AIM:To explore the potential targets and mechanisms of Angelica sinensis and Astraga-lus membranaceus ultrafiltration(RAS-AM)in the treatment of radiation induced myocardial fibrosis(RIMF)through network pharmacology combined experimental validation.METHODS:Using the TC-MSP database TCM@TAIWAN The Taiwan Tradition-al Chinese Medicine Database and TCMID Tradition-al Chinese Medicine Database screen the compo-nents and targets of RAS-AM,and use the Swiss Target Prediction database for target prediction.Obtain RIMF disease targets from Gene Cards and OMIM databases,obtain intersection targets of dis-eases and drugs through Wayne's online tool,ob-tain protein interaction relationships(PPIs)through STRING database,and use Cytoscape 3.9.1 soft-ware to construct a visualized network topology di-agram of"drug component target disease".Con-duct GO and KEGG enrichment analysis on core tar-gets through the David database,and use the mi-crobiome platform for mapping.Experimental veri-fication:Sixty Wistar rats were randomly divided in-to a blank group,a model group,a positive drug group,a RAS-AM low-dose group,a RAS-AM medi-um dose group,and a RAS-AM high-dose group.A RIMF model was established using a 38Gy dose of radiation induction,and was administered orally for 4 weeks.The general condition of the rats was also observed.After blood and heart collection in rats,HE staining was used to observe the morpho-logical changes of myocardial tissue,and ELISA and Western blot methods were used to detect key tar-gets for network pharmacology prediction.RE-SULTS:Network pharmacology analysis revealed 34 active components and 705 targets of Angelica si-nensis and Astragalus membranaceus ultrafiltra-tion,with a total of 154 targets,with IL-6,VEGFA,MMP2,MMP9,and ACE as the top five core tar-gets;GO enrichment analysis screened a total of 153 entries,and KEGG enrichment had 25 path-ways.Experimental part:HE staining results showed that the degeneration and necrosis of myo-cardial cells improved in each medication group,the infiltration of inflammatory cells in the myocar-dial interstitium decreased,and the proliferation of fibrous connective tissue in the myocardial intersti-tium decreased.ELISA and Western blot results showed that compared with the normal group,the expression of IL-6,VEGFA,and MMP-9 in the mod-el group increased.Compared with the model groupthe expression of IL-6,VEGFA,and MMP-9 in each medication group decreased to varying de-grees,in a dose-dependent manner.CONCLUSION:RAS-AM may inhibit RIMF by downregulating core targets such as IL-6,VEGFA protein,MMP-9 pro-tein,and regulating inflammatory pathways,colla-gen degradation,and other processes.

AIM:To study the effect of NEDD8-conjugating enzyme UBE2F on lung adenocarcino-ma metastasis.METHODS:The expression of UBE2F in lung adenocarcinoma was analyzed using TIMER2.0,UALCAN and HPA databases.Kaplan-Mei-er Plotter database was used to analyze the rela-tionship between UBE2F expression and survival rate of lung adenocarcinoma.A UBE2F-knockout lung adenocarcinoma cell line was constructed us-ing CRISPR/Cas9 technology,and a UBE2F-knockout lung adenocarcinoma metastasis model was con-structed in nude mice to verify the effect of UBE2F knockout on lung adenocarcinoma metastasis.The effects of UBE2F knockout on invasion and migra-tion of lung adenocarcinoma cells were examined by cell scratch assay and Transwell invasion and mi-gration assays.The effect of down-regulated UBE2F expression on snail expression,a key marker of epi-thelial-mesenchymal transition(EMT),was detect-ed by Western blot and Real time PCR.RESULTS:Multiple database analysis showed that UBE2F was highly expressed in lung cancer,and Kaplan-Meier Plotter analysis showed that high expression of UBE2F in lung adenocarcinoma had better progno-sis than low expression.In vivo experiments showed that compared with control group,the number of nodules metastasized on the lung sur-face of nude mice after UBE2F knockout was signifi-cantly increased(P<0.05).Cell scratch assay and Transwell assay showed that UBE2F enhanced the migration and invasion ability of lung cancer cells after knockout,and the difference were statistically significant(P<0.05).Western blot and Real time PCR results indicated that the level of EMT tran-scription factor snail protein and mRNA increased after UBE2F knockout.CONCLUSION:In lung ade-nocarcinoma cells,UBE2F down-regulation leads to Snail accumulation and promotes invasion and me-tastasis of lung adenocarcinoma cells.

AIM:To investigate the molecular mechanisms of KG-1 cell proliferation by profiling its responses to various protein kinase inhibitors.METHODS:CCK-8 assay,real time quantitative PCR(qRT-PCR)and Western-blot were used to detect the effect of various protein kinase inhibitors on KG-1 cell proliferation,the expression levels of mRNA and phosphorylation level of signaling pro-teins in the FGFR1 downstream pathways.RE-SULTS:NVP-BGJ398 and PD173074 effectively in-hibited the proliferation of KG-1 cells,indicative of a crucial role of FGFR downstream signaling.After treatment with FGFR inhibitors,the levels of p-FG-FR1OP2-FGFR1 and p-STAT5 decreased significantly(P<0.001),p-AKT decreased slightly(P<0.05),with-out affecting the p-ERK level(P>0.05).CONCLU-SION:FGFR1OP2-FGFR1 mainly acts on the down-stream STAT5 signaling pathway to promote cell proliferation.Comprehensive protein kinase inhibi-tion analysis is a reliable and direct approach to identify functional drivers of cancer cell prolifera-tion.

AIM:To observe the intervention ef-fect of Chinese medicine Kangzhen Zhijing spas-modic decoction Ⅰ on the progression of Parkin-son's disease in mice,and to explore the potential mechanism of neuroprotection.METHODS:Thirty-six C57BL/6 mice were randomly divided into con-trol group,model group,drug group and positive drug group.In the model group,the drug adminis-tration group and the positive drug group,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)(30 mg/kg)was injected intraperitoneally for 5 days to establish the mouse model.The control group was given the same amount of normal saline,the drug administration group was given 1.25 mg/kg,2.5 mg/kg,5 mg/kg dose of Chinese medicine Kang-zhen Zhijing spasmodic DecoctionⅠby gavage,and the positive drug group was given 75 mg/kg Madopar by gavage.Behavioral tests were per-formed on the second day after the administration in each group.Immunopositive cells of Tyrosine hy-droxylase(TH),Amyloid precursor protein(APP),α-synuclein(α-syn)and solute carrier family 6 mem-ber 11(SLC6A11)were detected by immunohisto-chemistry.The protein expressions of TH,APP,α-syn and SLC6A11 in each group were detected by Western blot.RESULTS:It could significantly im-prove the weight loss of mice in the model group,alleviate the decline of autonomic activity in open field test and the decline of coordination ability in pole test and suspension test.In the reverse immu-nohistochemistry and Western Blot experiments,the expressions of TH and SLC6A11 in the brain of the Parkinson's model group were significantly de-creased,and the expressions of APP and α-syn were significantly increased.CONCLUSION:Kang-zhen Zhijing spasmodic decoctionⅠcan significantly improve the behavioral performance of Parkinson's disease mice and effectively improve the reduction of neuronal transmitters.

AIM:To investigate the possible mech-anisms by observing the effects of sodium butyrate on the blood-brain barrier and cognitive function after intestinal ischemia/reperfusion in rats.METH-ODS:SD rats were randomly divided into 4 groups of 12 rats each,(1)sham-operated group(the Sham group);(2)intestinal ischemia/reperfusion group(the Ⅱ/R group);(3)intestinal ischemia/re-perfusion+sodium butyrate group(the NaB group):gavage of NaB 500 mg·kg-1·d-1 for 1 week before modeling;(4)intestinal ischemia/reperfusion+sodi-um butyrate+ITSA-1 group(the ITSA-1 group):NaB 500 mg·kg-1·d-1 gavage 1 week before modeling+IT-SA-1 0.5 mg/kg intraperitoneal injection in the first 5 d,3 d and 1 d.Intestinal mucosal injury was eval-uated by HE staining.Morris water maze test evalu-ated the cognitive function of rats.The microstruc-ture of the blood-brain barrier was observed by transmission electron microscope.The levels of in-flammatory cytokines IL-1β,IL-6,TNF-α,Claudin5,ZO-1,and MMP-9 in brain tissue were detected by ELISA.Western blotting detected Claudin5,ZO-1,CypA,and MMP-9 levels.RESULTS:Compared with the Sham group,Chiu's score in the Ⅱ/R group was increased(P<0.001).The swimming distance was increased(P<0.05),the proportion of the non-plat-form quadrant was increased(P<0.001),and the in-cubation period was prolonged(P<0.05).The micro-structure of the blood-brain barrier was changed under the transmission electron microscope.The inflammatory cytokines IL-1β,IL-6,and TNF-α were increased(P<0.001),the expressions of CypA and MMP-9 were increased(P<0.01),and the expres-sions of Claudin5 and ZO-1 were decreased(P<0.01,P<0.001).Compared with the Ⅱ/R group,neu-roinflammation,and blood-brain barrier damage were reduced,and cognitive function was im-proved in the Ⅱ/R+NaB group.The above injuries in group Ⅱ/R+NaB+ITSA-1 were similar to those in group Ⅱ/R.CONCLUSION:Sodium butyrate can ameliorate Ⅱ/R-induced neurocognitive dysfunction in rats by alleviating blood-brain barrier damage,possibly related to inhibiting the CypA/MMP-9 pathway.

AIM:To investigate the molecular mechanism of a novel bromobenzene substituted trifluoromethylbenzo Cyclopentanone WW02 inhib-iting the viability and proliferation of human lung cancer A549 and H1299 cells.METHODS:The ef-fect of different concentrations of WW02(6.25,12.5,25,50 μg/mL)on cell viability and prolifera-tion of A549 and H1299 were measured using CCK-8 and EdU methods.After 24 hours of stimulation of A549 and H1299 cells with different concentra-tions of WW02,the changes in Akt and mTOR phos-phorylation levels under different concentrations of WW02 were detected through Western blot as-say.Macromolecular docking was carried out be-tween WW02,AKT and mTOR through MOE Dock.RESULTS:After treating A549 and H1299 cells with WW02 using different concentrations(6.25,12.5,25,50 μg/mL),the activity of A549 and H1299 cells decreased in a concentration dependent manner compared with the DMSO control group(P<0.05).The proliferation of cells showed a concentration dependent decrease compared to the DMSO con-trol group(P<0.05).Compared with the DMSO con-trol group,after 24 hours of WW02 stimulation,the phosphorylation levels of Akt and mTOR in A549 cells decreased under the concentration of WW02(12.5,25,50 μg/mL,P<0.05).Compared with the DMSO control group,the phosphorylation levels of Akt and mTOR in H1299 cells decreased af-ter 24 hours of WW02 stimulation(25,50 μg/mL,P<0.05).Based on pattern analysis,it was found that WW02 had a strong binding with Akt and mTOR,with the highest score of-8.3 kcal/mol for WW02 and mTOR,while the highest score for WW02 and Akt was-7.3 kcal/mol.CONCLUSION:WW02 inhib-its the activity and proliferation of lung cancer A549 and H1299 cells,and its mechanism of action may be achieved by directly binding to Akt and mTOR proteins to inhibit Akt and mTOR phosphory-lation.

AIM:To develop and validate a predic-tive model for the risk of high plasma concentra-tion of voriconazole,and to guide clinical individual-ized medication of voriconazole.METHODS:Based on the real-world data from the hospital Informa-tion system(HIS),the clinical data of hospitalized patients who received voriconazole treatment and underwent voriconazole plasma concentration monitoring in our hospital from August 2017 to Au-gust 2021 were collected.Univariate and multivari-ate logistic regression analysis were performed on the included influencing factors.At the same time,in order to minimize the potential collinearity and overfitting between variables,the least absolute shrinkage and selection operator regression were used to screen the potential predictors.Logistic re-gression analysis was used to construct a predic-tion model for the risk of high plasma concentra-tion of voriconazole.C-index,calibration chart and clinical decision curve analysis were used to evalu-ate the discrimination,consistency and clinical ap-plicability of the model,and a nomogram was drawn.RESULTS:A total of 147 patients were en-rolled in this study.Plasma albumin and procalcito-nin were selected as predictive variables for Logis-tic regression analysis,and the prediction model was established.Draw predict voriconazole nomo-gram risk blood drug concentration on the high side.The receiver operating characteristic curve showed that the AUC of the prediction model for predicting the risk of high plasma concentration of voriconazole was 0.787(95%CI 0.663-0.911).Vori-conazole blood drug concentration was high inci-dence of cut-off value was 33.06%,sensitivity was 63.64%,87.65%and 58.33%positive predictive val-ue,negative predictive value of 89.87%.The cali-bration curve showed good consistency,and the clinical decision curve showed that the model had a positive net benefit when the threshold probabili-ty was between 6.67%and 99.99%.CONCLUSION:The predictive model for the risk of high plasma concentration of voriconazole has good predictive efficacy,which can provide guidance for clinical in-dividualized medication of voriconazole.

AIM:To explore the correlation between trimethylamine-N-oxide(TMAO)and type 2 diabetic kidney disease(DKD),and to provide new ideas for the early clinical diagnosis of DKD.METHODS:A total 246 patients with type 2 diabetes mellitus(T2DM)ad-mitted to the Department of Endocrinology of the First Hospital of Lanzhou University from January 1,2020 to May 31,2020 were divided into diabetic kidney disease group(DKD group)and simple diabetes mellitus group(NDKD group).According to urinary albumin/creatinine ratio(UACR),the patients were divided into A1,A2 and A3 subgroups.According to the estimated glomerular filtration rate(eGFR),the patients were divided into G1,G2,G3 and G4-5 sub-groups.According to the Kidney Disease:Improving Global Outcomes(KDIGO)guidelines,the risk of progression of DKD was assessed(low,medium,high or very high risk).General clinical data and laboratory indicators were collected.TMAO level was measured by euzymelinked immunosorbent assay.SPSS 25.0 software was used for statistical analysis.RESULTS:In T2DM patients,TMAO level was positively correlated with UACR(r=0.515,P<0.01)and negatively correlated with eGFR(r=-0.409,P<0.01).TMAO is an indepen-dent risk factor for the onset and progression of DKD.In diagnostic model,the AUROC was 0.745 with op-timal cut-off value was 5.37μmol/L.CONCLUSION:TMAO is closely related to the occurrence and de-velopment of DKD,and it has certain clinical predictive value for DKD.Therefore,TMAO may become a po-tential target for the early diagnosis and treatment of DKD.

AIM:To investigate the effect of sub-anesthetic dose of esketamine on chronic post-sur-gery pain(CPSP)in patients undergoing radical mastectomy of breast cancer.METHODS:A total of 120 patients undergoing elective radical mastecto-my of breast cancer in the operating room of our hospital from November 2021 to March 2022 were enrolled,aged 35-64 years old,and with American Society of Anesthesiologists(ASA)classification Ⅰ to Ⅱ.The subjects were allocated into esketamine group(group E)and sufentanil group(group S),with 60 subjects pergroup,according to a random number table method.At the beginning of anesthe-sia induction,patients in group E were given intra-venous injection of esketamine 0.3 mg/kg and suf-entanil 0.2 μg/kg,and during the maintenance of anesthesia,the administration rate of esketamine was 0.25 mg·kg-1·h-1,sevoflurane was continuously inhaled at 1%to 2%,and stopped 30 minutes be-fore the end of the operation,and a patient-con-trolled intravenous analgesia(PCIA)pump was con-nected immediately after the operation,and esket-amine 100 mg+sufentanil 100 μg+tropisetron 10 mg were added to the analgesia pump,supple-mented with medical 0.9%sodium chloride injec-tion to dilute to 100 mL.At the beginning of anes-thesia induction,patients in group O were intrave-nously injected with sufentanil 0.5 μg/kg,and the administration rate of remifentanil during the anes-thesia maintenance period was 0.1-0.3 μg·kg-1·min-1,and stopped 5 minutes before the end of the operation.Sufentanil 150 μg+tropisetron 10 mg was added to the PCIA pump,supplemented with medical 0.9%sodium chloride injection to dilute to 100 mL.The PICA pump parameters in both groups were set to background dose of 2 mL/h,bolus dose was 0.5 mL,and locked time was 15 min.The main outcome was the incidence of CPSP on postopera-tive 3 months,and the patients were followed up at 3 and 6 months postoperatively to record the oc-currence of CPSP.The secondary outcomes were vi-sual analogue scale of pain(VAS),Ramsay sedation scale and the incidence of postoperative adverse events within 48 hours after surgery.Peripheral ve-nous blood was drawn 1 day before operation and 1 day and 3 days after operation,and the concen-trations of serum inflammatory factors including tu-mor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-8(IL-8)were measured.RESULTS:There were 2 lost patients in group S and 3 lost pa-tients in group E.At 3 and 6 months after opera-tion,27(46.6%)and 19(32.8%)patients in group S had CPSP,including 18(31.0%)and 13(22.4%)pa-tients with mild pain,respectively.13(22.8%)and 8(14.0%)patients in group E had CPSP,including 8(14.0%)and 5(8.8%)patients with mild pain,re-spectively.The incidence of CPSP in group E was lower than that in group S at 3 and 6 months after operation(P<0.05).The VAS scores and Ramsay se-dation scores of the two groups of patients were similar at different time points after operation with-in48h(P>0.05).The analgesic rescue rate within 2 days after operation,the total number of PCIA pump compressions and the number of effective compressions were not similar between the two groups,and there was no statistical significance(P>0.05).Compared with group S,the incidence of nausea and vomiting in group E was significantly lower within 2 days after operation(P<0.05).The serum levels of TNF-α,IL-6 and IL-8 in the group E were significantly decreased on postoperative 1 and 3 d,compared with group S(P<0.05).CONCLU-SION:Sub-anesthetic dose of esketamine can inhib-it perioperative inflammatory response and lower the incidence of CPSP in patients undergoing breast cancer surgery.

Dysfunction of nuclear receptors(NRs),which are critical for maintaining renal lipid homeostasis,largely contributes to the progression of diabetic nephropathy(DN)by promoting renal lipid accumulation.However,there are few thera-pies in modern medicine that effectively inhibit re-nal lipid accumulation by modulating NRs.In this review,we first summarize recent advances in NRs-mediated renal lipid accumulation in DN.Then,we summarize recent studies on the effects and mech-anisms of Chinese herbal medicines on DN and highlight the effects of Chinese herbal medicines on renal lipid accumulation via NRs.In addition,the advantages and limitations of traditional Chi-nese medicine in the treatment of DN via NRs-me-diated renal lipid accumulation are analyzed,and the modulation of renal lipid accumulation via NRs is emphasized as a promising therapeutic strategy for the treatment of DN.