Based on the holistic view of "spleen-vessels-heart-spirit" system， this article explores the pathogenesis and progression of atrial fibrillation. It is proposed that the onset of atrial fibrillation is due to failure of the spleen to transport and disharmony of blood vessels； phlegm and blood stasis obstructing the collaterals and damage to the heart structure are the basis of its pathogenesis； the unclear mind and disorder of body and spirit are the causes of its progression. Based on the characteristics of pathological changes in different stages of the disease， it is proposed that early treatment should focus on restoring the middle jiao， clearing and promoting blood vessels， using modified Yigong Powder （异功散）； during the progression of the disease， treatment should remove blood stasis and phlegm， nourish heart and protect the pulse， using self-prescribed modified Mengshi Tongmai Decoction （礞石通脉汤）； meanwhile， calming mind and stabilizing palpitations， and regulating spirit should be sequentially incorporated， with self-prescribed Jiazao Ningmai Decoction （甲枣宁脉汤） or Shenying Dingji Decoction （参英定悸汤） and modified as appropriate. Clinical treatment should focus on the whole disease course of atrial fibrillation， implementing stage-based treatments to enable early intervention and holistic regulation.

ObjectiveTo investigate the potential mechanism of Shenqi Yiliu Formula （参芪抑瘤方） in treating precancerous lesions of gastric cancer （PLGC） by the Wnt/β-catenin signaling pathway. MethodsThe CCK-8 assay was used to determine the optimal intervention time for Shenqi Yiliu Formula drug-containing serum and the concentration of the Wnt/β-catenin pathway inhibitor XAV939 depends on the survival rate of AGS gastric cancer cell line. AGS cells were divided into the gastric cancer cell group （15% blank serum）， inhibitor group （selected concentration of XAV939）， high-dose Shenqi Yiliu Formula group （12% Shenqi Yiliu Formula drug-containing serum + 3% blank serum）， medium-dose Shenqi Yiliu Formula group （6% Shenqi Yiliu Formula drug-containing serum + 9% blank serum）， and low-dose Shenqi Yiliu Formula group （3% Shenqi Yiliu Formula drug-containing serum + 12% blank serum）. Each group was tested in triplicate. After culturing for 24 and 48 hours， cell migration and invasion were assessed by scratch assays； after a selected intervention period （48 hours）， cell cycle distribution was analyzed using flow cytometry， Ki67 protein levels were detected by immunofluorescence， the protein levels of Wnt， β-catenin， GSK-3β， and intranuclear T-cell specific factor（TCF） were measured by the protein immunoblotting assay， and the mRNA expressions of these above factors were determined by quantitative real-time PCR. ResultsThe optimal intervention time for Shenqi Yiliu Formula drug-containing serum was determined to be 48 hours， and the effective concentration of XAV939 was 20 μmol/L. Compared with the gastric cancer cell group， Shenqi Yiliu Formula at all doses reduced the cell migration rate at 24 and 48 hours （P＜0.05）， except for the low-dose group at 24 hours. Compared to the low-dose group at corresponding time points， high- and medium-dose Shenqi Yiliu Formula groups showed significantly reduced migration rates， particularly the high-dose group at 48 hours （P＜0.05）. Compared with the gastric cancer cell group， the high-dose Shenqi Yiliu Formula and inhibitor groups exhibited reduced protein and mRNA levels of Wnt， β-catenin， and TCF， along with reduced Ki67 protein levels and a decreased proportion of cells in the S and G2 phases of the cell cycle， but GSK-3β protein levels， GSK-3β mRNA expression， and the proportion of cells in the G1 phase increased （P＜0.05）. Compared to the inhibitor group， the high-dose Shenqi Yiliu Formula group showed a decreased proportion of G1-phase cells and an increased proportion of G2-phase cells （P＜0.05）， although differences in Wnt and β-catenin protein levels and mRNA expressions were not statistically significant （P＞0.05）. ConclusionShenqi Yiliu Formula drug-containing serum inhibits the migration and invasion of gastric cancer AGS cells and block the cell cycle at G1 phase， and its underlying mechanism may be related to the regulation of the Wnt/β-catenin signaling pathway.

Objective To investigate the protective effect of sodium (s)-2-(dithiocarboxylato((2R,3R,4R,5R,6R)-2,3,4,5,6-pentahydroxyhexyl) amino)-4-(methylthio) butanoate (GMDTC) against cisplatin-induced toxicity during antitumor treatment. Methods Specific pathogen-free female SD rats were inoculated with LLC-WRC-256 tumor cells to establish tumor-bearing models, which were randomly divided into the model control group, cisplatin control group, and low-, medium-, and high-dose GMDTC groups, with 10 rats in each group. Another negative control group with 10 rats was included. Rats in the cisplatin control group and the three GMDTC dose groups were injected intravenously with cisplatin at a dose of 5 mg/kg body mass for one time. After 2.0 hours, rats in the three GMDTC dose groups were injected intravenously with GMDTC at doses of 27, 54, and 108 mg/kg body mass, once per day for five consecutive days. Tumor volume, platinum levels in biological samples (whole blood, urine, kidney, and tumor tissue), serum creatinine (Cr) and urea nitrogen (BUN) levels were measured at different time points. The tumor mass was measured, the pathological changes of renal tissue were observed, and the complete blood count was tested. Results The dilation of renal tubules, cell necrosis and shedding, and the formation of renal tubule patterns in the kidneys of rats in the medium- and high-dose GMDTC groups were significantly reduced compared with those in the cisplatin control group. The tumor volume of rats in the cisplatin control group and the three GMDTC dose groups decreased on the 3rd, 5th and 7th days after cisplatin administration, and the tumor weight decreased on the 7th days compared with the model control group (all P<0.05). However, there was no significant difference in the above indexes among the four groups (all P>0.05). The levels of serum Cr and BUN of rats in the cisplatin control group on the 3rd, 5th, and 6th days after cisplatin administration, as well as the score of renal tubular injury degree on the 7th day, were higher than those in the negative control group and the model control group (all P<0.05). The serum Cr levels of rates on the 3rd and 5th days after cisplatin administration, the serum BUN levels on the 5th day in the medium- and high-dose GMDTC groups, the score of renal tubular injury degree, and renal platinum level on the 7th day decreased compared with the cisplatin control group (all P<0.05), while the serum Cr and BUN levels on the 6th day and the whole-blood platinum levels in the high-dose GMDTC group decreased (all P<0.05). The urinary platinum levels of rats in the three GMDTC dose groups increased on the 1st day after GMDTC administration (all P<0.05), but decreased on the 3rd day compared with the cisplatin control group (all P<0.05). The counts of white blood cells, neutrophils, lymphocytes and platelets of rats in the cisplatin control group were lower than those in the model control group (all P<0.05). There was no significant difference in the above indexes of rats between the three GMDTC dose groups and the cisplatin control group (all P>0.05). Conclusion Intravenous administration of GMDTC at doses of 54 or 108 mg/kg body mass effectively reduce the nephrotoxicity of cisplatin-treated rats with LLC-WRC-256 tumors without affecting the antitumor effect of cisplatin.

Objective To compare the efficacy and safety of different cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) for the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer. Methods Randomized controlled trials (RCTs) on CDK4/6i for the treatment of HR+/HER2− metastatic or advanced breast cancer were retrieved from databases including PubMed, EMbase, Web of Science, The Cochrane Library, CNKI, Wanfang, VIP, and SinoMed, with the search period ranging from database inception to August 2023. Bayesian network meta-analysis was conducted using R 4.2.0 software. Results A total of 18 RCTs from 25 articles, involving 8 031 patients and 11 treatment regimens, were included. There was no significant difference in progression-free survival (PFS) or overall survival (OS) among different CDK4/6i+ET combinations. The highest cumulative probability for PFS was observed with dalpiciclib (DAL)+fulvestrant (FUL), while ribociclib (RIB)+FUL ranked first for OS. In terms of efficacy, abemaciclib (ABE)+aromatase inhibitors (AI) and ABE+FUL ranked first in objective response rate and clinical benefit rate, respectively. Regarding safety, statistically significant difference in grade 3-4 adverse events was observed among certain types of CDK4/6i (P<0.05). Conclusion Current evidence suggests that CDK4/6i+ET is superior to ET alone for the treatment of HR+/HER2− advanced/metastatic breast cancer. Different CDK4/6i+ET combinations demonstrate comparable or similar efficacy; however, the incidence of adverse reactions is higher with combination therapy. Treatment regimens should be selected based on individual conditions.

To analyze the distribution of serotypes and antimicrobial resistance of clinical Salmonella isolates from multiple centers across China.

ObjectiveTo screen out the transcriptomes related to the intervention of Wuzi Yanzongwan on the spermatogenic function of semi-castrated male mice， and to explore its potential mechanism in the intervention of the progress of low spermatogenic function. MethodBalb/c mice were randomly divided into sham-operated group， model group， testosterone propionate group（0.2 mg·kg^-1·d^-1， intramuscular injection） and Wuzi Yanzongwan group（1.56 g·kg^-1·d^-1， intragastric administration） according to body weight， with 12 mice in each group. The right testicle and epididymis were extracted from the model group and the drug administration group to construct the semi-castrated model of low spermatogenic function， while the fur and the right scrotum of the sham-operated group were only cut and immediately sterilized and sutured. At the end of the intervention， hematoxylin-eosin（HE） staining was used to observe the histopathology of testis， enzyme-linked immunosorbent assay（ELISA） was used to detect the levels of serum testosterone（T）， luteinizing hormone（LH） and follicle stimulating hormone（FSH）. The sperm count and motility of epididymis were measured by automatic sperm detector of small animal. Transcriptomic microarray technology was used to detect the mRNA expression level of testicular tissue in each group， the transcriptome of genes related to the regulation of Wuzi Yanzongwan was screened， and three mRNAs were selected for Real-time fluorescence quantitative polymerase chain reaction（Real-time PCR） to verify the transcriptome data. Through the annotation analysis of Gene Ontology（GO） and the signaling pathway analysis of Kyoto Encyclopedia of Genes and Genomes（KEGG）， the related functions of drugs regulating transcriptome were analyzed. ResultCompared with the sham-operated group， the testicular tissue of mice in the model group showed spermatogenic injury， contraction and vacuolization of the seminiferous tubules， reduction of spermatogenic cells at all levels， widening of the interstitial space， obstruction of spermatogonial cell development and other morphological abnormalities， and serum T significantly decreased， LH significantly increased（P<0.01）， and FSH elevated but no statistically significant difference， the count and vitality of epididymal sperm significantly decreased（P<0.01）. There were 882 differentially expressed mRNAs in the testicular tissues， of which 565 were up-regulated and 317 were down-regulated. Cluster analysis showed that these differentially expressed mRNA could effectively distinguish between the sham-operated group and the model group. Compared with the model group， the damage to testicular tissue in the Wuzi Yanzongwan group was reduced， the structure of the seminiferous tubules was intact， vacuolization was reduced， and the number of spermatogenic cells at all levels was significantly increased and arranged tightly. The serum T significantly increased， LH significantly decreased（P<0.01）， and FSH decreased but the difference was not statistically significant. The count and vitality of sperm in the epididymis were significantly increased（P<0.01）. Moreover， Wuzi Yanzongwan could regulate 159 mRNA levels in the testes of semi-castrated mice， of which 32 were up-regulated and 127 were down-regulated， and the data of the transcriptome assay was verified to be reliable by Real-time PCR. GO and KEGG analysis showed that the transcriptome functions regulated by Wuzi Yanzongwan were involved in the whole cell cycle process of sperm development such as sex hormone production of interstitial cells in testis， renewal， differentiation， metabolism， apoptosis and signal transduction of spermatogenic cells， and were closely related to the biological behaviors of signaling pathways such as spermatogenic stem cell function， endoplasmic reticulum protein processing and metabolic program. ConclusionWuzi Yanzongwan can effectively improve the low spermatogenic function of semi-castrated male mice， and its mechanism may be related to the regulation of testicular transcriptional regulatory network， the synthesis of sex hormones in testicular interstitial cells， the function of spermatogenic stem cells， the whole cell cycle process of spermatogenesis， as well as the expression of endoplasmic reticulum protein processing and metabolic program related genes transcription.

Objective     To explore the correlation between the quantitative and qualitative features of CT images and the invasiveness of pulmonary ground-glass nodules, providing reference value for preoperative planning of patients with ground-glass nodules. Methods    The patients with ground-glass nodules who underwent surgical treatment and were diagnosed with pulmonary adenocarcinoma from September 2020 to July 2022 at the Third Affiliated Hospital of Kunming Medical University were collected. Based on the pathological diagnosis results, they were divided into two groups: a non-invasive adenocarcinoma group with in situ and minimally invasive adenocarcinoma, and an invasive adenocarcinoma group. Imaging features were collected, and a univariate logistic regression analysis was conducted on the clinical and imaging data of the patients. Variables with statistical difference were selected for multivariate logistic regression analysis to establish a predictive model of invasive adenocarcinoma based on independent risk factors. Finally, the sensitivity and specificity were calculated based on the Youden index. Results     A total of 555 patients were collected. The were 310 patients in the non-invasive adenocarcinoma group, including 235 females and 75 males, with a meadian age of 49 (43, 58) years, and 245 patients in the invasive adenocarcinoma group, including 163 females and 82 males, with a meadian age of 53 (46, 61) years. The binary logistic regression analysis showed that the maximum diameter (OR=4.707, 95%CI 2.060 to 10.758), consolidation/tumor ratio (CTR, OR=1.027, 95%CI 1.011 to 1.043), maximum CT value (OR=1.025, 95%CI 1.004 to 1.047), mean CT value (OR=1.035, 95%CI 1.008 to 1.063), spiculation sign (OR=2.055, 95%CI 1.148 to 3.679), and vascular convergence sign (OR=2.508, 95%CI 1.345 to 4.676) were independent risk factors for the occurrence of invasive adenocarcinoma (P<0.05). Based on the independent predictive factors, a predictive model of invasive adenocarcinoma was constructed. The formula for the model prediction was: Logit(P)=–1.293+1.549×maximum diameter of lesion+0.026×CTR+0.025×maximum CT value+0.034×mean CT value+0.72×spiculation sign+0.919×vascular convergence sign. The area under the receiver operating characteristic curve of the model was 0.910 (95%CI 0.885 to 0.934), indicating that the model had good discrimination ability. The calibration curve showed that the predictive model had good calibration, and the decision analysis curve showed that the model had good clinical utility. Conclusion     The predictive model combining quantitative and qualitative features of CT has a good predictive ability for the invasiveness of ground-glass nodules. Its predictive performance is higher than any single indicator.

Objective To investigate the bioequivalence of gliclazide sustained-release tablets in Chinese healthy subjects.Methods The study was designed using a single-center,open,randomized,single-dose,two-cycle,two-sequence administration method;subjects were orally administered the test/reference preparation 30 mg on an fasting or fed conditions,with self-cross-dosing.The concentration of gliclazide in human plasma was determined by liquid chromatography tandem mass spectrometry(LC-MS/MS)method.The main pharmacokinetic parameters of gliclazide(Cmax,AUC0-t and AUC0-∞)were analyzed by non-atrioventricular model of WinNonlin.Result In the fasting study,24 subjects were recruited and 22 completed the study.The main pharmacokinetic parameters of gliclazide sustained-release tablets test preparation and reference preparation in the fasting group were as follows:Cmax were(862.48±294.48)and(902.96±259.09)ng·mL-1;AUC0-t were(2.60 × 104±8 930.46)and(2.50 ×104±7 573.42)h·ng-1·mL-1;AUC0-∞ were(3.00 × 104±1.43 × 104)and(2.68 × 104±7 085.99)h·ng·mL-1.In the fed study,twenty-four subjects were enrolled and 23 completed the study.The main pharmacokinetic parameters of gliclazide sustained-release tablets test preparation and reference preparation in fed group:Cmax were(1 531.74±273.49)and(1 510.87±241.08)ng·mL-1;AUC0-t were(2.78 ×104±9 565.89)and(2.76 ×104±9 821.43)h·ng·mL-1;AUC0-∞ were(3.02 ×104±1.24 ×104)and(3.02 × 104±1.30 × 104)h·ng·mL-1 h·ng·mL-1.The 90％confidence intervals of the geometric mean ratios of Cmax,AUC0-t,AUC0-∞ for the test preparation and reference preparation gliclazide sustained-release tablets were all between 80％and 125％.Conclusion The test and the reference preparation of gliclazide sustained-release tablets are bioequivalent in Chinese healthy subjects.

Objective To construct an in vitro"metabolic memory"cell model of HT-22 mouse hippocampal neurons induced by high glucose,and to investigate the effect of"metabolic memory"on apoptosis and histone acetylation in HT-22 cells.Methods HT-22 cells were cultured in high glucose medium(glucose concentration was 55 mmol/L)and conventional glucose medium(glucose concentration was 25 mmol/L),and cells were divided into the control group(NG 4,6 and 8 groups,25 mmol/L glucose was cultured for 4,6 and 8 days,respectively),the high glucose group(HG 4,6 and 8 groups,respectively)and the metabolic memory group(HG2NG2,HG2NG4,HG2NG6,HG4NG2 and HG4NG4 groups,high glucose culture for 2 days to 25 mmol/L glucose culture for 2,4 or 6 days,high glucose culture for 4 days to 25 mmol/L glucose culture for 2 or 4 days).Cell viability was detected by CCK-8 method.The release of lactate dehydrogenase(LDH)in cell culture supernatant was detected,and the optimal time to establish a"metabolic memory"model was selected.Subsequently,cells were divided into the NG4 group,the NG8 group,the HG4 group,the HG4NG4 group and the HG8 group,and the cell morphology of each group was observed by optical microscope.The apoptosis rate was detected by flow cytometry.The activities of deacetylase(HDAC)and histone acetyltransferase(HAT)were detected by enzyme-linked immunosorbent assay(ELISA).Western blot assay was used to detect expression levels of histone deacetylase 4(HDAC4),B lymphocyte tumor 2(Bcl-2),Bcl-2 related X protein(Bax)and Caspase-3 protein.Results The HG4NG4 group was the ideal cell model with high glucose metabolic memory.Cells of the NG4 group and the NG8 group were interwoven into a dense network,growing well,with spindle shaped cells and distinct synaptic structures.However,in the HG4 group and the HG8 group,the cell body became round,synaptic structure disappeared and growth was inhibited.In the HG4NG4 group,the number of cells increased but their morphology was damaged.Results of flow cytometry showed that compared with the NG8 group,the apoptosis rates were significantly increased in the HG8 group and the HG4NG4 group(P＜0.05).ELISA results showed that compared with the NG8 group,the expression levels of HDAC4,Bax,and Caspase-3 proteins increased in the HG8 group and the HG4NG4 group,while the expression level of Bcl-2 protein significantly decreased(P＜0.05).Compared with the HG8 group,there were no significant differences in protein expression levels of HAT and HDAC in the HG4NG4 group.Western blot reslts showed that compared with the NG8 group,the levels of HDAC4,Bax and Caspase-3 protein increased in the HG8 group and the HG4NG4 group(P＜0.05).Compared with the HG8 group,there were no significant differences in protein expression levels in the HG4NG4 group.Conclusion HT-22 mouse hippocampal neurons cultured with 55mmol/L high glucose for 4 days,and then cultured with 25 mmol/L glucose for 4 days are the ideal"metabolic memory"cell model.The mechanism may be related to the increased activity of HDAC,HAT and HDAC4 expression in the hyperglycemic model.

Objective To explore the mechanism of Wumei pill on ulcerative colitis(UC)in mice based on the anti oxidative stress pathway of nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE).Methods Seventy SPF male C57BL/6 mice were randomly divided into the control group,the UC group,the mesalazine group(MES group,0.82 g/kg MES),the low dose Wumei pill group(WMW-L group,5 g/kg crude drug),the middle dose Wumei pill group(WMW-M group,10 g/kg crude drug),the high dose Wumei pill group(WMW-H group,20 g/kg crude drug)and the high dose Wumei pills+Nrf2 inhibitor ML-385 group(WMW-H+ML-385 group,Wumei pills crude drug 20 g/kg+20 mg/kg ML-385),with 10 rats in each group.The disease activity index(DAI)score and colonic mucosa injury score were performed in mice after the last administration.Pathological changes of colonic mucosa in mice were observed by HE staining.The levels of interleukin(IL)-1β,tumor necrosis factor-α(TNF-α)and IL-6 in serum and colon tissue of mice were measured by enzyme-linked immunosorbent assay(ELISA).The content of malondialdehyde(MDA)in serum and colon tissue of mice was determined by thiobarbituric acid colorimetry(TBA).The activity of superoxide dismutase(SOD)in serum and colon tissue of mice was measured by xanthine oxidase method.The activity of glutathione peroxidase(GSH-px)in serum and colon tissue of mice was determined by direct method with dithiodinitrobenzoic acid(DTNB).The positive expression of Nrf2 in colon tissue of mice was observed by immunohistochemistry.The expression of heme oxygenase-1(HO-1)and NAD(P)H:quinone oxidoreductase-1(NQO1)proteins in colon tissue of mice were detected by Western blot assay.Results Compared with the control group,the DAI score,colonic mucosa injury score,colonic histopathology score,levels of IL-1β,TNF-α,IL-6 and MDA in serum and colonic tissue,and expression levels of Nrf2,HO-1 and NQO1 protein in colonic tissue of mice were increased in the UC group,levels of SOD and GSH-px in serum and colon tissue decreased(P＜0.05),the colon mucosa of mice was seriously damaged.Compared with the UC group,changes of corresponding indexes were contrary to the above in the MES group,the WMW-M group and the WMW-H group.However,the expression levels of Nrf2,HO-1 and NQO1 proteins in colon tissue were increased(P＜0.05),and the damage of colon mucosa in mice was alleviated.Changes of the above indexes were dose-dependent in the WMW-L group,the WMW-M group and the WMW-H group.There were no significant differences in the above indexes between the WMW-H group and the MES group.ML-385 attenuated the improvement effect of high dose Wumei pill on colon mucosa injury.Conclusion Wumei pill may alleviate the colon mucosal damage of UC mice by activating Nrf2/ARE antioxidant stress pathway.