OBJECTIVE: To explore the therapeutic effects and underlying mechanisms of Dendrobium officinale (Tiepi Shihu) extract (DOE) on insomnia. METHODS: Forty-two male Sprague-Dawley rats were randomly divided into 6 groups (n=7 per group): normal control, model control, melatonin (MT, 40 mg/kg), and 3-dose DOE (0.25, 0.50, and 1.00 g/kg) groups. Rats were raised in a strong-light (10,000 LUX) and -noise (>80 db) environment (12 h/d) for 16 weeks to induce insomnia, and from week 10 to week 16, MT and DOE were correspondingly administered to rats. The behavior tests including sodium pentobarbital-induced sleep experiment, sucrose preference test, and autonomous activity test were used to evaluate changes in sleep and emotions of rats. The metabolic-related indicators such as blood pressure, blood viscosity, blood glucose, and uric acid in rats were measured. The pathological changes in the cornu ammonis 1 (CA1) region of rat brain were evaluated using hematoxylin and eosin staining and Nissl staining. Additionally, the sleep-related factors gamma-aminobutyric acid (GABA), glutamate (GA), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) were measured using enzyme linked immunosorbent assay. Finally, we screened potential sleep-improving receptors of DOE using polymerase chain reaction (PCR) array and validated the results with quantitative PCR and immunohistochemistry. RESULTS: DOE significantly improved rats' sleep and mood, increased the sodium pentobarbital-induced sleep time and sucrose preference index, and reduced autonomic activity times (P<0.05 or P<0.01). DOE also had a good effect on metabolic abnormalities, significantly reducing triglyceride, blood glucose, blood pressure, and blood viscosity indicators (P<0.05 or P<0.01). DOE significantly increased the GABA content in hippocampus and reduced the GA/GABA ratio and IL-6 level (P<0.05 or P<0.01). In addition, DOE improved the pathological changes such as the disorder of cell arrangement in the hippocampus and the decrease of Nissel bodies. Seven differential genes were screened by PCR array, and the GABA_A receptors (Gabra5, Gabra6, Gabrq) were selected for verification. The results showed that DOE could up-regulate their expressions (P<0.05 or P<0.01). CONCLUSION DOE demonstrated remarkable potential for improving insomnia, which may be through regulating GABA_A receptors expressions and GA/GABA ratio.
Animals ; Dendrobium/chemistry* ; Rats, Sprague-Dawley ; Male ; Sleep Initiation and Maintenance Disorders/blood* ; Plant Extracts/therapeutic use* ; Receptors, GABA-A/metabolism* ; Noise/adverse effects* ; Light/adverse effects* ; gamma-Aminobutyric Acid/metabolism* ; Sleep/drug effects* ; Rats ; Receptors, GABA/metabolism*

Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.

Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Objective To discuss the application effect of intravenous anesthesia with oxycodone plus propofol or oliceridine plus propofol for sedating elderly patients during endoscopic retrograde cholangiopancreatography(ERCP).Methods Sixty elderly patients,who were planned to receive ERCP in Shengli Oilfield Central Hospital from March to Sepcember 2024,were randomly divided into oxycodone group and oliceridine group,with 30 patients in each group.Intravenous anesthesia with oxycodone plus propofol or oliceridine plus propofol was adopted for the patients of the corresponding group.The patient's postoperative comfort score,the dosage of propofol used during surgery,the number of additional analgesics administered,the time of patient entering the operation room(T0),3 minutes after analgesia(T1),after anesthesia induction(T2),immediately upon examination(T3),time on arrival at the duodenal papilla(T4),and time on consciousness waking-up(T5)were recorded.The surgical time,consciousness waking-up time,endoscopist satisfaction degree,patient's satisfaction rate,and incidence of anesthesia-related adverse events were documented.Results The comparison of postoperative comfort scores showed that the score in the oliceridine group was(7.6±1.9)points,which was significantly higher than(6.6±1.3)points in the oxycodone group(t=2.23,P=0.03).The dosage of propofol used during surgery in the oliceridine group was significantly lower than that in the oxycodone group(P＜0.05).The mean arterial pressure(MAP),heart rate(HR),and respiratory rate(RR)at T1-T4 time points were significantly decreased in both groups when compared with their values at T0 time point(all P＜0.05).The reduction degrees of the above indexes at T1-T3 time points in the oxycodone group were more pronounced than those in the oliceridine group(all P＜0.05).At T4,MAP and HR were increased in both groups,which in the oxycodone group were remarkably higher than those in the oliceridine group(both P＜0.05).No statistically significantly difference in oxygen saturation(SpO2)existed between T1 time point and T0 time point(P＞0.05);but at the other time points,SpO2 was decreased to varying degrees in both groups,and the within-group comparison and between-group comparison showed that the differences in SpO2 were statistically significant(all P＜0.05).In oliceridine group,the time of patient's consciousness waking-up was obviously shorter than that in the oxycodone group(P＜0.05),and the endoscopist satisfaction degree and patient satisfaction rate were strikingly higher than those in the oxycodone group(both P＜0.05).The incidence of intraoperative adverse events in the oliceridine group was prominently lower than that in the oxycodone group(P＜0.05).No statistically significant difference in the incidence of adverse events during consciousness waking-up time existed between the two groups(P＞0.05),but the incidences of postoperative nausea,vomiting and respiratory depression in the oliceridine group was obviously lower than those in the oxycodone group(all P＜0.05).Conclusion In performing ERCP for elderly patients,oliceridine plus propofol is clinically safe and feasible with less adverse events,high satisfaction rate and higher patient's comfort level when compared with oxycodone plus propofol.

【Objective】 To explore the therapeutic effect of autologous platelet-rich plasma (PRP) in the treatment of patellofemoral osteoarthritis (PFOA) based on the Magnetic Resonance Observation of Cartilage Repair Tissue 2.0 (MOCART 2.0) knee score system. 【Methods】 A total of 22 patients (28 knees) with PFOA treated by intraarticular PRP injection in our hospital from January 2020 to December 2023 were enrolled in the study. The nuclear magnetic resonance(NMR) images before and after treatment were compared using the MOCART 2.0 knee score system. Visual Analog Scales (VAS) score and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score before and after treatment were evaluated and compared, and adverse reactions were observed during the treatment. 【Results】 The MOCART 2.0 knee score showed no difference before and after treatment (53.4±12.2 vs 49.9±2.1)(P>0.05). In the subgroup analysis, the "signal intensity of the repair tissue" score and the "subchondral changes" score were better than those before treatment as(5.5±1.5)vs(4.6±1.5)and(15.9±4.3)vs(13.2±6.4)(P<0.05). There were no significant changes in indicators as " degree of cartilage filling" , " integration with adjacent cartilage edges" , " repair of tissue surface structure" , " repair of tissue structure" and " bone changes" (P>0.05).The VAS score and WOMAC score gradually decreased at 1 month, 3 months and 6 months after treatment and were better than before treatment (P<0.05). Incidence of adverse reactions was 4% (4/112). 【Conclusion】 Intraarticular PRP injection is an effective and safe option for treatment of PFOA, and can improve the cartilage signal intensity and alleviating subchondral bone edema.

Objective To evaluate the characteristics of the mass balance and pharmacokinetics of[14 C]birociclib in Chinese male healthy volunteers after a single oral administration.Methods This study used a 14 C labeled method to investigate the mass balance and biological transformation of birociclib in human.Subjects were given a single oral dose of 360 mg/50 pCi of[14 C]birociclib suspension after meals.The blood,urine,and fecal samples were collected at specified time points/intervals after administration.The radiation levels of 14 C labeled birociclib-related compounds in the blood,plasma,urine,and feces were analyzed using liquid scintillation counting.In addition,a combination of high-performance liquid chromatography and on-line/off-line isotope detectors was used to obtain radioactive isotope metabolite spectra of plasma,urine,and fecal samples,and high-resolution mass spectrometry was used to identify the main metabolites.Results A total of 6 healthy male subjects were enrolled in this study.The median peak time of radioactive components in plasma was 5.00 h and the average terminal elimination half-life was 43.70 h after administration.The radioactive components were basically excreted and cleared from the body within 288.00 hours after administration,and average cumulative recovery rate of radioactive drugs was(94.10±8.19)％.The radioactive drugs were mainly excreted through feces,accounting for(84.60±7.10)％of the dose of radioactive drugs administered.Urine was the secondary excretory pathway,accounting for 9.41％of the dose of radioactive drugs administered.Metabolic analysis indicated that the prototype drug was the main radioactive components in plasma samples.The main metabolites in plasma were RM4(XZP-5286),RM6(XZP-3584),and RM7(XZP-5736).The drugs were mainly cleared from the body in the form of prototype drugs and metabolites.In addition to prototype drugs,a total of 9 metabolites were identified and analyzed in plasma,urine,and fecal samples,all of which were phase 1 metabolites.The main metabolic and clearance pathways of drugs in the body were deethylation,diisopropylat ion,oxidation,etc.Conclusion After a single oral administration of[14C]birociclib suspension to healthy subjects,it was mainly cleared from the body in the form of prototype drugs and metabolites,with feces as the main excretory pathway and urine as the secondary excretory pathway.Drugs mainly undergo metabolic reactions in the body,such as deethylation,diisopropylation,and oxidation.The subjects were well tolerance after administration.

Objective To explore the effects of low-dose esketamine on the median effective dose(ED50)of ciprofol for sedation in elderly patients undergoing ultrasound-guided transperineal prostate biopsy.Methods Forty-nine elderly male patients,aged 65-75 years,BMI 18.5-30.0 kg/m2,ASA physical stutas Ⅰ-Ⅲ,who underwent ultrasound-guided transperineal prostate biopsy,were randomly as-signed into the esketamine-ciprofol group(group E,n=23)and the ciprofol group(group C,n=26).After intravenous administration of sufentanil 0.1 μg/kg,patients in group E received esketamine 0.2 mg/kg,while patients in group C received the same volume of normal saline.The up-and-down sequential allocation method was used to calculate the effective dose of ciprofol.The initial dose of ciprofol was 0.2 mg/kg in group E and 0.3 mg/kg in group C,and the dose gradient was 0.05 mg/kg for both groups.If there was no body movement during the first puncture of prostate after the loss of eyelash reflex,the ciprofol dose in the next patient was reduced by 0.05 mg/kg.Otherwise,the ciprofol dose in the next patient was in-creased by 0.05 mg/kg.The study was completed until 7 inflection points alternating between non-body movement and body movement achieved.The total amount of ciprofol,surgical time,recovery time,stay in recovery room,hypotension,bradycardia,respiratory depression,injection pain,nausea and vomiting,and adverse reaction of the mental system were recorded.The Probit method was used to calculate the ED50 and 95%effective dose(ED95)with 95%confidence interval(CI)of ciprofol for inhibition of body movement.Results Compared with group C,the total amount of ciprofol in group E was significantly reduced(P＜0.05).There were no significant differences between the two groups in surgical time,recovery time,stay in recovery room,and adverse events.The ED50 of ciprofol in group E was 0.22 mg/kg(95%CI 0.19-0.26 mg/kg),and the ED50 in group C was 0.38 mg/kg(95%CI 0.31-0.46 mg/kg).Compared with group C,the ED50 in group E was significantly reduced(P＜0.05).The ED95 of ciprofol in group E was 0.28 mg/kg(95%CI 0.25-0.49 mg/kg),and the ED95 in group C was 0.51 mg/kg(95%CI 0.44-1.25 mg/kg).Compared with group C,the ED95 in group E was significantly reduced(P＜0.05).Conclusion The ED50 of ciprofol for inhibition of body movement in elderly patients undergoing ultrasound-guided transperi-neal prostate biopsy was 0.38 mg/kg,which was reduced to 0.22 mg/kg by using lose-dose esketamine 0.2 mg/kg as an adjuvant.

Objective To explore the value of 3D black bone sequence for measuring femoral head extrusion index and evaluating Herring classification of Legg-Calvé-Perthes disease(LCPD).Methods Data of hip joint MRI of 38 children with unilateral LCPD were retrospectively analyzed.Femoral head extrusion indices derived from coronal 3D black bone sequence and coronal fat suppression T2WI were compared to those from anteroposterior hip X-ray,respectively.Taken hip X-ray film as gold standards,receiver operating characteristic(ROC)curve was drawn,and the area under the curve(AUC)was calculated to evaluate the efficacy of 3D black bone sequence and fat suppression T2WI for evaluating Herring classification of LCPD,and DeLong test was performed for statistical comparison.Results Femoral head extrusion index of LCPD based on X-ray film and 3D black bone sequence simulated X-ray film was(11.31±6.16)％and(11.47±5.83)％on control side,respectively,being not significantly different(P＞0.05),while was(22.45±9.21)％and(22.82±7.92)％on the affected side,respectively,also being not significantly different(P＞0.05)but both higher than that on the control side(both P＜0.001).Femoral head extrusion index of LCPD based on fat suppression T2WI was(28.01±2.01)％on affected side and(27.25±1.92)％on control side,respectively,being not significantly different(P＞0.05)and both higher than those obtained based on X-ray film(both P＜0.001).AUC of 3D black bone sequence and fat suppression T2WI was 0.750-0.938 and 0.625-0.705,respectively.AUC of 3D black bone sequence for evaluating LCPD Herring B type was higher than that of fat suppression T2WI(P＜0.05),while no significant difference was found for evaluating other Herring type of LCPD(all P＞0.05).Conclusion 3D black bone sequences could be used to measure head extrusion index and assess Herring classification of LCPD,which was expected to replace hip X-ray to some extents combining with fat suppression T2WI.

A combined full-scan mass spectrometry/data-dependent acquisition(Full MS/ddMS2)and full-scan mass spectrometry/parallel reaction monitoring(Full MS/PRM)approach for qualitative and quantitative analysis of plasma acylcarnitines was established on the basis of ultra-performance liquid chromatography-high resolution mass spectrometry(UPLC-HRMS).A total of 165 kinds of acylcarnitines were identified,and 111 kinds of acylcarnitines were quantified.The method demonstrated good reproducibility,with a relative standard deviation of less than 20%for plasma acylcarnitine content.Statistical analyses,including t-tests,partial least squares-discriminant analysis,variable importance in projection and volcano plot analysis,indicated significant alterations in plasma acylcarnitine levels in heart failure patients after myocardial infarction,for instance,46 kinds of acylcarnitines showing marked increases compared to myocardial infarction patients.Acylcarnitines showed a strong positive correlation with the clinical biomarker NT-proBNP,which was associated with heart failure.The combined use of acylcarnitine markers AC(C14-OH),AC(C12:1a),long-chain acylcarnitines,total acylcarnitines and NT-proBNP significantly enhanced the diagnostic sensitivity and specificity for post-infarction heart failure,with the area under the receiver operating characteristic curve(AUC)reaching 0.9456.The results of this work indicated that acylcarnitine was poised to become a crucial metabolic target for precise diagnosis,treatment and nutritional intervention in the progression of heart failure after myocardial infarction.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis