Objective To systematically evaluate the impact of pulmonary hypertension (PH) on the prognosis of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Methods A computerized search was conducted in CNKI, Wanfang Data, VIP, CBM, PubMed, The Cochrane Library, EMbase, and Web of Science databases from inception to June 2023 for cohort studies on the prognostic impact of PH in severe AS patients undergoing TAVR. Two researchers independently screened the literature, extracted data, and assessed the quality of included studies. Stata 17.0 software was used for meta-analysis. Results A total of 16 cohort studies were included, all with Newcastle-Ottawa Scale scores≥7. Meta-analysis results showed that, compared with AS patients without PH, those with PH had significantly higher 1-year all-cause mortality after TAVR [OR=2.10, 95%CI (1.60, 2.75), P<0.01], 30-day all-cause mortality [OR=2.09, 95%CI (1.54, 2.83), P<0.01], and cardiovascular mortality [OR=1.49, 95%CI (1.18, 1.90), P<0.01]. The differences between the two groups in major bleeding events, stroke, myocardial infarction, pacemaker implantation, and postoperative renal failure were not statistically significant. For outcome indicators with significant heterogeneity, subgroup analyses were performed based on PH measurement methods, diagnostic criteria, and different types of PH. The results showed that most subgroup combined results were consistent with the overall findings and that heterogeneity was significantly reduced. Conclusion PH significantly increases the 30-day all-cause mortality, 1-year all-cause mortality, and cardiovascular mortality in patients with severe AS undergoing TAVR.

OBJECTIVE: To investigate the variability of bone metabolism levels among different populations and its association with knee osteoarthritis (KOA) pain. METHODS: A total of 50 people (control group) who participated in physical examination from January 2023 to June 2023 were selected, including 26 males and 24 females, wtih a mean aged of (52.14±9.04) years old ranging 41 to 65 years old. The other 50 patients with knee osteoarthritis(case group) who attended the outpatient clinic of the Orthopedics and Traumatology Department in the same time period, including 19 males and 31 females, with a mean age of (53.60±7.76) years old ranging 40 to 65 years. The two groups of Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC) and bone metabolism markers, such as 25-hydroxy-cholecalciferol[25(OH)D], β-isomerized typeⅠcollagen C-telopeptide breakdown products (β-CTX), total typeⅠprocollagen N-terminal propeptide (t-PINP), osteocalcin (OC), parathormone (PTH) levels were compared. Pearson correlation analysis was used to compare the correlation between two groups of bone metabolism related markers and WOMAC. RESULTS: The WOMAC score of the case group (39.90±2.34) was higher than that of the control group (3.60±0.57), with significant difference (P<0.05). There was no significant difference between the two groups of 25 (OH)D, β-CTX and PTH (P>0.05). The t-PINP and OC of the case group were (62.90±52.40) and (19.88±10.15) ng·ml-1, respectively, and those of the control group were (38.86±10.82) and (14.90±3.62) ng·ml^-1, respectively;the t-PINP and OC of the case group were higher than those of the control group, with significant difference (P<0.05). Pearson correlation analysis showed that t-PINP was positively correlated with WOMAC pain score in the case group (r²=0.045, P<0.01). CONCLUSION Bone metabolism levels in the serum of patients with knee osteoarthritis are different from those of healthy people, and the difference between OC and t-PINP is the most obvious, and the concentration of t-PINP levels is positively correlated with pain symptoms in patients with KOA. However, the specific mechanism of correlation between the bone metabolism levels of patients with KOA and their pain symptoms needs to be further elucidated by basic experimental research as well as by enlarging the samples.
Humans ; Female ; Male ; Middle Aged ; Osteoarthritis, Knee/metabolism* ; Aged ; Adult ; Bone and Bones/metabolism* ; Pain/etiology* ; Biomarkers/metabolism*

Objective To investigate the role of Yes-associated protein(YAP)in bone resorption exac-erbated by occlusal trauma during periodontitis and its molecular mechanisms,and to evaluate the interven-tional effect of YAP inhibition on alveolar bone destruction.Methods Osteoclasts were stimulated by in vitro mechanical loading combined with lipopolysaccharide(LPS)to simulate the in vitro synergistic effect of occlu-sal stress and inflammation.A murine periodontitis model with occlusal trauma was established.Flow cytome-try,Western blot,qPCR,and immunofluorescence staining were employed to analyze YAP dephosphorylation and nuclear translocation in cellular and animal models,and to investigate YAP's regulatory effect on the c-Jun N-terminal kinase(JNK)/receptor activator of nuclear factor kappa-B ligand(RANKL)pathway.The YAP inhibitor XAV939 was administered to evaluate its impact on osteoclast activation and bone resorption through pathway intervention.Results In vitro,combined mechanical stress and LPS stimulation significantly reduced YAP phosphorylation in osteoclasts,promoted YAP nuclear translocation,and activated the JNK-RANKL pathway.In vivo,the periodontitis with occlusal trauma group exhibited markedly elevated expres-sion of YAP,JNK,and RANKL compared to the periodontitis-alone group(P<0.001).XAV939 intervention reversed YAP nuclear translocation,suppressed JNK phosphorylation and RANKL expression(P<0.01),and reduced osteoclast numbers.Conclusion YAP acts as a central hub integrating mechanical and inflammatory signals,exacerbating osteoclast differentiation and bone resorption via activation of the JNK-RANKL axis.Targeted inhibition of YAP effectively blocks this pathological cascade,offering a new approach for the precise treatment of periodontitis complicated by occlusal trauma.

Objective To employ three dimensional high-resolution vessel wall magnetic resonance imaging(3D hr-VW-MRI)for analyzing the imaging characteristics of posterior circulation non-stenotic intracranial atherosclerotic plaque and to discuss its diagnostic value in identifying culprit plaques.Methods Ninety-three patients(age[62.94±9.70]years old,67 males,26 females)with non-stenotic atherosclerosis in our hospital from Jan.2019 to Jan.2021 were retrospectively recruited.The imaging features of plaques,including luminal area,maximum wall thickness and minimum wall thickness at the most stenotic site,stenosis rate,plaque burden,remodeling index,eccentricity index,enhancement ratio at the most stenotic site,and intraplaque hemorrhage,were measured based on T1-weighted imaging(T1WI)and contrast-enhanced T1WI.The culprit plaque was defined as a lesion arising from the responsible vascular supply area to a fresh infarction on the diffusion weighted imaging(DWI)and T2 fluid attenuated inversion recovery(T2-FLAIR)images with accompanying ischemic stroke/transient ischemic attack(TIA).A plaque was considered to be a nonculprit plaque when it occurred in patients with presumed ischemic stroke/TIA,but without an infarct on DWI and T2-FLAIR.Results Sixty-one culprit plaques and 32 non-culprit plaques were analyzed.The proportions of patients with hyperlipidemia,National Institutes of Health stroke scale(NIHSS)score,narrowest plaque enhancement rate,and incidence of intraplaque hemorrhage in the culprit plaque group were significantly higher than those in the non-culprit plaque group(all P＜0.05).Multivariate logistic regression analyses showed that NIHSS score(odds ratio[OR]=1.799,95％confidence interval[CI]1.303-2.484,P＜0.001),enhancement ratio(OR=1.076,95％CI 1.027-1.128,P=0.002)and intraplaque hemorrhage(OR=30.708,95％CI 2.563-367.925,P=0.007)were associated with plaque type.Conclusion NIHSS score,enhancement ratio at the most stenotic site,and intraplaque hemorrhage are independent risk factors for culprit plaques in patients with posterior circulation non-stenotic intracranial atherosclerotic disease.These indicators may help identify such culprit plaques and could be used to screen individuals with plaques having these characteristics,thereby providing a basis for early preventive interventions.

Objective To systematically evaluate the clinical effects of remote ischaemic preconditioning (RIPC) in elective vascular surgery. Methods Electronic searches were conducted in The Cochrane Library, PubMed, EMbase, Web of Science, CNKI, Wanfang Data, VIP Database, and CBM. Relevant randomized controlled trials (RCTs) were screened according to inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.3 software, and the risk of bias was assessed using the Cochrane risk of bias tool. Results A total of 15 studies involving 1 382 patients were included. The meta-analysis results showed no statistically significant difference between RIPC and non-RIPC groups in reducing perioperative mortality in elective vascular surgery (P>0.05). There were also no statistically significant differences between the two groups of vascular surgery patients regarding the incidence of myocardial infarction, renal injury, postoperative stroke, postoperative length of hospital stay, duration of surgery or total anesthesia time, or the incidence of limb injury, arrhythmia, heart failure, and pneumonia (P>0.05). Conclusion For patients undergoing elective vascular surgery, there are no significant differences between RIPC and non-RIPC in terms of perioperative mortality and other clinical endpoint outcomes.

Objective To evaluate the inhibitory effects of infigratinib and its pharmacologically active metabolites,BHS697 and CQM157,on cytochrome P450(CYPs)and UDP-glucuronosyltransferases(UGTs)in rat liver microsomes.Methods By adopting in vitro incubation method,the tested compounds(infigratinib,BHS697 or CQM157)and rat liver microsomes were incubated with the specific probe substrates of CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A4,respectively,or the specific probe substrates of UGT1A1,UGT1A3,UGT1A6,UGT1A9,UGT2B7,respectively.The production of characteristic metabolites was detected by high performance liquid chromatography-tandem mass spectrometry.The half maximal inhibitory concentration(IC50)and inhibition constant(Ki)were calculated by GraphPad Prism 8.0.Results Infigratinib,BHS697 and CQM157 weakly inhibited CYP2B6,CYP2C8,CYP2C9,CYP2C19,CYP2D6,CYP3 A4 and UGT1A6,UGT2B7 in rat liver microsomes,with IC50 values all more than 10 μmol·L-1,and moderately inhibited UGT1Al with IC50 values of 2.70,3.17,7.43 μmol·L-,respectively.Infigratinib had a moderate inhibitory effect on UGT1A9 and CQM157 had a moderate inhibitory effect on UGTIA3,with IC50 values of 5.61 and 9.57 μmol·L-1,respectively.The reversible inhibition analysis showed that infigratinib,BHS697 and CQM157 all non-competitively inhibited UGTIA1,with Ki values of 1.83,2.51 and 5.84 μmol·L-1,respectively.Conclusion Infigratinib had moderate inhibitory effects on UGT1A1 and UGT1A9 in rat liver microsomes and its pharmacologically active metabolites,BHS697 and CQM157,also had moderate inhibitory effects on UGT1A1.

ObjectiveTo elucidate the pharmacodynamic substances responsible for the anti-inflammatory and analgesic effects of Cyperi Rhizoma by structure-activity omics. MethodOn the basis of the previous in vitro efficacy study by our research group， this study explored the in vivo efficacy of the flavonoids in Cyperi Rhizoma. The flavonoids in Cyperi Rhizoma and their targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， PharmMapper， Swiss TargetPrediction， and available articles. The targets of the anti-inflammatory and analgesic effects were collected from DisGeNET and Online Mendelian Inheritance in Man （OMIM）. The common targets shared by flavonoids and the effects were selected as the direct targets of flavonoids endowing Cyperi Rhizoma with anti-inflammatory and analgesic effects， and protein-protein interaction （PPI） network of the core targets was constructed. The method of structure-activity omics was employed to correlate the structure and efficacy of one or more classes of chemical components in Cyperi Rhizoma with the targets as a bridge. The components were classified according to structure. Molecular docking of components to core targets was carried out via SYBYL-X 2.1.1， PyMol， and Discovery Studio 4.5 visualizer. Two targets with the highest binding affinity were selected to explore the relationship between compound structures and targets. ResultThe flavonoids in Cyperi Rhizoma exerted anti-inflammatory and analgesic effects on the mouse model of pain induced by formaldehyde. Eighteen components and 115 direct targets were screened out， and the core targets with high activities were protein kinase B1 （Akt1）， interleukin-1β （IL-1β）， cellular tumor antigen p53 （TP53）， prostaglandin-endoperoxide synthase 2 （PTGS2）， and matrix metalloproteinase-9 （MMP-9）. According to the structures， the flavonoids in Cyperi Rhizoma were classified into bioflavonoids， flavonols， flavones， and flavanes. The molecular docking results showed that flavonoids of Cyperi Rhizoma had the highest binding affinity to TP53 and PTGS2. The results of structure-activity omics showed that bioflavonoids represented the best binding structure to the targets， while their polyhydroxyl etherification resulted in a significant decrease in the binding affinity to PTGS2. Glycosides had higher binding affinity to PTGS2. The introduction of the long-chain hydrocarbon group to the A ring of flavonols facilitated the binding to TP53， while the change of B ring substituents was not the main factor affecting the binding affinity. The 3，4-dihydroxyl flavane outperformed 3-hydroxyl flavane in the binding to TP53， while the two compounds showed similar binding affinity to PTGS2. ConclusionThe method of structure-activity omics was used to analyze the material basis for the anti-inflammatory and analgesic effects of flavonoids in Cyperi Rhizoma. Structure-activity omics provides new ideas for revealing the pharmacodynamic substances of traditional Chinese medicine.

ObjectiveTo elucidate the active compounds for the anti-inflammatory and analgesic effects of Paeoniae Radix Alba from structure-activity omics. MethodOn the basis of the previous in vitro efficacy study by our research group， a mouse model of foot swelling was induced by methyl aldehyde and used to study the anti-inflammatory and analgesic effects of total glycosides of Paeoniae Radix Alba in vivo. The core targets of the active compounds for the anti-inflammatory and analgesic effects of Paeoniae Radix Alba were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， Online Mendelian Inheritance in Man （OMIM）， and Search Tool for Recurring Instances of Neighbouring Genes （STRING）. Molecular docking was conducted for the total glucosides of Paeoniae Radix Alba with the core targets， and the key core targets with high binding affinity were screened out according to the comprehensive score of each target and active structure. The structure-activity relationship was analyzed with targets as a bridge through the combination of compound structures and pharmacological effects. ResultThe total glucosides of Paeoniae Radix Alba had good anti-inflammatory and analgesic effects in vivo. The core targets of 23 active components of Paeoniae Radix Alba were epidermal growth factor receptor （EGFR）， signal transducer and activator of transcription 3 （STAT3）， vascular endothelial growth factor A （VEGFA）， cellular tumor antigen p53 （TP53）， and proto-oncogene transcription factor （JUN）. According to the structure of the parent nucleus， there were 16 pinane monoterpene glycosides， 4 pinene monoterpene glycosides， 2 monoterpene lactone glycosides， and 1 monoterpene ketone. The key core targets screened out by molecular docking were EGFR and STAT3. The structure-activity analysis of the active compound structures and the key core targets showed that the introduction of ketone group and benzene ring group on the parent nucleus affected the binding activity. ConclusionThis study analyzed the material basis for the anti-inflammatory and analgesic effects of total glycosides of Paeoniae Radix Alba from structure-activity omics， providing new ideas and methods for revealing the pharmacodynamic substances in traditional Chinese medicine.

Orodispersible films (oral dispersible films), a novel form of oral solid dosage forms, are widely used for patients with dysphagia and those with uncontrollable autonomic behavior. In this study, suvorexant orodispersible film was prepared by hot melt extrusion technology, and the disintegration time, mechanical properties, in vitro dissolution and pharmacokinetics were evaluated, compared with other orodispersible films and commercially available tablets Belsomra. All experiments were approved by the Committee on the Management and Use of Laboratory Animals of Academy of Military Medical Sciences (IACUC-DWZX-2024-504). The results showed that the dissolution rate of suvorexant orodispersible film was faster and the mechanical strength was better than that of other commercially available orodispersible film, which could meet the needs of storage and transportation. Differential scanning calorimetry and X-ray diffraction results showed that suvorexant was dispersed within the orodispersible film in an amorphous state. The in vitro dissolution of the film was observed to be four times faster than that of the commercial tablets, achieving complete dissolution within five minutes. Pharmacokinetic evaluations in Beagle dogs revealed that the self-formulated orodispersible film exhibited no significant differences in the area under the blood concentration-time curve when compared with Belsomra. However, the film showed a faster onset of action, with a peak time that was twice as rapid, and a maximum blood concentration that was twice as high as that of Belsomra. Leveraging hot melt extrusion technology, the suvorexant orodispersible film offers a straightforward, continuous production process with consistent quality. It serves as an excellent platform for the development of solvent-free film preparations tailored for patients with special needs.

The rheological properties of drug and carrier materials have a wide range of guiding significance for the formulation and process development of solid dispersions. In this study, the rheological properties of materials with different drug carrier ratios were systematically studied with suvorexant as the model drug and copovidone as the carrier material, which provided a sufficient basis for determining the formulation and process of solid dispersions. The optimal suvorexant-copovidone ratio obtained by oscillating temperature scanning was 1∶4. If the ratio is greater than 1∶ 4, the glass transformation temperature of the material will increase significantly, and the solubilization effect of the solid dispersion will show a downward trend. The results of oscillation temperature scanning and oscillation temperature sweep can show that when the extrusion temperature is greater than 150 ℃, the viscosity of the material is less than 10 000 Pa·s, and the melt can be extruded smoothly, and the best extrusion temperature of 160-180 ℃ can be obtained by combining the dissolution results. Finally, the dissolution of suvorexant tablets guided by rheological property studies in multiple media is similar to that of the commercially available tablets Belsomra. Therefore, rheological studies can screen and optimize the formulation and process of suvorexant solid dispersions at the mechanism level, which is of great significance to improve the success rate of R&D and shorten the R&D cycle of solid dispersions prepared by hot melt extrusion.