OBJECTIVE To investigate the effects of quercetin （QUE） on intervertebral disc degeneration in rats with lumbar intervertebral disc herniation （LDH） and explore its mechanism based on the forkhead box protein O3/silent information regulator 1 （FOXO3/Sirt1） pathway. METHODS A rat model of LDH was established. The successfully modeled rats were randomly divided into LDH group （gavaged with and intraperitoneally injected with an equal volume of normal saline）， QUE-L group （gavaged with 50 mg/kg QUE+intraperitoneally injected with an equal volume of normal saline）， QUE-H group （gavaged with 100 mg/kg QUE+ intraperitoneally injected with an equal volume of normal saline）， and QUE-H+EX-527 （a Sirt1 inhibitor） group （gavaged with 100 mg/kg QUE+intraperitoneally injected with 1 mg/kg EX-527）， with 12 rats in each group. Additionally， 12 healthy normal rats were selected as the control group （gavaged with and intraperitoneally injected with an equal volume of normal saline）. All rats were administered the corresponding agents once daily for consecutive 8 weeks. After the final administration， the pain threshold and serum levels of inflammatory factors in rats were measured； pathological damage of lumbar intervertebral disc tissue was observed， the apoptosis of nucleus pulposus cells in lumbar intervertebral disc tissue was assessed， and the expression levels of matrix metalloproteinase-3 （MMP-3）， phospholipase A2 （PLA2）， as well as apoptosis-related proteins and FOXO3/Sirt1 pathway- related proteins in intervertebral disc tissue were determined. RESULTS Compared with LDH group， pathological damage of intervertebral disc tissue were improved significantly in QUE-L group and QUE-H group； paw withdrawal mechanical threshold， paw withdrawal thermal latency， the serum levels of transforming growth factor-β1 and interleukin-10 （IL-10） as well as the expression levels of B-cell lymphoma-2 （Bcl-2）， FOXO3 and Sirt1 were significantly increased or prolonged （P＜0.05）. Serum levels of tumor necrosis factor-α and IL-1β， histopathological score of intervertebral disc tissue， apoptotic rate of nucleus pulposus cells， positive expressions of MMP-3 and PLA2 in intervertebral disc tissue and expression levels of Bcl-2 associated X protein were significantly decreased （P＜0.05）. Compared with the QUE-H group， the QUE-H+EX-527 group presented aggravated pathological damage of intervertebral disc tissue， and the trends of all the above indicators were significantly reversed（P＜0.05）. CONCLUSIONS QUE can ameliorate intervertebral disc degeneration in LDH rats， and its mechanism may be related to the activation of the FOXO3/Sirt1 pathway.

OBJECTIVE To investigate the effects and mechanism of the Yishen paidu formula on renal fibrosis in rats with chronic renal failure （CRF） through the reactive oxygen species （ROS）/thioredoxin-interacting protein （TXNIP）/NOD-like receptor thermal protein domain associated protein 3 （NLRP3） pathway. METHODS Rats were randomly divided into control group， model group， Yishen paidu formula low-dose （Yishen paidu formula-L） group， Yishen paidu formula high-dose （Yishen paidu formula- H） group， Yishen paidu formula-H+pcDNA-NC group， and Yishen paidu formula-H+ pcDNA-TXNIP group， with 10 rats in each group. Except for control group， all other rats were fed a diet containing 0.5% adenine to establish a CRF model； the rats were then administered corresponding drugs or normal saline intragastrically or via tail vein， once daily， for 8 consecutive weeks. After the last administration， the levels of serum creatinine （Scr）， blood urea nitrogen （BUN）， ROS， superoxide dismutase （SOD）， malondialdehyde （MDA）， tumor necrosis factor-α （TNF-α）， interleukin （IL）-6， and IL-1β were measured in each group. Pathological changes in renal tissue were observed， and the protein expression levels of Collagen Ⅲ， α-smooth muscle actin （α-SMA）， transforming growth factor-β1 （TGF-β1）， TXNIP and NLRP3 in renal tissue were detected. RESULTS Compared with model group， the renal histopathological damage and fibrosis of rats in Yishen paidu formula-L group and Yishen paidu formula-H group were significantly alleviated. The levels of Scr， BUN， ROS， MDA， TNF- α， IL-6 and IL-1β， and the protein expressions of Collagen Ⅲ， α-SMA， TGF-β1， TXNIP and NLRP3 were significantly decreased， while SOD levels were significantly increased （P＜0.05）. Moreover， the changes were more pronounced in the Yishen paidu formula-H group （P＜0.05）. Compared with Yishen paidu formula-H+pcDNA-NC group， above indexes of rats in Yishen paidu formula-H+pcDNA-TXNIP group were reversed significantly （P＜0.05）. CONCLUSIONS Yishen paidu formula can inhibit renal fibrosis in CRF rats by suppressing the ROS/TXNIP/NLRP3 pathway.

Objective: To explore the relationship of physical activity (PA) and sedentary behavior (SB) with cardiorespiratory fitness (CRF) among middle schoold students in Tibet, so as to provide empirical references for improving the cardiorespiratory fitness and health levels of adolescents in Tibet. Methods: From August to December 2020, 1 225 junior and senior high school students were selected from 2 middle schools in Lhasa, Tibet Autonomous Region, using the stratified cluster random sampling method. Triaxial accelerometers were used to evaluate PA and SB behaviors, and the 20 meter shuttle run was employed to assess CRF among the middle school students. Isochronous substitution modeling was used to analyze the associations of SB, low intensity physical activity (LPA), and moderate vigorous physical activity (MVPA) with CRF, and the saturation threshold effect in the dose response relationship between MVPA and CRF was analyzed through restricted cubic spline and two stage linear regression. Results: After adjusting for covariates such as gender, body mass index and sleep quality score, isotemporal substitution analysis showed that among junior high school students aged 13-15, replacing 30 minutes of SB ( B =1.73) or LPA ( B =2.38) with MVPA were positively associated with CRF (both P <0.05). Among senior high school students aged 16-18, replacing SB ( B =0.99) or LPA ( B =1.38) with MVPA were also positively associated with CRF (both P <0.05). Restricted cubic spline and two piecewise linear regression analyses indicated that only middle school girls aged 13-18 exhibited a saturation threshold effect between MVPA and CRF (logarithmic likelihood ratio test=0.03), with the optimal CRF improvement observed at 60 minutes of MVPA per day ( B=0.13, P ＜ 0.01). Conclusions Reducing SB and LPA while increasing MVPA can improve CRF in Tibetan middle school students. To maximize CRF improvement, middle school girls should engage in at least 60 minutes of MVPA daily.

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective To investigate whether glaucocalyxin A can reduce inflammatory response in rats with trau-matic fracture.Methods The rats were randomly divided into control group,model group,low GLA(GLA-L),high GLA dose group(GLA-H)and GLA?H+YC?1(HIF?1α inhibitor)group.The level of TNF?α,IL?6,CTX?Ⅰ,CTX?Ⅱ,S?Ca,S?P,BGP and the activities of iNOS and ALP were detected by ELISA.The density and thickness of bone trabeculae were measured by computed tomography.Apoptosis of femur tissue was detected by TUNEL.The cartilage morphology was observed by saffranin O?fast green staining.Western blot was applied to de?tect the expression of HIF?1α,VEGF,CD31,BMP?2,and collagenⅠ proteins in femoral tissue.Results Compared with the control group,the cartilage morphology of rats in the model group was significantly damaged,the level of serum TNF?α,IL?6,CTX?Ⅰ,CTX?Ⅱ,iNOS activity and apoptosis rate of femur tissue were in?creased.Serum S?Ca,S?P,BGP levels,ALP activity,bone trabecular density and thickness,HIF?1α,VEGF,CD31,BMP?2,collagen Ⅰ protein expression levels in femur tissue were all decreased(P<0.05).The mor?phology of cartilage tissue in GLA?L and GLA?H groups was significantly improved,and the level of serum TNF?α,IL?6,CTX?Ⅰ,CTX?Ⅱ,iNOS activity and apoptosis rate of femur tissue were all significantly de?creased.Serum levels of S?Ca,S?P,BGP,ALP activity,bone trabecular density and thickness,HIF?1α,VEGF,CD31,BMP?2,collagen Ⅰ protein expression level in femur tissue were significantly increased(P<0.05).YC?1 was able to weaken the therapeutic effect of GLA on traumatic fracture rats(P<0.05).Conclusions GLA alleviates inflammation and cartilage damage in rats with traumatic fractures,promotes angio?genesis and improves femoral morphology,possibly by activating the HIF?1α/VEGF signaling pathway.

Objective:To evaluate the morphological characteristics of the fetal heart and the contractile function of the left and right ventricles in fetuses with pulmonary stenosis (PS) and pulmonary atresia (PA) using fetal heart quantitative analysis technology (fetal HQ), and to assess the impact of different degrees of right ventricular outflow tract obstruction (RVOTO) on the contractile function of the fetal left and right ventricles. To accumulate early data and explore parameters for constructing a predictive model and clinical decision-making tool for the progression of fetal PS and PA.Methods:A retrospective analysis was conducted on 42 cases of mild to moderate PS and 23 cases of severe PS or PA detected through fetal echocardiography in the Department of Ultrasound, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, from July 2020 to December 2021. A control group of 195 normal fetal cases matching gestational weeks was selected. The fetal HQ technique was employed to measure the global sphericity index (GSI), left ventricular ejection fraction (EF), left/right ventricular area change percentage (LVFAC, RVFAC), and left/right ventricular longitudinal strain (LVGLS, RVGLS). Additionally, 24-segment sphericity index (SI) and fractional shortening (FS) for both left and right ventricles were measured. Comparative analyses were performed between the case and control groups, as well as within the case group.Results:In comparison with the control group, the case group exhibited significantly decreased GSI, LVGLS, LVEF, LVFAC, RVGLS, and RVFAC.The differences were statistically significant in the mild to moderate PS group (all P<0.05) and highly significant in the severe PS/PA group (all P<0.01). In the mild to moderate PS group, the left ventricle′s 2nd segment, right ventricle′s 24th segment SI, and the left ventricle′s 1st-13th segments, right ventricle′s 1st-16th and 20th-24th segments FS showed statistically significant differences compared to the control group (all P<0.05). In the severe PS/PA group, the right ventricle′s 1st-22nd segment SI, and the left ventricle′s 6th-13th, 21st-24th segments, and the right ventricle′s 1st-14th segments FS were reduced, showing statistically significant differences compared to the control group (all P<0.05). The severe PS/PA group showed lower RVGLS, RVFAC, and SI for the right ventricle′s 1st to 17th segments when compared to the mild to moderate PS group, with statistically significant differences (all P<0.05). Conclusions:Quantitative indices derived by fetal HQ is capable of evaluating the cardiac morphology and function of fetuses with PS/PA, which may provide for reference information for comprehensive understanding of cardiac morphological and functional changes in such fetuses.

Objective:To explore the potential application of two-dimensional speckle tracking echocardiography (2D-STE) in terms of quantification and evaluating left and right atrial function in normal fetuses, and to investigate the relevant factors affecting left and right atrial function in normal fetuses as well as differences between both atrial function.Methods:A total of 100 single fetuses underwent fetal echocardiography in the Department of Diagnostic Ultrasound & Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine from January 2019 to October 2022 were retrospectively enrolled. The standard basal or apical four-chamber view clips were obtained, and the left and right atrial function were quantitatively analyzed using TomTec-ARENA off-line cardiac analysis software for quantitative assessment of both atrial strain measurements including left atrial reservoir phase longitudinal strain (LASr), left atrial ductal phase longitudinal strain (LAScd), left atrial systolic phase longitudinal strain (LASct), right atrial reservoir phase longitudinal strain (RASr), right atrial ductal phase longitudinal strain (RAScd), right atrial systolic phase longitudinal strain (RASct), and the ratio of systolic longitudinal strain to conduit longitudinal strain in left and right atrial systolic display groups were calculated which was denoted as Sct/Scd.Routine fetal obstetric ultrasound measurements and fetal echocardiographic parameters in the two groups were obtained including fetal heart rate (FHR), left atrial end-systolic length (LAESL), left atrial end-systolic diameter (LAESD), left atrial end-systolic area (LAESA), left ventricular end-diastolic transverse diameter (LVEDD), right atrial end-systolic length (RAESL), right atrial end-systolic diameter (RAESD), right atrial end-systolic area (RAESA), right ventricular end-diastolic transverse diameter (RVEDD), peak blood flow velocity of mitral valve and tricuspid valve in early and late diastolic period (E, A), peak ratio of E and A: E/A (MV), E/A (TV), and the difference between the left and right atrial strain indices and the routine fetal obstetric ultrasound and fetal echocardiographic parameters, as well as the correlation between the above parameters and gestational age were analyzed. The repeatability tests were performed using the intra-class correlation coefficientt (ICC).Results:Significant differences were found in LASr and RASr, LAScd and RAScd, LASct and LAScd, Sct/Scd between the left atrium and right atrium, E/A (MV) and E/A (TV), LAESD and RAESD, LAESL and RAESL (all P<0.05), there was significant difference in FHR between the left atrial contraction display group and the no atrial contraction display group ( P=0.011), no significant difference in other parameters (all P>0.05). Correlation analysis showed that, LASr, LASct, RASr, and RASct showed moderate negative correlation with gestational age ( rs=-0.570, -0.601, -0.469, -0.568; all P<0.001). While LAScd, RAScd, E/A (MV), E/A (TV) were moderately positively related with gestational age ( rs=0.310, 0.350, 0.330, 0.343; all P<0.05). LAESL, LAESD, LAESA, RAESL, RAESD, RAESA, LVEDD and RVEDD were significantly positively related with gestational age ( rs=0.662, 0.768, 0.792, 0.728, 0.828, 0.822, 0.838, 0.802, all P<0.001). The inter-examiner ICC of fetal LASr and RASr were 0.89 and 0.84 (both P<0.05) and the intra-examiner ICC of fetal RASr and LASr both were 0.80 (both P<0.05), with good consistency. Conclusions:2D-STE is highly feasible and reproducible in assessing fetal atrial function. The corresponding variation values of fetal atria at different gestational weeks were obtained in this study, which provides a new reference index for us to further study normal fetal atria as well as comparative analysis of fetal cardiac function under prenatal pathological conditions.

Objective:To explore the potential application of two-dimensional speckle tracking echocardiography (2D-STE) in terms of quantification and evaluating left atrial function in normal fetuses and fetuses with left ventricular outflow tract obstruction (LVOTO).Methods:A total of 32 fetuses diagnosed with LVOTO, who underwent fetal echocardiography at Sir Run Run Shaw Hospital, Zhejiang University College of Medicine between May 2020 to June 2022, were selected as the case group, and 100 pregnant women with normal singleton fetuses between January 2019 to October 2022 were chosen as the control group. The standard basal or apical four-chamber view clips were obtained and were quantitatively analyzed using TomTec-Arena off-line cardiac analysis software to obtain the left atrial strain parameters of the two groups of fetuses including left atrial reservoir phase longitudinal strain(LASr), left atrial ductal phase longitudinal strain(LAScd), left atrial systolic phase longitudinal strain (LASct), as well as the routine obstetric ultrasound measurements and fetal echocardiographic parameters of the two groups: biparietal diameter (BPD), femur length (FL), aortic annulus end-systolic inner diameter (AO), pulmonary annulus end-systolic inner diameter (PA), left atrial end-systolic long length (LAESL), left atrial end-systolic transverse diameter (LAESD), right atrial end-systolic long length (RAESL), right atrial end-systolic transverse diameter (RAESD), left ventricular end-diastolic transverse diameter (LVEDD) and right ventricular diastole end-diastolic transverse diameter (RVEDD). The ratio of right ventricular end-diastolic transverse diameter to left ventricular end-diastolic transverse diameter (RVd/LVd) and the ratio of pulmonary annulus diameter to aortic annulus diameter (PA/AO) were calculated. The differences of strain parameters between the two groups were compared, and the correlation between strain parameters and gestational age, RVd/LVd and other conventional measurement parameters were analyzed. ROC curve was used to compare the specificity and sensitivity of LASr and RVd/LVd in evaluating fetal cardiac dysfunction with LVOTO.Results:There were significant differences in LASr, LAScd, LASct, MAPSE, AO, LAESL, LVEDD, RVd/LVd and PA/AO between the two groups (all P<0.05), there were no significant differences in other parameters (all P>0.05). Correlation analysis showed that LASr was negatively correlated with RVd/LVd in LVOTO group ( rs=-0.394, P=0.025), and LASct was negatively correlated with RVd/LVd ( rs=-0.626, P=0.004). In the control group, LASr was negatively correlated with gestational age, AO and PA ( r/ rs=-0.570, -0.440, -0.493; all P<0.001), and LASct was negatively correlated with gestational age, AO and PA ( r/ rs=-0.601, -0.532, -0.568; all P<0.001). LAScd was positively correlated with gestational age, AO and PA ( r/ rs=0.310, 0.370, 0.314; all P<0.05). There were no significant correlations between the other parameters (all P>0.05). ROC curve analysis showed that the area under the curve(AUC) in LASr evaluation of fetal cardiac dysfunction with LVOTO was 0.890 (0.826, 0.953) and the AUC in RVd/LVd evaluation of fetal cardiac dysfunction with LVOTO was 0.742 (0.637, 0.846), there were significant differences between them( P<0.05). Conclusions:2D-STE is highly feasible and reproducible in assessing fetal left atrial function. Evaluation of fetal left atrial function by 2D-STE provides a new reference index for quantitative analysis of fetal cardiac dysfunction.

At present,pharmaceutical services for Alzheimer's disease (AD) patients are mostly based on the western medication therapy management (MTM) model,which includes conducting drug treatment evaluations for patients,identifying drug treatment issues,proposing drug treatment recommendations,restructuring drug treatment checklists,follow-up visiting and recording,etc.However,in recent years,more and more domestic clinical practices have proven that individualized treatment with dialectical treatment of traditional Chinese medicine can effectively prevent and delay the occurrence and development of AD,while the MTM pharmaceutical service model has some limitations when facing such AD patients.Therefore,it is necessary to explore a new pharmaceutical service model with Chinese medicine characteristics for AD MTM,so as to provide pharmaceutical services for patients receiving individualized treatment of AD through the combination of traditional Chinese and Western medicine.Combining the traditional Chinese medicine sequential therapy of AD with the MTM concept,MTM was conducted on a typical outpatient AD patient,which effectively solved the medication related problems of the patient and ensured the medication safety and efficacy.

ObjectiveTo investigate the differences in clinical features and mortality rate between native patients with chronic liver failure （CHF） and migrated patients with CHF after treatment with double plasma molecular adsorption system （DPMAS） in high-altitude areas. MethodsA total of 63 patients with CHF who received DPMAS treatment in the intensive care unit of General Hospital of Tibet Military Command from January 2016 to December 2021 were enrolled， and according to their history of residence in high-altitude areas， they were divided into native group with 29 patients and migrated group with 34 patients. The two groups were compared in terms of baseline data and clinical features before and after DPMAS treatment. The independent-samples t test was used for comparison of normally distributed continuous data between groups， and the paired t-test was used for comparison before and after treatment within each group； the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups， and the Wilcoxon signed rank sum test was used for comparison before and after treatment within each group； the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves， and the Log-rank test was used for comparison of the risk of death. ResultsCompared with the native group， the migrated group had a significantly higher proportion of Chinese Han patients （χ²=41.729， P<0.001）， and compared with the migrated group， the native group had a significantly longer duration of the most recent continuous residence in high-altitude areas （Z=3.364， P<0.001）. Compared with the native group， the migrated group had significantly higher MELD score and incidence rates of hepatic encephalopathy， hepatorenal syndrome， and gastrointestinal bleeding （Z=2.318， χ²=6.903， 5.154， and 6.262， all P<0.05）. Both groups had significant changes in platelet count （PLT）， hemoglobin count （HGB）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， albumin， total bilirubin （TBil）， direct bilirubin （DBil）， lactate dehydrogenase （LDH）， creatinine （Cr）， and international normalized ratio （INR） after DPMAS treatment （all P<0.05）. Before DPMAS treatment， compared with the native group， the migrated group had significantly higher levels of ALT， AST， TBil， DBil， LDH， Cr， BUN， and INR （all P<0.05） and a significantly lower level of HGB （P<0.05）； after DPMAS treatment， compared with the native group， the migrated group had significantly greater reductions in PLT and HGB （both P<0.05） and still significantly higher levels of ALT， AST， TBil， DBil， LDH， BUN， and INR （all P<0.05）. The 60-day mortality rate of patients after DPMAS treatment was 52.5% （95% confidence interval ［CI］： 41.7 — 63.8） in the native group and 81.3% （95%CI： 77.9 — 85.6） in the migrated group. Compared with the native group （hazard ratio ［HR］=0.47， 95%CI： 0.23 — 0.95）， the migrated group had a significant increase in the risk of death on day 60 （HR=2.14， 95%CI： 1.06 — 4.32， P=0.039）. ConclusionCompared with the native patients with CHF in high-altitude areas， migrated patients have a higher degree of liver impairment， a lower degree of improvement in liver function after DPMAS treatment， and a higher mortality rate. Clinical medical staff need to pay more attention to migrated patients with CHF， so as to improve their survival rates.