ObjectiveTo investigate the anti-Alzheimer's disease （AD） effect of Dipsacus asper（DA） in the Caenorhabditis elegans model， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor α （PPARα）/transcription factor EB （TFEB） pathway. MethodsFirst， transgenic AD C. elegans individuals were assigned into the blank control， model， positive control （WY14643， 20 µmol·L^-1）， and low-， medium-， and high-dose （100， 200， and 400 mg·L^-1， respectively） DA groups. The amyloid β-42 （Aβ₄₂） formation in the muscle cells， the paralysis time， and the deposition of amyloid β-protein （Aβ） in the head were detected. The lysosomal autophagy in the BV2 cell model was examined by Rluc-LC3wt/G120A. The expression levels of lysosomal autophagy-related proteins LC3Ⅱ， LC3I， LAMP2， and TFEB were detected by Western blot. Real-time quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of autophagy-related genes beclin1 and Atg5 and lysosome-related genes LAMP2 and CLN2 downstream of PPARα/TFEB. A reporter gene assay was used to detect the transcriptional activities of PPARα and TFEB. Immunofluorescence was used to detect the fluorescence intensity of PPARα， and the active components of the ethanol extract of DA were identified by UPLC-MS. RCSB PDB， Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and Autodock were used to analyze the binding between the active components and PPARα-ligand-binding domain （LBD）. ResultsCompared with the model group， the positive control group and 200 and 400 mg·L^-1 DA groups showed prolonged paralysis time （P<0.05）， and all the treatment groups showed decreased Aβ deposition in the head （P<0.01）. DA within the concentration range of 50-500 mg·L^-1 did not affect the viability of BV2 cells. In addition， DA enhanced the autophagy flux （P<0.05）， up-regulated the mRNA levels of beclin1， Atg5， LAMP2， and CLN2 （P<0.05， P<0.01）， promoted the nuclear translocation of TFEB （P<0.05）， increased LAMP2 expression and autophagy flux （P<0.05， P<0.01）， and enhanced the transcriptional activities of PPARα and TFEB （P<0.01）. The positive control group and 200 and 400 mg·L^-1 DA groups showed enhanced fluorescence intensity of PPARα in the BV2 nucleus （P<0.01）. UPLC-MS detected nine known compounds of DA， from which 8 active components of DA were screened out. The docking results suggested that a variety of components in DA could bind to PPARα-LBD and form stable hydrogen bonds. ConclusionDA may reduce the pathological changes in AD by regulating the PPARα-TFEB pathway.

OBJECTIVE To analyze the characteristics of severe cutaneous adverse reactions （SCARs） induced by oral anticoagulants （OACs）， and provide a reference for clinical safety of drug use. METHODS Case reports of SCARs caused by OACs （warfarin， apixaban， rivaroxaban， edoxaban， dabigatran etexilate） were retrieved from PubMed， Embase， CNKI， Wanfang Data， VIP and other databases with search terms as “oral anticoagulants”“factor Ⅹa inhibitor”“direct thrombin inhibitor” and their Chinese equivalents. A descriptive statistical analysis was performed. RESULTS A total of 11 articles were included， involving 11 patients in total， among whom there were 5 males （45.5%） and 6 females （54.5%）， with an average age of （59.6±21.5） years. The primary underlying diseases were mainly atrial fibrillation， pulmonary embolism， joint replacement and valve replacement. The OACs involved included warfarin in 3 cases， rivaroxaban in 4 cases， apixaban in 2 cases， and dabigatran etexilate in 2 cases. SCARs occurred from 10 hours to 42 days after treatment， and 7 cases （63.6%） within 10 to 28 days. Among 11 patients， 5 cases were diagnosed as drug reaction with eosinophilia and systemic symptoms， 4 cases were diagnosed as Stevens-Johnson syndrome or toxic epidermal necrolysis， and 2 cases were diagnosed as acute generalized exanthematous pustulosis. The clinical manifestations mainly included rash， fever and mucosal damage， etc. Except for 1 patient who died of sepsis and diffuse intravascular coagulation， the rest of the patients improved or recovered after withdrawal and treatment with glucocorticoids. CONCLUSIONS SCARs are rare but serious adverse reactions caused by OACs， typically occurring 10 to 28 days after medication. Once SCARs are suspected to be caused by OACs， the medication should be discontinued immediately， and a treatment plan should be formulated based on the type of SCARs to ensure the safety of patients’ drug use.

Objective:To analyze the effect of recombinant human thrombopoietin(rhTPO)on platelet(PLT)reconstitution after autologous peripheral blood stem cell transplantation(APBSCT)in patients with multiple myeloma(MM).Methods:The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed.According to whether rhTPO was used during APBSCT,the patients were divided into rhTPO group(80 cases)and control group(67 cases).The time of PLT engraftment,blood product infusion requirements,the proportion of patients with PLT recovery to ≥ 50 × 109/L and ≥ 100 × 109/L at+14 days and+100 days after transplantation,and adverse reactions including the incidence of bleeding were compared between the two groups.Results:There were no significant differences between the two groups in sex,age,M protein type,PLT count at the initial diagnosis,median duration of induction therapy before APBSCT,and number of CD34+cells reinfused(all P＞0.05).The median time of PLT engraftment in the rhTPO group was 10(6-14)days,which was shorter than 11(8-23)days in the control group(P＜0.001).The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U,which was less than 20(0-80)U in the control group(P=0.001).At+14 days after transplantation,the proportions of patients with PLT 2 50 × 109/L in the rhTPO group and the control group were 66.3％and 52.2％,while the proportions of patients with PLT ≥ 100 × 109/L were 23.8％and 11.9％,respectively,with no significant differences(all P＞0.05).At+100 days after transplantation,the proportion of patients with PLT ≥ 50 × 109/L in rhTPO group and control group was 96.3％and 89.6％,respectively(P＞0.05),but the proportion of patients with PLT ≥ 100 × 109/L in rhTPO group was higher than that in control group(75.0％vs 55.2％,P=0.012).There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups.In rhTPO group,the rhTPO administration was well tolerated,and the incidences of abnormal liver and kidney function and infection were similar to those in the control group.Conclusion:When MM patients undergo first-line APBSCT,subcutaneous injection of rhTPO can shorten the time of platelet engraftment,reduce the transfusion volume of blood products,and be well tolerated,moreover,more patients have achieve a high level of PLT recovery after transplantation,which is very important for ensuring the safety of APBSCT and maintenance therapy.

Objective:To explore the relationship between weight change and the development of hyperuricemia (HUA) in adults receiving health checkups.Methods:A retrospective cohort study. A total of 37 722 subjects who underwent two or more health checkups at the Health Management Center of the Second Affiliated Hospital of Dalian Medical University from January 2014 to December 2022 were included, and the general information and laboratory findings at the time of the initial health checkups and follow-up were collected. Weight change was defined as the ratio of difference between the weight at the last follow-up and the baseline weight to baseline weight. The subjects were grouped with weight change: significant weight loss group (weight change ≤-5.0%), mild weight loss group (-5.0%

Objective:To investigate the association between different dietary patterns and subtypes of metabolic associated fatty liver disease(MAFLD).Methods:A total of 6 022 check-ups at the health management center of the Second Hospital of Dalian Medical University from January 2022 to March 2023 were selected as study subjects. MAFLD was categorised into three subtypes: overweight/obese type, metabolic disorder type, and diabetic type. Factor analysis was used to extract dietary patterns. Logistic regression was used to assess the impact of dietary patterns on MAFLD occurrence, constructing interaction models between dietary patterns intake and age, gender, and physical exercise levels. Results:Four dietary patterns were extracted based on feature sorting after factor analysis and were named as the high-quality protein pattern, the fruit-vegetable pattern, egg-aquatic pattern, and the processed meat pattern. Regression analysis of the unadjusted model showed that overweight/obese and diabetic types of MAFLD were negatively associated with the high-quality protein mode, while model-adjusted regression analysis showed that the processed meat pattern was positively associated with the risk of MAFLD, and fruit-vegetable pattern was positively associated with overweight/obese MAFLD( P<0.05). The results of subgroup analyses suggested that female( OR=1.55, 95% CI 1.14-2.15) with a high intake of pickle pattern had a higher risk of overweight/obese MAFLD than male( OR=1.18, 95% CI 1.02-1.49). Conclusion:High-quality protein pattern was negatively correlated with MAFLD, whereas fruit-vegetable pattern and processed meat pattern were positively correlated with MAFLD. Female with high consumption of processed meat pattern are more likely to develop overweight/obesity MAFLD compared with male. It is recommended that people with MAFLD reduce their intake of processed products and high-fructose food, and consume adequate amounts of high-quality protein food to maintain a balanced diet.

Objective:To investigate the relationship between obesity and incident chronic kidney disease(CKD) in a population undergoing health check-ups.Methods:This is a retrospective cohort study. A total of 31 251 participants who had at least 2 health physical examinations in the Health Management Center of the Second Affiliated Hospital of Dalian Medical University from January 2017 to December 2022 and met the inclusion criteria were selected. The participants were divided into normal body weight group, overweight group, and obese group according to baseline body mass index. Cox proportional hazard regression model was used to analyze the relationship between obesity and new-onset CKD, and the dose-response relationship between body mass index and CKD was analyzed with restricted cubic splines.Results:Multivariate Cox regression analysis showed that the risk of developing CKD increased by 13%( HR=1.13, 95% CI 1.01-1.25) and 55%( HR=1.55, 95% CI 1.36-1.76) in the overweight and obese group compared to the normal weight group. Subgroup analysis indicated that obese women had a higher risk of developing CKD compared to men. There was a " U-shaped" correlation between body mass index and CKD in male population, with the lowest risk of CKD occurring at body mass index of 19.6-24.2 kg/m 2. In women, the relationship between body mass index and CKD was approximately linear, with the risk of CKD gradually increasing when body mass index exceeded 22.5 kg/m 2. Conclusions:Obesity is an independent risk factor for new-onset CKD, and obese women have a higher risk of developing CKD than men. Regarding CKD prevention, men are advised to maintain a higher level of body weight within the normal range of body mass index, while women are encouraged to control their weight to a lower level within the normal body mass index range.

Objective:To explore the correlation between systemic immunity-inflammation index(SII) and hyperuricemia(HUA).Methods:Participants who had at least 3 health checkups in the Health Management Center of the Second Affiliated Hospital of Dalian Medical University from January 2014 to December 2022 were selected to construct a dynamic cohort. The SII, reflecting the inflammatory state of the body, was constructed using neutrophil, platelet, and lymphocyte counts. A Cox proportional hazard regression model was used to explore the association between SII and HUA in the overall population and different subgroups of the population, and sensitivity analysis was performed twice. Results:A total of 20 022 subjects were included, and the mean follow-up time was 3.67 years. After adjusting for confounding factors, each unit increase in the natural logarithm of SII(lnSII) was associated with a 24% increased risk of hyperuricemia( HR=1.24, 95% CI 1.16-1.32, P<0.001). As a categorical variable, compared with the lowest quartile array( Q1), the risk of HUA in the total population increased by 12%( HR=1.12, 95% CI 1.03-1.21, P=0.006), 14%( HR=1.14, 95% CI 1.06-1.24, P=0.001), 27%( HR=1.27, 95% CI 1.17-1.37, P<0.001) in Q2, Q3 and Q4 groups within the general population, respectively. All subgroup analysis and sensitivity analysis showed that SII was positively correlated with HUA. Conclusions:Elevated levels of SII significantly increase the risk of HUA. Assessing the body′s inflammatory status using SII can aid in risk screening and preventive management for individuals at high risk of HUA.

Objective To investigate the predictive value of combined detection of serum vascular cell adhesion molecule-1(VCAM-1),platelet endothelial cell adhesion molecule-1(PECAM-1)levels and mini mental state examination(MMSE)score for postoperative delirium(POD)in elderly patients underwent total hip arthroplasty(THA).Methods A total of 200 elderly patients with hip fracture underwent surgical treatment were selected as the research objects.Patients were divided into the POD group(n=44)and the non-POD group(n=156)according to whether POD occurred within 3 days after operation.The clinical data of patients in the two groups were collected.The preoperative cognitive status was evaluated by MMSE,and serum levels of VCAM-1 and PECAM-1 were detected before operation and 1st and 3rd day after operation.The differences of the above indexes between the two groups were compared,and the correlation between preoperative serum VCAM-1,PECAM-1 levels and MMSE score were analyzed.Multivariate Logistic regression analysis was utilized to investigate influencing factors of POD in elderly patients underwent THA.A receiver operating characteristic(ROC)curve was constructed to assess the predictive value of preoperative serum levels of VCAM-1 and PECAM-1,as well as MMSE score,both individually and in combination for POD in elderly patients undergoing THA.Results The age,hospital anxiety and depression scale score,incidence of intraoperative hypotension and postoperative hospital stay were significantly higher or longer in the POD group than those in the non-POD group,and the MMSE score was lower than that in the non-POD group(P＜0.05).The serum levels of VCAM-1 and PECAM-1 before operation,1st and 3rd day after operation were increased in the POD group,and which were significantly higher than those in the non-POD group(P＜0.05).The serum levels of VCAM-1 and PECAM-1 were significantly negatively correlated with MMSE score in elderly patients undergoing THA(r=-0.390,-0.501,P＜0.01).The elevated serum levels of VCAM-1 and PECAM-1 before operation and prolonged postoperative hospital stay were independent risk factors for POD in elderly patients underwent THA,and the elevated value of MMSE score was independent protective factor(P＜0.05).Preoperative serum VCAM-1(AUC=0.793,95%CI:0.730-0.847),PECAM-1(AUC=0.799,95%CI:0.736-0.852)and MMSE score(AUC=0.805,95%CI:0.744-0.858)showed high predictive value for POD in elderly patients underwent THA,and the combined detection of the three indicators had higher predictive efficiency.Conclusion The elevated serum levels of VCAM-1 and PECAM-1 are related to the impairment of cognitive function in elderly patients undergoing THA,and they are independent predictors for POD in elderly patients undergoing THA,thus may be helpful for early diagnosis and prevention of POD.

ObjectiveTo explore the molecular mechanism of Sanhuang Xiexintang （SHXXT） in protecting stress gastric ulcer （SGU） in rats through network pharmacology， molecular docking， and animal experiments. MethodThe active ingredients and corresponding targets in SHXXT were collected and screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， Traditional Chinese Medicine Information Database （TCMID）， Bioinformation Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine （BATMAN-TCM）， and Swiss Target Prediction database. SGU-related targets were screened from the Online Mendelian Inheritance in Man （OMIM）， Therapeutic Target Database （TTD）， GeneCards database， and PharmGKB database. Herbal-ingredient-target （H-C-T） network was constructed by using Cytoscape 3.9.1 software. Protein-protein interaction （PPI） of drug and disease intersection targets was analyzed by using the Protein Interaction Platform （STRING） database. Gene ontology （GO） enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway analysis were conducted through the Database for Annotation Visualization and Integrated Discovery （DAVID）. The active ingredients and key targets were validated using AutodockVina 1.2.2 molecular docking software， and the experimental results were further validated through animal experiments. ResultThe 55 active ingredients were screened， and 255 potential target genes for SHXXT treatment of SGU were predicted. The PPI analysis showed that protein kinase B （Akt）， phosphatase and tensin homolog deleted on chromosome ten （PTEN）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and cyclooxygenase-2 （COX-2） are the core targets of SHXXT for protecting SGU. GO and KEGG analyses showed that SHXXT may affect the development of SGU by regulating various biological processes such as the phosphoinositide 3-kinase （PI3K）/Akt signaling pathway and inflammatory processes. The molecular docking results showed that both the active ingredients and key targets had good binding ability. Animal experiments showed that compared with the blank group， the ulcer index （UI） of the model group was significantly increased （P<0.01）， and the serum levels of TNF-α and IL-1β significantly increased （P<0.01）. The phosphorylation level of PTEN in gastric mucosal tissue was significantly down-regulated （P<0.05）. The phosphorylation levels of PI3K， Akt， and nuclear factor kappa-B （NF-κB） were significantly up-regulated （P<0.05）. Compared with the model group， the UI of the treatment group was significantly reduced （P<0.01）， and the serum levels of TNF-α and IL-1β were significantly reduced （P<0.01）. The phosphorylation level of PTEN in gastric mucosal tissue was significantly up-regulated （P<0.01）， and the phosphorylation levels of PI3K， Akt， and NF-κB were significantly downregulated （P<0.01）. ConclusionThe application of network pharmacology prediction， molecular docking simulation， and animal experimental validation confirms that SHXXT regulates the PI3K/Akt/NF-κB signaling pathway to regulate the inflammatory response of rats and thus protects the gastric mucosa of SGU rats.

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG^@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.