) in BCP mice. Spinal SIRT2 overexpression upregulated FoxO3a and antioxidant genes (SOD2 and catalase) and inhibited FoxO3a acetylation, phosphorylation, and ubiquitination. Moreover, intrathecal administration of SIRT2 shRNA induced pain hypersensitivity in normal mice. Spinal SIRT2 knockdown downregulated FoxO3a and antioxidant genes and increased FoxO3a acetylation, phosphorylation, and ubiquitination. In summary, spinal SIRT2 increases FoxO3a expression in BCP mice and inhibits oxidative stress by deacetylating FoxO3a and further reducing FoxO3a phosphorylation, ubiquitination, and degradation, leading to BCP relief.

BACKGROUND:Myocardial ischemia/reperfusion (I/R) injury is a fatal event that usually occurs after reperfusion therapy for myocardial infarction. Dexmedetomidine (Dex) has been shown to be beneficial in the treatment of myocardial infarction, however, its underlying mechanism for regulating I/R injury is unclear.METHODS:H9c2 cell and rat models of I/R injury were established via oxygen-glucose deprivation reoxygenation (OGD/R) and occlusion of the left anterior descending branch of coronary artery, respectively. Flow cytometry, MTT, or DHE assay detected cell activity, ROS, or apoptosis, respectively. The expression levels of miR-34b-3p and related mRNAs were determined using qRT-PCR. Related protein expression levels were detected by Western blotting and ELISA test. The interaction between miR-34b-3p and Jagged1 was assessed by dual luciferase reporter and RIP assays. The morphology of cardiac tissue was examined by TTC, HE, and TUNEL labeling.RESULTS:Dex markedly inhibited the inflammatory damage and apoptosis caused by OGD/R in H9c2 cells. MiR-34b-3p and Jagged1 levels were increased and decreased in myocardial I/R injury model, respectively, while Dex reversed this effect. Moreover, miR-34b-3p was firstly reported to directly bind and decrease Jagged1 expression, thereby inhibiting Notch signaling pathway. Transfection of agomiR-34b-3p or Jagged1 silencing eliminated Dex's defensive impact on OGD/R-induced cardiomyocytes damage. Dex relieved the myocardial I/R injury of rats via inhibiting miR-34b-3p and further activating Notch signaling pathway.CONCLUSION:Dex protected myocardium from I/R injury via suppressing miR-34b-3p to activate Jagged1-mediated Notch signaling pathway. Our findings revealed a novel mechanism underlying of Dex on myocardial I/R injury.