ObjectiveTo explore the effects of different dosage forms of Kaixinsan （KXS） on the morphology and function of mitochondria in rat models of Alzheimer's disease （AD） and potential mechanisms of action. MethodsMale SD rats were randomly assigned to a sham group， model group， treatment groups receiving KXS decoction， powders， and granules （3.08 g·kg^-1）， as well as donepezil group （0.51×10^-3 g·kg^-1）， with 10 rats in each group. AD model was created using intracerebroventricular injection of streptozocin （STZ）. After 30 days of administration， behavioral assessments were conducted， and mitochondrial morphology was observed using transmission electron microscopy. Mitochondrial respiratory chain complex content was measured via enzyme-linked immunosorbent assay （ELISA）. Changes in mitochondrial membrane potential were measured via JC-1 staining， and superoxide dismutase （SOD） activity and reactive oxygen species （ROS） levels were measured via biochemical assays. The mRNA expression of adenosine 5'-monophosphate-activated protein kinase （AMPK）， peroxisome proliferator-activated receptor gamma coactivator-1α （PGC-1α）， and silent information regulator 3 （SIRT3） was detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， and Western blot was used to examine the protein expression levels of optic atrophy protein1 （OPA1）， mitochondrial fission protein 1 （FIS1）， AMPK， p-AMPK， PGC-1α， and SIRT3. ResultsCompared with the sham group， rats in the model group had significantly lower recognition index， spontaneous alternation rate， escape latency， number of platform crossings， time spent in the target quadrant， and percentage of distance traveled in the target quadrant distance （P<0.05， P<0.01）. Significant mitochondrial damage was observed in the hippocampal tissue， with a marked decrease in mitochondrial respiratory chain complex content （P<0.01） and reduced mitochondrial membrane potential （P<0.05）. Additionally， the SOD activity was reduced， while ROS levels were elevated （P<0.01）. The mRNA expression of PGC-1α and SIRT3 was significantly downregulated （P<0.01）， along with decreased protein expression levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， whereas FIS1 protein expression was significantly upregulated （P<0.05， P<0.01）. Compared with the model group， rats in KXS-treated groups （various dosage forms） showed significant improvement in behavioral indexes （P<0.05， P<0.01）， reduced hippocampal mitochondrial damage， and more organized mitochondrial cristae. Mitochondrial respiratory chain complex content was significantly increased （P<0.05， P<0.01）， and mitochondrial membrane potentials were elevated （P<0.05）. SOD activity was elevated， and ROS levels were significantly reduced （P<0.05， P<0.01）. Furthermore， the mRNA expression of PGC-1α and SIRT3 was upregulated， with increased protein levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， while FIS1 protein expression levels were significantly reduced （P<0.05， P<0.01）. Across the KXS-treated groups， the granule group showed a higher spontaneous alternation rate than the decoction and powder groups （P<0.05）. ConclusionKXS decoction， powders， and granules can improve the learning and memory ability of rats， with granules being the most effective. The mechanism of action may involve activation of the AMPK/PGC-1α/SIRT3 signaling pathway， improvement of the mitochondrial function， and subsequent amelioration of the brain energy metabolism disorders.

ObjectiveTo explore the effects of different dosage forms of Kaixinsan （KXS） on the morphology and function of mitochondria in rat models of Alzheimer's disease （AD） and potential mechanisms of action. MethodsMale SD rats were randomly assigned to a sham group， model group， treatment groups receiving KXS decoction， powders， and granules （3.08 g·kg^-1）， as well as donepezil group （0.51×10^-3 g·kg^-1）， with 10 rats in each group. AD model was created using intracerebroventricular injection of streptozocin （STZ）. After 30 days of administration， behavioral assessments were conducted， and mitochondrial morphology was observed using transmission electron microscopy. Mitochondrial respiratory chain complex content was measured via enzyme-linked immunosorbent assay （ELISA）. Changes in mitochondrial membrane potential were measured via JC-1 staining， and superoxide dismutase （SOD） activity and reactive oxygen species （ROS） levels were measured via biochemical assays. The mRNA expression of adenosine 5'-monophosphate-activated protein kinase （AMPK）， peroxisome proliferator-activated receptor gamma coactivator-1α （PGC-1α）， and silent information regulator 3 （SIRT3） was detected by real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）， and Western blot was used to examine the protein expression levels of optic atrophy protein1 （OPA1）， mitochondrial fission protein 1 （FIS1）， AMPK， p-AMPK， PGC-1α， and SIRT3. ResultsCompared with the sham group， rats in the model group had significantly lower recognition index， spontaneous alternation rate， escape latency， number of platform crossings， time spent in the target quadrant， and percentage of distance traveled in the target quadrant distance （P<0.05， P<0.01）. Significant mitochondrial damage was observed in the hippocampal tissue， with a marked decrease in mitochondrial respiratory chain complex content （P<0.01） and reduced mitochondrial membrane potential （P<0.05）. Additionally， the SOD activity was reduced， while ROS levels were elevated （P<0.01）. The mRNA expression of PGC-1α and SIRT3 was significantly downregulated （P<0.01）， along with decreased protein expression levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， whereas FIS1 protein expression was significantly upregulated （P<0.05， P<0.01）. Compared with the model group， rats in KXS-treated groups （various dosage forms） showed significant improvement in behavioral indexes （P<0.05， P<0.01）， reduced hippocampal mitochondrial damage， and more organized mitochondrial cristae. Mitochondrial respiratory chain complex content was significantly increased （P<0.05， P<0.01）， and mitochondrial membrane potentials were elevated （P<0.05）. SOD activity was elevated， and ROS levels were significantly reduced （P<0.05， P<0.01）. Furthermore， the mRNA expression of PGC-1α and SIRT3 was upregulated， with increased protein levels of OPA1， p-AMPK/AMPK， PGC-1α， and SIRT3， while FIS1 protein expression levels were significantly reduced （P<0.05， P<0.01）. Across the KXS-treated groups， the granule group showed a higher spontaneous alternation rate than the decoction and powder groups （P<0.05）. ConclusionKXS decoction， powders， and granules can improve the learning and memory ability of rats， with granules being the most effective. The mechanism of action may involve activation of the AMPK/PGC-1α/SIRT3 signaling pathway， improvement of the mitochondrial function， and subsequent amelioration of the brain energy metabolism disorders.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma, accompanied by dynamic changes in the tumor microenvironment (TME). A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction (SBJDD) in preventing colorectal tumorigenesis. However, the mechanism remains unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry. Bulk RNA sequencing was utilized to assess the underlying mechanisms. Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc ^Min/+ mice and clinical patients. There was a marked accumulation of CCL22⁺ dendritic cells (DCs) and an enhanced immunosuppressive action, which SBJDD and berberine reversed. Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22⁺ DCs, which may represent "exhausted DCs". Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects. TMEM131 derived CCL22⁺ DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis. These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer (CRC), suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.

Objective To investigate whether activation of PI3K/AKT/mTOR pathway can reduce inflammation in acute pancreatitis(AP)rats.Methods SD rats were grouped into sham surgery group,model group,Gln group,and Gln+LY294002 group(PI3K/AKT/mTOR pathway inhibitors).Intra-abdominal pressure(IAP),ascites volume(AS),serum amylase(AMY),diamine oxidase(DAO),interleukin(IL-1β,IL-6),Tumor necrosis factor(TNF-α)were measured.The pathological change in pancreatic and small intestinal tissues was evaluated by microscopy;The expression of PI3K,Akt and mTOR genes and cytoplasm compact linking protein(ZO-1),compact linking protein(occludin-1),PI3K,Akt and mTOR in ileum of each group were detected.Results Compared with the sham surgery group,the IAP and AS,IL-1β,IL-6,TNF-α,AMY,DAO,and pathological injury scores of pancreas and small intestine in the model group were obviously increased;The expression of PI3K mRNA,Akt mRNA,mTOR mRNA,ZO-1,occludin-1,p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR in rat ileum tissue significantly reduced(P＜0.05).Compared with the model group,the level of IAP and AS,IL-1β,IL-6,TNF-α,AMY,DAO and pathological injury scores of pancreas and small intestine in the Gln group were significantly reduced;The expression of PI3K mRNA,Akt mRNA,mTOR mRNA,ZO-1,occludin-1,p-PI3K/PI3K,p-Akt/Akt and p-mTOR/mTOR in rat ileum tissue was significantly increased(P＜0.05);LY294002 could specifically reverse the therapeutic effect of Gln on acute pancreatitis in rats.Conclusions Acti-vation of PI3K/AKT/mTOR pathway may reduce inflammation and improve gastrointestinal function in rats with acute pancreatitis.

ObjectiveTo explore the function of DANCR during the differentiation of human embryonic stem cells （hESC） toward definitive endoderm （DE）. MethodsThe in vitro DE differentiation system was established and its efficiency was verified. The correlation between the expression level of DANCR and DE differentiation process was detected. Using lentivirus system， we stably knocked down DANCR in hESC. The shDANCR hESC line was applied to DE differentiation， using qPCR and Western blot to detect the expression of DE marker genes SOX17 and FOXA2， and that of primitive streak marker genes Brachyury （T）， EOMES， MIXL1 and GSC. Dual luciferase reporter assay and qPCR were used to confirm the interaction between DANCR and the WNT pathway during DE differentiation. ResultsThe in vitro differentiation system mimicked DE differentiation efficiently. And the expression of DANCR was gradually downregulated during differentiation. DANCR was efficiently knocked down in the shDANCR hESC line （P < 0.001）. Compared with those in the control group， the expression levels of primitive markers Brachyury （T）， EOMES， MIXL1 and GSC， as well as DE markers SOX17 and FOXA2， were significantly decreased in shDANCR groups （P < 0.05）. Furthermore， the transcriptional activity of the WNT pathway in shDANCR groups was lower than that in the control group （P < 0.05）. And RNA levels of downstream genes of the WNT pathway， FZD5， FZD8， SFRP1， FRZB and ANKRD6， were significantly decreased in shDANCR groups （P < 0.05）. However， differences in protein levels of the TGFβ pathway effectors SMAD2/3 and p-SMAD2 were statistically insignificant in shDANCR and control groups （P > 0.05）. Forced activation of β-CATENIN rescued DANCR knock down-induced deficiency in DE differentiation. ConclusionsThe expression of DANCR decreases during DE differentiation. DANCR may promote DE differentiation through modulating the activity of the WNT pathway.

Objective To analyze the predictive value of serum levels of procalcitonin(PCT)and cytokines on the prognosis of patients with COVID-19 at admission.Methods From November 2022 to February 2023,patients diagnosed with COVID-19 who were admitted to Beijing Chest Hospital were enrolled.Chemiluminescence was used to detect serum PCT levels,and flow microsphere array was used to detect serum cytokines IL-1β,IL-2,IL-4,IL-5,IL-6,IL-8,IL-10,IL-12p70,IL-17A,IL-17F,IL-22,TNF-α,TNF-β,IFN-γ level.ICU admission,mechanical ventilation and in-hospital death were defined as poor prognosis.After excluding patients with bacterial infection,the relationship between serum PCT and cytokine levels at admission and the prognosis of COVID-19 patients was analyzed.After excluding patients with bacterial infection,the relationship between serum PCT and cytokine levels at admission and the prognosis of COVID-19 patients was analyzed.Results A total of 176 patients with complete data were included,including 134 in the PCT-normal group and 42 in the PCT-elevated group,with a median age of 71.50 years and 71.59%males.Patients in the PCT elevated-group had significantly higher rates of ICU admission(38.41%vs.13.11%,P<0.05),mechanical ventilation(76.92%vs.24.59%,P<0.001)and in-hospital mortality(38.46%vs.6.56%,P<0.001)were significantly higher than those in the PCT-normal group.Serum levels of cytokines IL-6(7.40 pg/mL vs.4.78 pg/mL,P = 0.033 4)and IL-8(10.97 pg/mL vs.5.92 pg/mL,P<0.001)were significantly higher in patients with poor prognosis than in those with good prognosis.The area under the curve for PCT,IL-6,and IL-8 to predict poor prognosis in COVID-19 patients was 0.687,0.660,and 0.746,respectively;sensitivity was 52.78%,55.17%,and 72.41%,respectively;and specificity was 81.58%,74.19%,and 74.19%,respectively,as calculated from the ROC curve.When PCT,IL-6 and IL-8 jointly predict the prognosis of COVID-19 patients,the area under the curve is 0.764,the sensitivity is 70.00%,and the specificity is 80.00%.Conclusion Serum PCT and cytokines IL-6 and IL-8 could be used as predictive markers for poor prognosis in patients with COVID-19.

Objective:To explore the predictive value of uterine artery blood flow parameters of Doppler ultrasound combined with coagulation related indicators on the pregnancy outcome of recurrent abortion caused by thrombophilia.Methods:A total of 82 patients with recurrent abortion who admitted to the department of gynecology outpatient of Beijing Haidian Hospital from January 2020 to January 2023 were selected.All patients received relevant treatment,and the follow-up results were calculated as statistic method.Before treatment on the day after admission,uterine artery pulse index(PI),resistance index(RI),the ratio of the maximum blood flow velocity of systolic pressure(S)to the maximum blood flow velocity of end-diastolic(D)(S/D),and activated partial thromboplastin time(APTT),prothrombin time(PT),fibrinogen(FIB),thrombin time(TT)and D-dimer(D-D)of all patients were detected.Pearson correlation analysis was adopted to analyze the correlations between PI,RI,S/D and each of APTT,PT,FIB,TT and D-D.Receiver operating characteristic(ROC)curve was used to analyze the values of single PI,RI,S/D,APTT,PT,FIB,TT and D-D,and the value of the combined detection of them in predicting the pregnancy outcome of recurrent abortion caused by thrombophilia.Results:Follow up results showed that 49 cases of 82 patients with recurrent abortion were successful pregnancy and 33 cases of them occurred pregnancy loss,and the PI,RI and S/D of pregnant women with successful pregnancy were significantly lower than those of pregnant women who occurred pregnancy loss,with statistical significance(t=10.598,6.693,3.059,P<0.05).The levels of APTT,PT,FIB,TT and D-D of pregnant women with successful pregnancy were significantly lower than those of pregnant women who occurred pregnancy loss,and the differences were statistically significant(t=9.552,96.462,22.767,5.100,95.805,P<0.05),respectively.PI appeared respectively positive correlation with APTT,PT,FIB,TT and D-D(r=3.178,P<0.05),and RI appeared respectively positive correlation with APTT,PT,FIB and D-D(r=3.246,P<0.05),and S/D also appeared respectively positive correlation with PT,FIB,TT and D-D(r=3.246,P<0.05).The sensitivities of single PI,RI,S/D,APTT,PT,FIB,TT and D-D detection,and the combined detection of them were respectively 42.40%,48.50%,39.40%,48.50%,63.60%,72.70%,42.40%,39.40%and 84.80%in predicting the pregnancy outcome of recurrent abortion caused by thrombophilia.The specificities of them were respectively 98.00%,71.40%,55.10%,75.50%,59.20%,71.40%,77.60%,85.70%and 98.80%,and the AUC values of them were respectively 0.674,0.685,0.409,0.646,0.784,0.788,0.566,0.563 and 0.941.Conclusion:Both single and combination of PI,RI and S/D of uterine artery blood flow parameters,as well as APTT,PT,FIB,TT and D-D of coagulation related indicators,have a certain value in predicting pregnancy outcome of recurrent abortion caused by thrombophilia,and the combined detection has higher predictive value.

AIM: To observe the changes of corneal densitometry(CD)in patients with keratoconus after corneal cross-linking(CXL).METHODS: Retrospective study. A total of 32 patients(43 eyes)with keratoconus in Ningxia Eye Hospital from April 2020 to April 2022 were selected. Pentacam analysis system divided the cornea into three layers: anterior 120 μm, middle layer and posterior 60 μm, and divides it into five regions with diameters of 0-2, 2-6, 6-10, 10-12 mm and full diameter according to the diameter, and measures the CD in different ranges. The changes of CD were compared before operation and at 1, 3 and 6 mo after operation.RESULTS: There were differences in uncorrected visual acuity, best corrected visual acuity and intraocular pressure before and 6 mo after operation(all P<0.05), and there was no difference in corneal endothelial cells(P=0.477). CD reached its peak at 1 mo after operation, and decreased at 3 mo and 6 mo after operation, but it was still higher than that before operation. There is a significant positive correlation between CD and Kmax in the anterior layer and the whole layer(r=0.164, P=0.016; r=0.152, P=0.023).CONCLUSION: The values of CD peaked at 1 mo after CXL, then it gradually decreased, tending to become stable at 6 mo postoperatively.

BackgroundThe prevalence of depressive disorder in adolescents is on the rise. There have been studies on the pairwise relations between dysfunctional attitude， negative automatic thoughts， positive coping style and depressive symptoms in the past. However， the impact of the intrinsic relations among dysfunctional attitude， negative automatic thoughts and positive coping style on depressive symptoms is still unclear. ObjectiveTo explore the influence of dysfunctional attitude on adolescent depressive symptoms and examine the action path of negative automatic thoughts and positive coping style on it， in order to provide references for intervention for adolescent patients with depressisve disorder. MethodsThis study involved 162 adolescent patients with depressive disorder， who met the diagnostic criteria for depressive episodes in the International Classification of Diseases， 10th edition （ICD-10） and received treatment in Taiyuan Psychiatric Hospital from October 1， 2022 to October 31， 2023. These patients were evaluated using Self-rating Depression Scale （SDS）， Dysfunction Attitude Scale （DAS）， Positive Coping Style Subscale in Simplified Coping Style Questionnaire（SCSQ） and Automatic Thoughts Questionnaire （ATQ）. Pearson correlation analysis was adopted to examine the correlation among scores of scales above. Model 6 in Process 3.4.1 was adopted to test the acting path of negative automatic thoughts and positive coping style between dysfunctional attitude and adolescent depression symptoms. ResultsA total of 148 adolescent patients with depressive disorder completed an effective questionnaire survey， with a response rate of 91.36%. The direct effect value of dysfunctional attitude on depressive symptoms was 0.423 and the effect size was 63.32%. Negative automatic thoughts and positive coping style affected as acting path between dysfunctional attitude and depressive symptoms， with effect values of 0.156 （accounting for 23.35% of the total effect） and 0.045 （accounting for 6.74% of the total effect） respectively. Meanwhile， negative automatic thoughts and positive coping style affected as a chain reaction pathway between dysfunctional attitude and depressive symptoms， with an effect value of 0.044， accounting for 6.59% of the total effect. ConclusionDysfunctional attitude can not only directly affect the depressive symptoms of adolescent patients with depressive disorder， but also affect the depressive symptoms of adolescent patients with depressive disorder through the independent path or chain path of negative automatic thoughts and positive coping style.