OBJECTIVE To explore the regulatory effect of syringic acid in cholestatic mice based on bile acid metabolism and intestinal barrier.METHODS Twenty mice were randomly divided into control group,model group and low and high dose of syringic acid(70,140 mg·kg-1)groups.Intrahepatic cholestasis was induced by intraperitoneal injection of α-naphthalene isothiocyanate af-ter 2 h of administration on the fifth day.After the last dose,the changes of body weight and liver mass of mice were recorded.Liver function indexes in serum and histopathology were detected,qPCR verified the expression of tight junction proteins Zonula Occludens Protein 1(ZO-1),Occludin and Claudin-5 in mouse colon tissues,the changes of metabolites in serum were analyzed by using nontar-geted metabolomics,and the changes of total bile acids in liver and feces were detected.RESULTS Syringic acid could significantly reduce the serum alanine aminotransferase(ALT),aspartate transaminase(AST),alkaline phosphatase(ALP)activity,total biliru-bin(TBIL)and direct bilirubin(DBIL)levels(P<0.05,P<0.01)in the model group mice,and reduce liver damage and necrosis.Syringic acid reduced lymphocyte infiltration in the colon of mice in the model group and restored crypt morphology,while the high-dose syringic acid group significantly increased the mRNA expression levels of ZO-1,Occludin,and Claudin-5 in the colon(P<0.05).The high-dose intervention of syringic acid significantly upregulated 11 metabolites and 29 metabolites,and the metabolites mainly involved the biosynthesis of secondary metabolites,secondary bile acid biosynthesis and bile secretion pathways.Syringic acid reduced the content of total bile acids in the liver and increased the excretion of total bile acids in feces(P<0.05,P<0.01).CON-CLUSION Syringic acid can significantly improve the phenotype of cholestasis in cholestatic mice,improve the damage of intestinal barrier,and promote the metabolism of bile acids in cholestatic mice,which may be the key pathway for syringic acid to improve chole-stasis.

Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria bai-calensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of bio-physical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe-193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential β2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.

Objective:To explore the value of amide proton transfer-weighted (APTw) imaging and intravoxel incoherent motion (IVIM) imaging for diagnosing and evaluating the pathological differentiation of cervix squamous cell carcinoma (CSCC).Methods:This study was a diagnostic trial. Totally 56 patients pathologically diagnosed with CSCC at the First Hospital of Lanzhou University from October 2021 to October 2022 were retrospectively collected, as the CSCC group. And 36 female healthy volunteers who underwent physical examinations at the First Hospital of Lanzhou University from October 2021 to October 2023 were recruited as the control group. CSCC patients were divided into well-moderately differentiated ( n=34) and poorly differentiated groups ( n=22). The region of interest was placed in the lesions of CSCC group and normal cervical stroma of control group, and the quantitative parameters for asymmetric magnetization transfer ratio (MTR asym) of APTw imaging and pure diffusion coefficient (D), false diffusion coefficient (D *) and perfusion fraction (f) for IVIM were obtained. The independent sample t test was used to compare the differences in quantitative parameters between the two groups, the logistic regression model was used to establish combined parameters for the quantitative parameters with statistical significance between the two groups. The receiver operator characteristic curve was used to evaluate the diagnostic efficacy of single quantitative parameters and combined parameters to distinguish the CSCC group from the control group, and the well-moderately differentiated group from the poorly differentiated group in CSCC patients. The area under the curve (AUC) was compared using the DeLong test. Results:There were significant differences in MTR asym, D and f between CSCC group and control group ( t=-9.79, 10.09, 11.35, P<0.001). Also, significant differences were found for MTR asym and D between the well-moderately differentiated and poorly differentiated group ( t=4.11, -3.76, P<0.001). There was no significant difference in other quantitative parameters ( P>0.05). When comparing the CSCC group and control group, the AUC (95% CI) of MTR asym, D, f and combined parameter (MTR asym+D+f) were 0.887 (0.804-0.944), 0.940 (0.871-0.979), 0.968 (0.909-0.993), 0.995 (0.950-1.000). The AUC of the combined parameter was higher than those of MTR asym and D, with statistical significance ( Z=3.07, 2.06, P=0.002, 0.040). When comparing the well-moderately differentiated and poorly differentiated group, the AUC (95% CI) of MTR asym, D, and combined parameter (MTR asym+D) were 0.789 (0.660-0.887), 0.775 (0.644-0.876), 0.852 (0.731-0.932). There was no significant difference between each two AUCs ( P>0.05). Conclusion:The quantitative parameters of APTw and IVIM imaging can be used to diagnose and preliminarily evaluate the pathological differentiation of CSCC. Joint parameters can improve the diagnostic efficiency of CSCC.

Objective? To?Study?the?changes?of?short-chain?acyl-CoA?dehydrogenase?(SCAD)?in?heart?failure?(HF)?after?myocardial?infarction?(MI),?and?the?effect?of?aerobic?exercise?on?SCAD.? Methods? Healthy?male?Sprague-Dawley?(SD)?rats?were?divided?into?sham?operation?group?(Sham?group),?sham?operation?swimming?group?(Sham+swim?group),?HF?model?group?(LAD?group)?and?HF?swimming?group?(LAD+swim?group)?by?random?number?table?method,?with?9?rats?in?each?group.?The?left?anterior?descending?branch?of?coronary?artery?(LAD)?was?ligated?to?establish?a?rat?model?of?HF?after?MI.?In?Sham?group,?only?one?loose?knot?was?threaded?under?the?left?coronary?artery,?and?the?rest?operations?were?the?same?as?those?in?LAD?group.?Rats?in?Sham+swim?group?and?LAD+swim?group?were?given?swimming?test?for?1?week?after?operation?(from?15?minutes?on?the?1st?day?to?60?minutes?on?the?5th?day).?Then?they?were?given?swimming?endurance?training?(from?the?2nd?week?onwards,?60?minutes?daily,?6?times?weekly,?10?weeks?in?a?row).?Tail?artery?systolic?pressure??(SBP)?was?measured?before?swimming?endurance?training?and?every?2?weeks?until?the?end?of?the?10th?week.?Ten?weeks?after?swimming?training,?echocardiography?was?performed?to?measure?cardiac?output?(CO),?stroke?volume?(SV),?left?ventricular?ejection?fraction?(LVEF),?shortening?fraction?(FS),?left?ventricular?end-systolic?diameter?(LVESD),?left?ventricular?end-diastolic?diameter?(LVEDD),?left?ventricular?end-systolic?volume?(LVESV),?and?left?ventricular?end-diastolic??volume?(LVEDV).?Morphological?changes?of?heart?were?observed?by?Masson?staining.?Apoptosis?of?myocardial?cells?was?detected?by?transferase-mediated?deoxyuridine?triphosphate-biotin?nick?end?labeling?stain?(TUNEL)?and?apoptosis?index?(AI)?was?calculated.?Reverse?transcription-polymerase?chain?reaction?(RT-PCR)?and?Western?Blot?were?used?to?detect?the?mRNA?and?protein?expression?of?myocardial?SCAD?respectively.?In?addition,?the?enzyme?activity?of?SCAD,?the?content?of?adenosine?triphosphate?(ATP)?and?free?fatty?acid?(FFA)?in?serum?and?myocardium?were?detected?according?to?the?kit?instruction?steps.? Results? Compared?with?Sham?group,?Sham+swim?group?showed?SBP?did?not?change?significantly,?with?obvious?eccentric?hypertrophy?and?increased?myocardial?contractility,?and?LAD?group?showed?persistent?hypotension,?obvious?MI,?thinning?of?left?ventricle,?and?decreased?myocardial?systolic/diastolic?function.?Compared?with?LAD?group,?SBP,?systolic/diastolic?function?and?MI?in?LAD+swim?group?were?significantly?improved?[SBP?(mmHg,?1?mmHg?=?0.133?kPa):?119.5±4.4?vs.?113.2±4.5?at?4?weeks,?120.3±4.0?vs.?106.5±3.7?at??6?weeks,?117.4±1.3?vs.?111.0±2.3?at?8?weeks,?126.1±1.6?vs.?119.4±1.9?at?10?weeks;?CO?(mL/min):?59.10±6.31?vs.?33.19±4.76,?SV?(μL):?139.42±17.32?vs.?84.02±14.26,?LVEF:?0.523±0.039?vs.?0.309±0.011,?FS:?(28.17±2.57)%?vs.?(15.93±3.64)%,?LVEDD?(mm):?8.80±0.19?vs.?9.35±0.30,?LVESD?(mm):?5.90±0.77?vs.?7.97±0.60,?LVEDV?(μL):?426.57±20.84?vs.?476.24±25.18,?LVESV?(μL):?209.50±25.18?vs.?318.60±16.10;?AI:?(20.4±1.4)%?vs.?(31.2±4.6)%;?all?P??0.05).? Conclusion? The?expression?of?SCAD?in?HF?was?significantly?down-regulated,?and?the?expression?was?significantly?up-regulated?after?aerobic?exercise?intervention,?indicating?that?swimming?may?improve?the?severity?of?HF?by?up-regulating?the?expression?of?SCAD.

Objective To observe the changes of short-chain acyl-CoA dehydrogenase (SCAD) expression on human umbilical vein endothelial cell (HUVEC) apoptosis and investigate its relationship with apoptosis. Methods The HUVEC was cultured normally for 2-3 days. The apoptotic model of HUVEC was established by tert-butyl hydrogen peroxide (tBHP). The HUVEC was treated by different concentrations of tBHP (0, 10, 20, 30, 40, 50 μmol/L) for 12 hours and different time (0, 3, 6, 9, 12 hours) with 50 μmol/L tBHP to establish the apoptotic model of HUVEC. The cell viability was detected by methyl thiazolyl tetrazolium (MTT), the mRNA expression of SCAD was determined by real-time polymerase chain reaction (PCR), the protein expression of SCAD was achieved by Western Blot. The best concentrate and time were determined to interfere the HUVEC to achieve the apoptotic model of HUVEC. The SCAD gene of HUVEC was knocked down by RNA interference sequence (siRNA274, siRNA414, siRNA679). The mRNA expression of SCAD, the protein expression of SCAD and the activity of SCAD enzyme were detected to achieve the best RNA interference sequence. The HUVEC was intervened by the best RNA interference sequence and tBHP. The cell activity and apoptosis rate, the enzyme activity of SCAD, the mRNA and protein expression of SCAD, the contents of reactive oxygen species (ROS), aderosine triphosphate (ATP) and free fatty acid (FFA) were detected to observe the effect of SCAD on apoptosis of HUVEC. Results ① The cell viability, the mRNA expression and the protein expression of SCAD were decreased gradually in a concentration and time dependent manner with the increase of tBHP concentration and the prolongation of intervention time. The decline was most significant in the group of the 50 μmol/L tBHP to interfere HUVEC for 12 hours. ② The siRNA679 transfection was the most significant in reducing SCAD mRNA and protein expressions among the three interference sequences (siRNA274, siRNA414, siRNA679). ③ Compare with blank control group, the cell viability was significantly decreased in the siRNA679 group (A value: 0.48±0.09 vs. 1.00±0.09, P < 0.01), the apoptotic rate of HUVEC was significantly increased [(29.96±2.09)% vs. (2.90±1.90)%, P < 0.01], the expression of SCAD mRNA and SCAD protein, the activity of SCAD enzyme and the content of ATP were significantly decreased [SCAD mRNA (2-ΔΔCt): 0.50±0.16 vs. 1.34±0.12, SCAD/α-Tubulin: 0.67±0.11 vs. 1.00±0.06, the activity of SCAD enzyme (kU/g): 0.38±0.04 vs. 0.53±0.04, the content of ATP (μmol/g): 0.14±0.02 vs. 0.19±0.01, all P < 0.05], the contents of FFA and ROS were significantly increased [FFA (nmol/g): 0.84±0.07 vs. 0.47±0.04, ROS (average fluorescence intensity): 647.5±23.7 vs. 434.2±46.5, both P < 0.01]. Meanwhile, SCAD siRNA treatment triggered the same apoptosis as HUVEC treated with tBHP. Conclusions Down-regulation of SCAD may play an important role in HUVEC apoptosis. Increase in the expression of SCAD may become an important part in intervening HUVEC apoptosis.

The elaboration of the mechanism and pharmacodynamic substance are the main obstacles to the modernization of Chinese medicine.The rich ingredient of Chinese medicine is almost attention,with a research strategy of forward pharmacology.This strategy often neglects the study of trace components of Chinese medicine.Synthetic lethality,a extremely complex gene interactions,is to magnify the effects of the co-regulation of biological effects (＞ 1 000 times).The theory of synthetic lethality has achieved good results in the development of anti-tumor drugs,including the discovery of PARP inhibitors,the clinical use of chemotherapy drug addition and attenuation combination.In view of this,this research model may be used to elucidate trace effective substance.Based on the reverse thinking of "targetcomponent-effect"and clear synergistic targets,the mechanism of traces and weak-potency substance of traditional Chinese medicine was studied,and the synergistic combination of potential was found.

Aim To screen the potential inhibitors of post-transcriptional activity of pro-inflammatory media-tor TNF-α from the lipophilic constituents in Chinese Medicine Salvia miltiorrhiza Bunge ( Danshen) , we es-tablished dual luciferase reporter gene system pGL3-TNF-α3′UTR ( 3′untranslated region ) co-transfected with Renilla control gene. Methods Complementary DNA ( cDNA) template was obtained from human um-bilical vein endothelial cells ( HUVECs ) . The full length DNA of TNF-α 3′-UTR was amplified through PCR, and then connected the luciferase reporter vector pGL3-control after enzyme digestion. pGL3-TNF-α 3′UTR constructs were co-transfected with pSVRenilla into the mononuclear macrophages RAW264. 7 cells. The relative activity of reporter genes was measured by dual luciferase reporter ( DLR ) assay system after the stimulus of lipopolysaccharide ( LPS ) in presence or absence of tanshinones compounds. Results The pGL3-TNF-α3′UTR luciferase reporter gene was suc-cessfully constructed. The cloning DNA fragment and sequence were both consistent with the GENBANK da-tabase. LPS significantly induced the relative reporter activityof RAW264 . 7 cells transfected with pGL3-TNF-α 3′UTR. Among four tanshinones compounds, we found only cryptotanshinone could significantly de-crease LPS-induced relative reporter activity. Conclu-sion The pGL3-TNF-α 3′UTR construct combined with DLR assay system was successfully established, which can be used to discover the agents such as cryp-totanshinone that regulate the post-transcription of TNF-α in treatment of inflammatory and malignant dis-eases.

Tumor metastasis is one of the most important biologi-cal characteristics of malignant tumor, and it is also the main factors that cause treatment failure and poor prognosis. Clinical studies have shown that the number of platelets in patients with malignant tumor increased more significantly than that in benign tumor patients and healthy people, which indicate that platelet might be involved in the development process of tumor. Further study found that in the process of cancer spreading to blood, platelet could interact with tumor cells to form tumor emboli, helped tumor cells escape from immune surveillance, thus pro-moted the tumor metastasis. In recent years, related mechanisms on platelets in promoting tumor metastasis were revealed gradual-ly, and several targeted therapies based on platelets were also carried out. This paper reviews the role of platelet in mediating tumor metastasis by hematogenous spread and its mechanisms and discusses the therapy strategies that target platelet, which may provide references for follow-up research and clinical treat-ment.

As the major member of serine/threonine protein ki-nases family, glycogen synthase kinase 3β ( GSK-3β) has well characterized roles in the development of a variety of diseases. However, it is noticed that modulation of GSK-3β in tumor pro-gress is two-faced. Once the activity of GSK-3βas a“pro-onco-genic factor” is inhibited, opposing role as a“tumor suppressor”can also be disrupted, which will trigger the consequent side effect on activation of Wnt/β-catenin signaling pathway. The is-sue has placed a major obstacle to anti-GSK-3β in cancer treat-ment. In fact, functional compartmentalization of a large number of intracellular signaling events cross-talked with GSK-3β can prevent their mutual interference and determine the cell fate. Therefore, understanding the specific mechanisms of GSK-3β in regulation of diverse signaling systems or refinement of a sub-strate competitive inhibitor may have great significance to exploit approaches selectively target GSK-3β in tumor treatment.

Objective To establish a comprehensive evaluation indexing system to appraise the implications of prevention and treatment of HIV/AIDS ,and to calculate the weight of each indicator .Methods Based on the idea of performance and input-out-put ,professional consultation ,and Delphi method was determined as the evaluation index system ,analytical hierarchy process (AHP) was used to calculate the weight value for each indicator .Results The evaluation indexing system had been established af-ter three rounds of professional consultation .It contained two 1st class indicators ,six 2nd class indicators and thirty-one in 3rd class indicators .The weight value of each indicator was calculated .Conclusion The evaluation indexing system that has been established and the weight value quantities are of completeness ,practicality ,operability and logic .They have important value for application in the future .