Objective To investigate the effect of sodium-glucose cotransporter 2 inhibitor (empagliflozin, EMPA) on myocardial remodeling in a mouse uremic cardiomyopathy (UCM) model induced by 5/6 nephrectomy, through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (PKB/AKT)/p65 signaling pathway. Methods The animals were divided into three groups: Sham group (n=6), UCM group (n=8), and UCM＋EMPA group (n=8). A UCM model was established in C57BL/6N mice using the 5/6 nephrectomy. Starting from 5 weeks post-surgery, EMPA or a placebo was administered. After 16 weeks, blood pressure, serum creatinine, blood urea nitrogen, 24-hour urine glucose and urine sodium were measured. Cardiac structure and function were assessed by echocardiography. Hematoxylin-eosin (HE) staining and Masson trichrome staining were used to observe pathological changes in the heart and kidneys. Wheat germ agglutinin (WGA) staining was used to evaluate myocardial hypertrophy. The real-time quantitative PCR (RT-qPCR) was used to detect the expression levels of myocardial hypertrophy- and fibrosis-related mRNAs. Western blotting was used to detect the expression levels of PI3K, AKT and p65 in myocardial tissues. Results After 16 weeks, UCM group exhibited significantly higher blood pressure, serum creatinine, blood urea nitrogen than sham group (P＜0.01); UCM＋EMPA group exhibited lower blood pressure, serum creatinine, blood urea nitrogen, and higher 24 h urine sodium and glucose than UCM group (P＜0.05). Echocardiographic results showed ventricular remodeling in the UCM group, evidenced by left ventricular wall thickening, left ventricular enlargement, increased left ventricular mass, and decreased systolic function (P＜0.05); ventricular remodeling was alleviated (P＜0.05), though there was no significant improvement in systolic function in UCM＋EMPA group. HE and Masson stainings revealed myocardial degeneration, necrosis, and interstitial fibrosis in UCM group (P＜0.01); the myocardial pathology improved with reduced collagen deposition in UCM＋EMPA group (P＜0.01). WGA staining confirmed myocardial hypertrophy in UCM group (P＜0.01), while myocardial hypertrophy was alleviated in UCM＋EMPA group (P＜0.01). RT-qPCR results showed myocardial hypertrophy- and fibrosis-related genes (NPPA, NPPB, MYH7, COL1A1, COL3A1, TGF-β1) were upregulated in UCM group (P＜0.05), but downregulated in UCM＋EMPA group. Western blotting showed PI3K, p-AKT/AKT ratio, and p-p65/p65 ratio were increased in UCM group, but decreased in UCM＋EMPA group (P＜0.05). Conclusion EMPA can improve myocardial hypertrophy and fibrosis in the UCM mouse model, and it may play the role through inhibiting the PI3K/AKT/p65 signaling pathway.

Objective: To investigate the correlation of chemerin levels in the serum and intestinal mucosal with in- testinal mucosal inflammation in IBS-D mice . Methods: A total of 128 female C57BL/6J mice were randomly di- vided into IBS-D group and control group , with 64 mice in each group . Wire Restraint Stress method (WRS) was used to construct an animal model of IBS-D . Enzyme-linked immunosorbent assay was used to detect serum and co- lonic mucosal chemerin levels in mice . Hematoxylin-eosin (HE) staining was used to observe colonic mucosal in- flammation . Geboes value was used to evaluate the severity of colonic mucosal inflammation . Results: In the IBS- D group , the concentration of serum chemerin increased and reached the peak in the first week of the experiment ( t = 6. 538 , P < 0. 001) , and the concentration of colonic mucosa chemerin increased and reached the peak in the fourth week of the experiment ( t = 8 . 104 , P < 0. 001) ; in the first week of experiment , the colonic mucosa of IBS- D mice showed inflammatory reaction , which was the most significant in the fifth week (P < 0. 05) . Geboes score was ( 1 . 75 ±0. 50) vs (0. 55 ±0. 52) . Conclusion There is a temporal sequence between the elevation of serum and intestinal mucosal chemerin levels and the severity of intestinal mucosal inflammation , and it is hypothesized that the elevated serum and intestinal mucosal chemerin levels correlate with the onset and progression of intestinal mucosal inflammation .

Objective:To explore the molecular mechanism of miR-4508 regulating the inflammatory response of human bronchial epithelial cells induced by representative chrysotile asbestos.Methods:The chrysotile asbestos was ground into ultrafine dust using a horizontal planetary instrument, and human bronchial epithelium (16HBE) cells were taken as the object of infection. Cell survival rate was detected by cell counting kit-8 method, cytotoxicity was detected by lactate dehydrogenase (LDH) kit. The released of inflammatory factor IL-6 was detected by electrochemical luminescence. The released inflammatory factor IL-8 was detected by enzyme-linked immunosorbent assay. The expression level of miR-4508 was screened and verified by reverse transcription-quantitative real-time polymerase chain reaction. After 16HBE cells were treated with AKT inhibitor MK2206, the phosphorylation levels of AKT and PTEN were detected by western blot. The expression levels of AKT and PTEN and the contents of IL-6 and IL-8 were detected in miR-4508 overexpression and interference experiments.Results:With the increase of chrysotile asbestos exposure concentration, the cell survival rate decreased in a concentration-dependent manner, and the LDH content gradually increased. The secretion of IL-6 and IL-8 in chrysotile 25, 50 and 75 μg/ml groups were (325.92±8.61) pg/ml, (331.51±4.96) pg/ml, (378.74±13.77) pg/ml, and (94.95±3.11) pg/ml, (357.60±1.80) pg/ml, (537.19±3.11) pg/ml, respectively, while the group with 0 μg/ml chrysotile was (95.85±1.20) pg/ml and (7.81±0.00) pg/ml ( P＜0.05). In addition, chrysotile asbestos exposure to 16HBE could induce the high expression of miR-4508 . After pretreatment with MK2206, the phosphorylation levels of AKT and PTEN were decreased, the contents of IL-6 and IL-8 were significantly decreased, and the expression level of miR-4508 was significantly reduced. Overexpression of miR-4508 significantly increased the expressions of AKT and PTEN, and the contents of IL-6 and IL-8 ( P＜0.01). After interfering with miR-4508, the expressions of AKT and PTEN were significantly decreased, and the contents of IL-6 and IL-8 were significantly decreased ( P＜0.01). Conclusions:Chrysotile asbestos can induce the inflammatory response of 16HBE cells and up-regulate the expression level of miR-4508. The up-regulation of miR-4508 promotes the 16HBE inflammatory response induced by chrysotile asbestos through the PI3K/AKT pathway.

Objective To investigate the role of STK4-AS1 in regulating the proliferation,invasion,and migration of esophageal squamous cell carcinoma(ESCC)cells through the MYG1/Notch signaling pathway.Methods Quantitative real-time PCR(qRT-PCR)was used to detect the expression of STK4-AS1 in ESCC cells.MTS assay,wound healing and Transwell assay were conducted to explore the proliferation,migration,and invasion abilities in each group in Eca109 and Kyse150 cells.mRNA sequencing(mRNA-seq)was used to detect the down-stream target genes of STK4-AS1.KEGG functional enrichment analyses were used to predict the possible biological processes and signaling pathways.qRT-PCR and western blot were performed to identify mRNA expression of MYG1 and the key downstream transcription factors HES1,HES5,and HEY1 of the Notch signaling pathway,as well as the protein expression of NICD1.Co-transfection plasmids(for over-expressing STK4-AS1 and MYG1)were used to detect the mRNA expression of HES1,HES5,and HEY1 and the protein expression of NICD1 which acted as the key downstream transcription factors in the Notch signaling pathway,as well as the effects on the proliferation,migration,and invasion abilities of ESCC cells.Results The expression of STK4-AS1 was decreased in ESCC cell lines(P<0.01).Over-expression of STK4-AS1 inhibited the proliferation,migration and invasion abilities in Eca109 and Kyse150 cells(P<0.05).STK4-AS1 negatively regulated the expression of MYG1(P<0.01),and the expression of MYG1 was increased in ESCC cell lines(P<0.01).Over-expression of MYG1 could partially reverse the effect of STK4-AS1 on the malignant biological behavior of Eca109 and Kyse150 cells(P<0.05),as well as the mRNA expressions of HES1,HES5,and HEY1 and the protein expression of NICD1(P<0.05).Conclusion STK4-AS1 affects the malignant biological behaviors of ESCC through the MYG1/Notch signaling pathway.

AIM:To investigate the effects of glutathione-S-transferase(GST)gene polymorphism on the concentration of 6-thioguanine nucleotides(6-TGN),an active metabolite of azathioprine(AZA),in patients with inflammatory bowel disease(IBD),in order to provide reference for the optimization of AZA treatment in patients.METHODS:The clini-cal data of patients with IBD treated by AZA were collected prospectively,the genotypes of GST-A1,GST-M1,GST-P1 and GST-T1 were detected by tar-geted sequencing of multiplex PCR combined with high-throughput sequencing technology before ad-ministration,and the steady-state trough concen-trations of 6-TGN in patients' red blood cells were determined by HPLC.Statistical analysis was carried out by SPSS 26.0 software.RESULTS:A total of 90 patients were included in this study.The alleles fre-quencies of GST-A1,GST-M1,GST-P1 and GST-T1 were consistent with Hardy-Weinberg equilibrium law.Logistic regression analysis showed that carry-ing GST-A1 mutant gene was an independent risk factor for the increase of trough concentration of 6-TGN(low concentration OR=17.50,P=0.030;high concentration OR=3.60,P=0.033),while the gene polymorphism of GST-M1,GST-P1,GST-T1 had no significant correlation with the concentration of 6-TGN(P＞0.05).CONCLUSION:The gene polymor-phism of GST-A1 may affect the concentration of 6-TGN,an active metabolite of AZA,and detection of GST-A1 genotype before AZA treatment will contrib-ute to clinical individualized medication.

AIM:To investigate the effects of glutathione-S-transferase(GST)gene polymorphism on the concentration of 6-thioguanine nucleotides(6-TGN),an active metabolite of azathioprine(AZA),in patients with inflammatory bowel disease(IBD),in order to provide reference for the optimization of AZA treatment in patients.METHODS:The clini-cal data of patients with IBD treated by AZA were collected prospectively,the genotypes of GST-A1,GST-M1,GST-P1 and GST-T1 were detected by tar-geted sequencing of multiplex PCR combined with high-throughput sequencing technology before ad-ministration,and the steady-state trough concen-trations of 6-TGN in patients' red blood cells were determined by HPLC.Statistical analysis was carried out by SPSS 26.0 software.RESULTS:A total of 90 patients were included in this study.The alleles fre-quencies of GST-A1,GST-M1,GST-P1 and GST-T1 were consistent with Hardy-Weinberg equilibrium law.Logistic regression analysis showed that carry-ing GST-A1 mutant gene was an independent risk factor for the increase of trough concentration of 6-TGN(low concentration OR=17.50,P=0.030;high concentration OR=3.60,P=0.033),while the gene polymorphism of GST-M1,GST-P1,GST-T1 had no significant correlation with the concentration of 6-TGN(P＞0.05).CONCLUSION:The gene polymor-phism of GST-A1 may affect the concentration of 6-TGN,an active metabolite of AZA,and detection of GST-A1 genotype before AZA treatment will contrib-ute to clinical individualized medication.

Objective To investigate the role of STK4-AS1 in regulating the proliferation,invasion,and migration of esophageal squamous cell carcinoma(ESCC)cells through the MYG1/Notch signaling pathway.Methods Quantitative real-time PCR(qRT-PCR)was used to detect the expression of STK4-AS1 in ESCC cells.MTS assay,wound healing and Transwell assay were conducted to explore the proliferation,migration,and invasion abilities in each group in Eca109 and Kyse150 cells.mRNA sequencing(mRNA-seq)was used to detect the down-stream target genes of STK4-AS1.KEGG functional enrichment analyses were used to predict the possible biological processes and signaling pathways.qRT-PCR and western blot were performed to identify mRNA expression of MYG1 and the key downstream transcription factors HES1,HES5,and HEY1 of the Notch signaling pathway,as well as the protein expression of NICD1.Co-transfection plasmids(for over-expressing STK4-AS1 and MYG1)were used to detect the mRNA expression of HES1,HES5,and HEY1 and the protein expression of NICD1 which acted as the key downstream transcription factors in the Notch signaling pathway,as well as the effects on the proliferation,migration,and invasion abilities of ESCC cells.Results The expression of STK4-AS1 was decreased in ESCC cell lines(P<0.01).Over-expression of STK4-AS1 inhibited the proliferation,migration and invasion abilities in Eca109 and Kyse150 cells(P<0.05).STK4-AS1 negatively regulated the expression of MYG1(P<0.01),and the expression of MYG1 was increased in ESCC cell lines(P<0.01).Over-expression of MYG1 could partially reverse the effect of STK4-AS1 on the malignant biological behavior of Eca109 and Kyse150 cells(P<0.05),as well as the mRNA expressions of HES1,HES5,and HEY1 and the protein expression of NICD1(P<0.05).Conclusion STK4-AS1 affects the malignant biological behaviors of ESCC through the MYG1/Notch signaling pathway.

Objective:To explore the molecular mechanism of miR-4508 regulating the inflammatory response of human bronchial epithelial cells induced by representative chrysotile asbestos.Methods:The chrysotile asbestos was ground into ultrafine dust using a horizontal planetary instrument, and human bronchial epithelium (16HBE) cells were taken as the object of infection. Cell survival rate was detected by cell counting kit-8 method, cytotoxicity was detected by lactate dehydrogenase (LDH) kit. The released of inflammatory factor IL-6 was detected by electrochemical luminescence. The released inflammatory factor IL-8 was detected by enzyme-linked immunosorbent assay. The expression level of miR-4508 was screened and verified by reverse transcription-quantitative real-time polymerase chain reaction. After 16HBE cells were treated with AKT inhibitor MK2206, the phosphorylation levels of AKT and PTEN were detected by western blot. The expression levels of AKT and PTEN and the contents of IL-6 and IL-8 were detected in miR-4508 overexpression and interference experiments.Results:With the increase of chrysotile asbestos exposure concentration, the cell survival rate decreased in a concentration-dependent manner, and the LDH content gradually increased. The secretion of IL-6 and IL-8 in chrysotile 25, 50 and 75 μg/ml groups were (325.92±8.61) pg/ml, (331.51±4.96) pg/ml, (378.74±13.77) pg/ml, and (94.95±3.11) pg/ml, (357.60±1.80) pg/ml, (537.19±3.11) pg/ml, respectively, while the group with 0 μg/ml chrysotile was (95.85±1.20) pg/ml and (7.81±0.00) pg/ml ( P＜0.05). In addition, chrysotile asbestos exposure to 16HBE could induce the high expression of miR-4508 . After pretreatment with MK2206, the phosphorylation levels of AKT and PTEN were decreased, the contents of IL-6 and IL-8 were significantly decreased, and the expression level of miR-4508 was significantly reduced. Overexpression of miR-4508 significantly increased the expressions of AKT and PTEN, and the contents of IL-6 and IL-8 ( P＜0.01). After interfering with miR-4508, the expressions of AKT and PTEN were significantly decreased, and the contents of IL-6 and IL-8 were significantly decreased ( P＜0.01). Conclusions:Chrysotile asbestos can induce the inflammatory response of 16HBE cells and up-regulate the expression level of miR-4508. The up-regulation of miR-4508 promotes the 16HBE inflammatory response induced by chrysotile asbestos through the PI3K/AKT pathway.

The management of antibiotic-resistant, bacterial biofilm infections in skin wounds poses an increasingly challenging clinical scenario. Pseudomonas aeruginosa infection is difficult to eradicate because of biofilm formation and antibiotic resistance. In this study, we identified a new benzothiazole derivative compound, SN12 (IC₅₀ = 43.3 nmol/L), demonstrating remarkable biofilm inhibition at nanomolar concentrations in vitro. In further activity assays and mechanistic studies, we formulated an unconventional strategy for combating P. aeruginosa-derived infections by targeting the two-component (Gac/Rsm) system. Furthermore, SN12 slowed the development of ciprofloxacin and tobramycin resistance. By using murine skin wound infection models, we observed that SN12 significantly augmented the antibacterial effects of three widely used antibiotics-tobramycin (100-fold), vancomycin (200-fold), and ciprofloxacin (1000-fold)-compared with single-dose antibiotic treatments for P. aeruginosa infection in vivo. The findings of this study suggest the potential of SN12 as a promising antibacterial synergist, highlighting the effectiveness of targeting the two-component system in treating challenging bacterial biofilm infections in humans.

Objective Explore effective strategies for hospitals to manage the National Natural Science Foundation of China.Methods A retrospective analysis was conducted on the population characteristics of a certain tertiary comprehensive hospital's National Natural Science Foundation project application and approval from 2016 to 2022.Single factor analysis and bi-nary multivariate logistic regression analysis were used to analyze the factors that affect the approval of the National Natural Sci-ence Foundation project,and a function prediction model was established.Results A total of 1 098 applicants were collected in this study,including 653 young project applicants and 178 approved,445 general project applicants and 114 approved;Multi fac-tor logistic results show that in youth programs,the younger the age,the doctor's degree,scientific research posts,the experi-ence of studying abroad,the average impact factor of publishing SCI papers as the first/corresponding author is 3-5 points Appli-cants who have published SCI papers as the first/corresponding author with an average impact factor of more than 5 points,pub-lished SCI papers in four districts as the first/corresponding author,presided over national level and academic level topics are more likely to be approved by the Youth Program of the National Natural Science Foundation of China;Among general programs,applicants who have doctoral degree,overseas study experience,published Zone 1and Zone 2 SCI essays,and presided over na-tional projects as the first/corresponding author are more likely to be approved as general programs of the National Natural Science Foundation of China.The area under the AUC curve of the youth project regression prediction model is 0.860,and the area under the AUC curve of the surface project regression prediction model is 0.838.The model has high predictive value.Conclusion Hospitals should strengthen policy guidance,increase economic investment,encourage applicants to carry out preliminary work layout,focus on talent cultivation,and comprehensively promote the effective management of the National Natural Science Foun-dation of the hospital.