BACKGROUND:Various proteins,signaling pathways,and inflammatory mediators are involved in the pathophysiological process of osteoarthritis.The development of small molecule drugs targeting these proteins,signaling pathways,and inflammatory mediators can effectively delay the progression of osteoarthritis and ameliorate its clinical manifestations. OBJECTIVE:To review the research progress of small molecule drugs in the treatment of osteoarthritis based on the pathogenesis of osteoarthritis. METHODS:PubMed,CNKI,and WanFang databases were searched with English search terms"osteoarthritis,arthritis,osteoarthrosis,degenerative,arthritides,deformans,small molecule drugs,small molecule inhibitors,small molecule agents"and Chinese search terms"osteoarthritis,small molecule drugs,small molecule inhibitors."A total of 68 articles were included for review according to the inclusion and exclusion criteria. RESULTS AND CONCLUSION:(1)Currently,studies concerning the pathogenesis of osteoarthritis remain unclear.The occurrence and development of osteoarthritis are strongly associated with proteins,cytokines,and signal transduction pathways,so its therapeutic mechanism is relatively complex.Currently,targeting proteins,cytokines,and signal transduction pathways related to osteoarthritis with small molecule drugs has become a major research focus.(2)Small molecule drugs frequently possess visible intracellular or extracellular targets and efficacy,containing enhancing cartilage repair,resisting joint degradation,attenuating inflammation,and relieving pain.Other anti-osteoarthritis small molecule drugs have shown promise in promoting stem cell chondrogenic differentiation and cartilage matrix reconstruction.(3)At present,small molecule drugs targeting the pathophysiological process of osteoarthritis to delay the progression of osteoarthritis are still in the experimental stage,but most of these small molecule drugs have shown the expected results in the experimental process,and there are no relevant studies to illustrate the efficacy of small molecule drugs in the treatment of osteoarthritis.(4)Small molecule drugs for the treatment of osteoarthritis have reached the expected experimental results in the basic experimental stage.Numerous studies have exhibited that small molecule drugs can target the suppression of specific proteins,cytokines,and signal transduction pathways that cause osteoarthritis,so as to treat osteoarthritis.Nevertheless,its safety and effectiveness still need to be identified by further basic and clinical studies.This process needs to be investigated and studied by more scholars.(5)At present,many scholars in and outside China have made contributions to the treatment of osteoarthritis.Compared with traditional treatment methods,small molecule drugs reveal better efficacy and safety in the basic experimental stage,and it is expected to become an emerging method for the treatment of osteoarthritis in the future to rid patients of pain.

Objective:The predictive value of oxidized low density lipoprotein(ox-LDL)and electrocardiogram(ECG)ischaemia grade for major adverse cardiovascular events(MACE)in patients with ST elevation myocardial infarction(STEMI)after percutaneous coronary intervention(PCI)was assessed by a retrospective cohort study de-sign.Methods:A total of 336 STEMI patients admitted to Cangzhou People's Hospital between October 2019 and May 2022 were selected,and the medical record information was obtained through the hospital medical record sys-tem,and all patients received PCI and physician-recommended basic treatment.With occurrence of MACE with in 12-month follow-up as the evaluation index,they were divided into MACE group(n=65)and no MACE group(n=271).Multifactorial Logistic regression model was used to study the influencing factors of MACE after PCI in STEMI patients,and Spearman test for association of ox-LDL level,ECG ischaemia grade with MACE after PCI.ROC curve was used to evaluate the predictive efficacy of ox-LDL,ECG ischaemia grade and their combination for MACE after PCI.Results:The overall MACE incidence was 19.35％.Compared with patients in no MACE group,those in MACE group had significant higher ox-LDL level[46.34(29.46,66.29)U/L vs.33.00(23.02,50.03)U/L]and proportion of ECG grade Ⅲ ischaemia(64.62％vs.42.80％)(P＜0.01 all).Multifactorial Logistic re-gression analysis showed that ox-LDL(OR=1.022,95％CI 1.011～1.033,P=0.001)and ECG grade Ⅲ ischae-mia(OR=1.878,95％CI 1.007～3.504,P=0.048)were the independent risk factors of post-PCI MACE in STEMI patients.Spearman test showed that ox-LDL and ECG grade Ⅲ ischaemia were positively correlated with post-PCI MACE(r=0.209,0.173,P＜0.001 all).ROC curve analysis showed that the AUCs of ox-LDL,ECG grade Ⅲ ischaemia and their combination in predicting post-PCI MACE were respectively 0.653(95％CI 0.599～0.704),0.609(95％CI 0.555～0.662)and 0.758(95％CI 0.709～0.803),in which the predictive value of the combination of the two was significantly higher than any single detection(Z=2.030,3.097,P=0.042,0.002).Conclusion:ox-LDL combined with ECG ischaemia grading has a high predictive value for the occurrence of MACE with in 12 months after PCI in STEMI patients.

Objective To explore the impact factors of misjudge of pneumoconiosis stage based on GBZ70-2015 criteria.Methods Sixty-five case of pneumoconiosis were retrospectively enrolled.Chest high-resolution CT were independently analyzed by one associate chief physician,one attending physician and one resident physician,respectively.The stage of pneumoconiosis was judged,and the inter-observer consistency was observed.Taken the results of 5 experts using Delphi method as gold standard,the impact factors of misjudge of pneumoconiosis stage were analyzed.Results Among 65 cases,there were 42 cases of stage 1,16 cases of stage 2 and 7 cases of stage 3 pneumoconiosis.The inter-observer consistency of pneumoconiosis stage was relatively high(Kappa=0.653),of stage 3 pneumoconiosis was the best(Kappa=0.803),followed by stage 1(Kappa=0.661),while of stage 2 was the lowest(Kappa=0.518).Radiologist lack experience(OR=4.872),the lesions mainly located in the posterior upper area of lungs(OR=2.317),the present of r-type small shadows(OR=3.105)and high CT pulmonary emphysema index(OR=1.214)were all independent impact factors of misjudge of pneumoconiosis stage(all P＜0.05).Conclusion Both the experience of radiologist and lesions'heterogeneity were main impact factors of misjudge of pneumoconiosis stage based on GBZ70-2015 criteria.

Aim To explore the mechanism of ligustil-ide(LIG)improving demyelination by inhibiting in-flammatory response in mice with distal middle cerebral artery occlusion(dMCAO)through AIM2/caspase-1 signal pathway.Methods Thirty C57BL/6N male mice were randomly divided into three groups:sham operation group(Sham group,n=10),model group(dMCAO group,n=10)and treatment group(LIG group,n=10).The dMCAO mouse model was estab-lished by electrocoagulation in dMCAO group and LIG group.The mice were scored by Longa after waking up,and the changes of cerebral blood flow were moni-tored by laser speckle blood flow imaging system after dMCAO.One hour after modeling,LIG(30 mg·kg-1·d-1)was injected intraperitoneally in LIG group,and the same amount of normal saline was injected in sham group and dMCAO group for one week until the end of the experiment.The mice in each group were stained with TTC,and the brain injury was observed pathologically.Fatigue turning bar test and open field test were used to evaluate the motor function and anxie-ty degree of mice,and then the brain tissues of mice were taken for black gold staining to compare the chan-ges of myelin sheath in each group.Immunofluores-cence staining was used to detect the average fluores-cence intensity of MBP,IBA1 and GFAP in CC,CPU and CX regions of mouse brains.ELISAwas used to de-tect the contents of TNF-α,IL-6,IL-1 β,IL-17A and BDNF in brain tissue proteins of mice.Western blot-ting was used to detect the protein expressions of AIM2,caspase-1 and ASC-in each group.Results Compared with the dMCAO group,the infarct area was reduced,the behavior was significantly improved and the demyelination was reduced in the LIG group.The expression of MBP protein in CC,CPU and CX regions increased(P＜0.05),the expression of IBA1 in CX decreased(P＜0.01),and the expression of GFAP in-creased in CC,CPU and CX regions(P＜0.01).The results of ELISA showed that the levels ofTNF-α(P＜0.01),IL-6(P＜0.01),IL-1β(P＜0.05)and IL-17A(P＜0.01)significantly decreased,while the ex-pression of BDNF increased(P＜0.05).The protein expression levels of AIM2,caspase-1 and ASC in mouse brain decreased after treatment(P＜0.01).Conclusion LIG has a protective effect on demyelina-tion in dMCAO mice,which may be related to the inhi-bition of AIM2/caspase-1 signaling pathway and in-flammation and to the promotion of BDNF secretion.

Objective To quantify the volume and movement of cardiac substructures by using coronary computed tomography angiography(CCTA)to provide guidance for the design of deep inspiratory breath-holding radiation therapy for left breast cancer and the protection of organs at risk.Methods Totally 18 female patients who received conventional chest plain scan and CCTA were selected to simulate the design process of radiotherapy plan for left breast cancer patients with internal mammary lymph nodes.Retrospective reconstruction of CCTA data was performed for each patient,with 10 phase images(with an interval of 10％)within a R-R cardiac cycle(10％-100％)to simulate the true range of motion of the heart.The heart,left atrium(LA),left ventricle(LV),right atrium(RA),right ventricle(RV),left anterior descending artery(LAD),left circumflex coronary artery(LCX)and right coronary artery(RCA)were contoured at each phase.The distances from the centroid position to the average position of LAD,LCX and RCA were measured at each phase in the superior-inferior(SI),anterior-posterior(AP)and left-right(LR).The average volume and range of volume changes of LA,LV,RA,RV and heart were analyzed within a cardiac cycle.The expansion margins of planning organs at risk volume(PRV)were calculated.SPSS 19.0 software was used for statistical analysis.Results The following average absolute displacements were found in SI,AP and LR coordinates:(1.8±0.7)mm,(1.2±0.5)mm and(1.5±0.5)mm for LAD,respectively;(2.1±0.7)mm,(1.5±0.6)mm and(1.9±0.7)mm for LCX,respectively;(1.6±0.5)mm,(2.2±0.9)mm and(2.2±0.8)mm for RCA,respectively.The volume changes of LA,LV,RA,RV and heart within a cardiac cycle ranged from 34.3 to 63.9 cm3,122.1 to 154.3 cm3,29.3 to 53.6 cm3,57.2 to 94.3 cm3 and 480.1 to 515.4 cm3,respectively.The theoretical expansion margins of LAD,LCX and RCA in all the three directions were within 2 mm.Conclusion The ranges of movement and volume changes of cardiac substructure are quantitati-vely displayed,and references are provided for the planning of deep inspiratory breath-holding radiation therapy for left breast cancer and the protection of organs at risk.[Chinese Medical Equipment Journal,2025,46(3):54-58]

Objective:To observe the clinical effect of aripiprazole combined with non-convulsive electroshock(MECT)for children and adolescents with first episode schizophrenia.Methods:94 children and adolescents with first episode schizophrenia who were admitted to Yiling Kangning Mental Hospital of Yichang from August 2022 to August 2024 were divided into control group(received aripiprazole,n=47)and study group(received aripiprazole combined with MECT,n=47)by using random number table method.The clinical efficacy,dysfunction scale[Positive and Negative Symptom Scale(PANSS),Montreal Cognitive Assessment Scale(MoCA),Wechsler Memory Scale(WMS)],glucose and lipid metabolism indexes[low density lipoprotein cholesterol(LDL-C),glycated hemoglobin(HbAlc),total cholesterol(TC),fasting blood glucose(FBG),High density lipoprotein cholesterol(HDL-C),inflammatory factor indexes[interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)],neurocytokine levels[serum brain-derived neurotrophic factor(BDNF),s100βprotein(s100β),homocysteine(Hcy)]and the occurrence of adverse reactions were compared between the two groups.Results:Compared with the control group after treatment,the clinical total effective rate,MoCA,WMS score,HDL-C,BDNF were higher,PANSS score,HbAlc,FBG,TC,LDL-C,TNF-α,IL-1β,IL-6,s100β and Hcy were lower in the study group(P＜0.05).There was no difference in the incidence of adverse reactions between the two groups(P＞0.05).Conclusion:Aripiprazole combined with MECT in the treatment of in children and adolescents with first episode schizophrenia can reduce the degree of inflammation,regulate glucose and lipid metabolism,improve clinical symptoms and neurological function of children,with good safety.

Objective To quantify the volume and movement of cardiac substructures by using coronary computed tomography angiography(CCTA)to provide guidance for the design of deep inspiratory breath-holding radiation therapy for left breast cancer and the protection of organs at risk.Methods Totally 18 female patients who received conventional chest plain scan and CCTA were selected to simulate the design process of radiotherapy plan for left breast cancer patients with internal mammary lymph nodes.Retrospective reconstruction of CCTA data was performed for each patient,with 10 phase images(with an interval of 10％)within a R-R cardiac cycle(10％-100％)to simulate the true range of motion of the heart.The heart,left atrium(LA),left ventricle(LV),right atrium(RA),right ventricle(RV),left anterior descending artery(LAD),left circumflex coronary artery(LCX)and right coronary artery(RCA)were contoured at each phase.The distances from the centroid position to the average position of LAD,LCX and RCA were measured at each phase in the superior-inferior(SI),anterior-posterior(AP)and left-right(LR).The average volume and range of volume changes of LA,LV,RA,RV and heart were analyzed within a cardiac cycle.The expansion margins of planning organs at risk volume(PRV)were calculated.SPSS 19.0 software was used for statistical analysis.Results The following average absolute displacements were found in SI,AP and LR coordinates:(1.8±0.7)mm,(1.2±0.5)mm and(1.5±0.5)mm for LAD,respectively;(2.1±0.7)mm,(1.5±0.6)mm and(1.9±0.7)mm for LCX,respectively;(1.6±0.5)mm,(2.2±0.9)mm and(2.2±0.8)mm for RCA,respectively.The volume changes of LA,LV,RA,RV and heart within a cardiac cycle ranged from 34.3 to 63.9 cm3,122.1 to 154.3 cm3,29.3 to 53.6 cm3,57.2 to 94.3 cm3 and 480.1 to 515.4 cm3,respectively.The theoretical expansion margins of LAD,LCX and RCA in all the three directions were within 2 mm.Conclusion The ranges of movement and volume changes of cardiac substructure are quantitati-vely displayed,and references are provided for the planning of deep inspiratory breath-holding radiation therapy for left breast cancer and the protection of organs at risk.[Chinese Medical Equipment Journal,2025,46(3):54-58]

Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*