Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound RP20, which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning RP20 as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

OBJECTIVE： To establish a method for the determination of piperitylmagnolol in the incubation system of liver microsomes， and to investigate the metabolic characteristics of it in different species of liver microsomes. METHODS： The piperitylmagnolol were respectively dissolved in NADPH activated liver microsome incubation systems of human， rat， mouse， monkey and dog， and then incubated in water at 37 ℃. The reaction was terminated with methanol at 0， 2， 5， 10， 15， 20， 30， 45 and 60 minutes of incubation， respectively. Using magnolol as internal standard， UPLC-MS/MS method was used to determine the concentration of piperitylmagnolol in the incubation system. The determination was performed on Acquity UPLCTM CSH C18 column with mobile phase consisted of 0.1％ formic acid-methanol （gradient elution） at the flow rate of 0.3 mL/min. The column temperature was set at 30 ℃， and the sample size was 2 μL. The ion source was electrospray ion source， and the positive ion scanning was carried out in the multiple reaction monitoring mode. The ion pairs used for quantitative analysis were m/z 401.2→331.1 （piperitylmagnolol） and m/z 265.1→247.0 （internal standard）， respectively. Using the concentration of piperitylmagnolol at 0 min of incubation as a reference， the residual percentage， metabolism half-life in vitro （t1/2） and intrinsic clearance （CLint） were calculated for different incubation systems. The metabolic pathway of piperitylmagnolol was studied by chemical inhibitor method. Under the above chromatographic conditions， the metabolites in vitro were preliminarily analyzed by first-order full scanning and positive ion detection. RESULTS： The linear range of piperitylmagnolol was 3.91-500.00 ng/mL. The limit of quantitation was 3.91 ng/mL. RSDs of intra-day and inter-day were less than 10％. The accuracy ranged 87.40％-103.75％. Matrix effect didn’t affect the determination of the substance to be measured. The piperitylmagnolol was metabolized significantly in human， rat， mouse and dog liver microsomes， but not in monkey liver microsomes. After incubating for 30 min， residual percentage of piperitylmagnolol kept stable in different species of liver microsomes. The t1/2 of piperitylmagnolol were 12.07， 17.68， 17.59， 216.56 and 61.88 min in human， rat， mouse， monkey and dog liver microsomes； CLint were 0.115， 0.078， 0.079， 0.006， 0.022 mL/（min·mg）， respectively. Inhibitory rates of CYP2A6， CYP2D6， CYP2C19， CYP3A4， CYP2C9， CYP2E1 and CYP1A2 to compound metabolism were 55.76％， 93.94％， 96.01％， 93.69％， 71.81％， 23.25％， 28.04％， respectively. Quasi-molecular ion peaks of the two main metabolites of piperitylmagnolol in human liver microsomes were m/z 441.2（[M+Na]+） and m/z 337.2（[M+H]+）， respectively. CONCLUSIONS： Established UPLC-MS/MS method is simple， rapid and specific， and can be used for the determination of piperitylmagnolol concentration in the incubation system of liver microsomes and pharmacokinetic study. The metabolic characteristics of the compound are different among liver microsomes of human， rat， mouse， monkey and dog. Its metabolism process may be associated with CYP2D6， CYP2C19， CYP3A4， CYP2C9， etc.

OBJECTIVE:To establish the detection method for anti-inflammatory compound HB0314 in plasma of rats,and study on its pharmacokinetic characteristics in rats in vivo. METHODS:UPLC-MS/MS was performed on the column of Waters Ac-quity UPLCTM BEH C18 with mobile phase of 0.1% formic acid aqueous solution(A)-methanol(B)by gradient elution(0-2 min, 70%-90% B) at flow rate of 0.25 mL/min,column temperature was 30 ℃,and injection volume was 5 μL. Electrospray ion source was used,capillary voltage was 3 kV,ion source temperature was 150 ℃,desolvation gas temperature was 450 ℃,desol-vent air flow volume was 600 L/h,cone air flow volume was 45 L/h,and the inner standard was tetrahydropalmatine. 12 rats were randomly divided into iv group and ig group,6 in each group. Rats were intravenously injected and intragastrically administrated HB0314 solution 5,10 mg/kg. Sample blood 0.4 mL were taken from the jugular vein blood before administration and after 5,15, 30,60,120,240,360,480,600,720,1440 min of administration to determine the HB0314 plasma concentration. DAS 2.0 software was used to calculate the pharmacokinetic parameters and absolute bioavailability. RESULTS:The linear range of HB0314 was 1-1000 ng/mL(r=0.9955),and the lower limit of quantification was 1 ng/mL. RSDs of extra-day and daytime precision,sta-bility were not higher than 8.45%(n=5);recovery were 68.21%-90.29%(RSD≤11.20%,n=5),and matrix effects were 82.63%-106.90%(RSD≤6.75%,n=5). After intravenous injection and intragastric administration,AUC0-24 h were (270.267 ± 21.164), (252.755 ± 26.169)μg·h/L (n=6);t1/2z were (8.722 ± 2.266),(11.877 ± 4.517) h (n=6);and absolute bioavailability was 56.79%. CONCLUSIONS:The method is rapid,simple,and can be used for the determination of HB0314 content in plasma of rats. HB0314 shows high oral absolute bioavailability in rats in vivo,indicating that post-dosage form design may be considered as oral anti-inflammatory drugs.

Objective To evaluate the effect of electrical stimulation of the pelvic floor muscles combined with bladder training on urinary dysfunctionafter incomplete spinal cord injury.Methods Sixty-two incomplete spinal cord injury patients who had received an operation between November 2009 and December 2014 were enrolled and divided randomly into a control group (n=32) and a treatment group (n =30).Both groups were treated with conventional intermittent catheterization,while the treatment group was additionally given electrical stimulation of the pelvic floor muscles combined with bladder training.The residual urine volume was recorded before and after the treatment.Uurodynamic examinations were conducted,and the rate of successful catheter extraction and of urinary tract infection on the 15th and 30th day of treatment,were recorded and analyzed.Results All of the patients were followed-up for an average of 18.5 months.Significant improvement was observed in the residual urine volume,the maximum or average urinary flow rate,and the detrusor pressure at peak flow of both groups.However,at the end of follow-up the treatment group recorded significantly better results on all these measures than the control group.The successful catheter extraction rate of the treatment group (96.7％) was significantly higher than that of the control group and their average number of catheterization days was significantly fewer.The urinary tract infection rates on the 15th and 30th day of treatment were 16.7％ and 6.7％ in the treatment group,significantly lower than in the control group.Conclusions Electrical stimulation of the pelvic floor combined with bladder training significantly improves urination function after an operation for incomplete spinal cord injury,decreases the days of catheterization and lowers the rate of urinary tract infection.Such combined therapy is worth promoting in clinical practice.

In order to affirm the cardioactive components in Fuzi, we identified a group of aminoalcohol- diterpenoid alkaloids in Fuzi using ultra high-performance liquid chromatography coupled with electrospray ionization mass spectrometer (UPLC-ESI-MS) method. Among a total of forty-one isolated ingredients, thirteen major aminoalcohol-diterpenoid alkaloids were identified by comparing their retention times and MS spectra with those of the reference substances. Moreover, Fuzi samples from different places of origin and with different processing methods were examined and their components displayed a pattern of high similarity, though the relative abundance varies probably due to their different processing methods. Furthermore, the cardiac effect of each identified alkaloid was individually evaluated using the isolated bullfrog heart perfusion experiment. Among the thirteen aminoalcohol diterpenoid alkaloids tested, six of them significantly enhanced the amplitude rates. Taken together, we affirm that the cardioactive components in Fuzi are aminoalcohol-diterpenoid alkaloids, shedding light on future studies of the mechanisms and development of these cardioactive compounds.

Objective To evaluate the accuracy of thoracic pedicle screw placement using the "funnel technique" and investigate its consistency in experimental study and clinical application.Methods The clinical data of three human cadavers and 11 patients with the installation of at least one thoracic pedicle screw at T1 -T12 from August 2006 to July 2008 were retrospectively analyzed. One junior spine surgeon lack of experience were responsible for placing these screws with the "funnel technique".The accuracy of screw placement and the complications related to the use of thoracic pedicle screws were analyzed by assessing postoperative CT scans. Results The mean follow-up time was 23.1 months,which showed no vascular or visceral complications, or iatrogenic neurological injury. The rate of unintended cortex perforations was 14% (10/72) in cadavers and 15% (8/55) in patients, respectively.The critical perforation occurred in two screws (3%) in cadavers and one screw (2%) in patients. There was no statistical difference between the percentage of cortex perforations in cadavers and patients. Of all the 11 patients, screw violation occurred laterally in six ( 11% ), medially in one ( 2% ) and superiorly in one (2%). No violations occurred inferiorly or anteriorly. For all patients, only one screw needed revision. The perforations made by the junior spine surgeon occurred in six screws in the first cadaver, three in the second cadaver and one in the third cadaver. Conclusions The "funnel technique" is a simple,safe, accurate and cost-effective technique for pedicle screw placement. The result of the experimental study is consistent with that of the clinical application. "funnel technique" is helpful for junior spine surgeons to master the technique of thoracic pedicle screw placement.

In this paper are analyzed the disadvantages of CGO-3000 digital subtraction angiography table Operating Box. The authors put forward a communication control scheme between single-chip microcomputer(SCM) and programmable logic controller(PLC). The details of hardware and software of communication are given.
Angiography, Digital Subtraction ; instrumentation ; Equipment Design ; Humans ; Image Processing, Computer-Assisted ; instrumentation ; Microcomputers ; Radiographic Image Enhancement ; instrumentation ; Software

Objective: To investigate the efficacy of horizontal acupuncture with sticking needles plus plucking manual technique in treating scapular, dorsal and lumbar myofascitis.Methods: One hundred and seventy-eight patients with scapular, dorsal and lumbar myofascitis were randomly allocated to observation group treated by horizontal needling with sticking needles plus plucking manual technique and control group treated by perpendicular acupuncture at the pain point. Results and conclusion: The cure rate, and the total effective rate in the observation group were 69.6%, and 100% respectively and those in the control group were 13.1%, and 82.5% respectively. Statistical analysis showed a very significant difference in curative effect between the two groups (P＜0.01), indicating that the effect was significantly better in the observation group than in the control group.