Aim To investigate the effects of SAHA on the expression of P-gp and the pharmacokinetic pa-rameters of its substrate phenytoin sodium in rats under hypoxic environments.Methods Wistar rats were randomly divided into the normioxic group,the hypoxic model group,and the low-,medium-and high-dose vorinostat(SAHA)groups.Liver tissues were col-lected,and the expression levels of P-gp and HDAC5 were detected by Real-time PCR and Western blot.The morphological changes of liver tissues were ob-served by HE staining.Following intragastric adminis-tration of 50 mg·kg-1 phenytoin sodium to each group,blood samples were collected,and the plasma concentration of phenytoin sodium was determined u-sing UFLC-MS/MS to calculate pharmacokinetic pa-rameters.Results Compared with the normoxic group,the expression of HDAC5 in the liver tissues of hypoxia model rats increased,while the expression of P-gp decreased.After SAHA treatment,HDAC5 expression decreased,and P-gp expression increased.Among the SAHA groups,the medium-dose group showed the most significant effect,and HE staining re-sults indicated that this concentration did not cause damage to rat liver tissues.Compared with the normox-ic group,the AUC,Cmax,and T1/2 of phenytoin sodium in hypoxia model rats were significantly raised.After administration of the medium dose of SAHA,the AUC,Cmax,MRT,and T1/2 were significantly reduced,while CLZ/r was significantly increased.Conclusions Un-der hypoxic environments,the expression of P-gp in rat liver tissue is significantly downregulated,leading to increased systemic exposure of phenytoin,reduced clearance,and consequently elevated blood concentra-tions,raising the risk of central nervous system toxici-ty.In contrast,SAHA suppresses HDAC5 expression,thereby activating P-gp transcription and enhancing its efflux function.This results in decreased systemic ex-posure and improved clearance of phenytoin,signifi-cantly reducing drug accumulation in body and ulti-mately lowering the risk of adverse effects.

Aim To investigate the effect of Brusatol a-gainst small cell lung cancer(SCLC)and its potential mechanism.Methods CCK-8 assay and flow cytome-try were used to detect the cytotoxic effect of Brusatol on SCLC cells.Western blot was employed to measure the expression levels of apoptosis-related proteins,in-cluding cleaved poly(ADP-ribose)polymerase(cleaved-PARP),B-cell lymphoma 2(Bcl-2)and Bcl-2-associated X protein(Bax).Network pharma-cology databases were utilized to identify common tar-gets of Brusatol,SCLC,and apoptosis.Kyoto Encyclo-pedia of Genes and Genomes(KEGG)and Gene On-tology(GO)enrichment analyses were performed on the intersecting genes.Molecular docking simulations between Brusatol and core targets were conducted using the CB-DOCK2 online platform to calculate binding en-ergies and sites.Western blot was further applied to detect the expression levels of signal transducer and ac-tivator of transcription 3(STAT3)and phosphorylated-STAT3(p-STAT3).Results Brusatol inhibited SCLC cell growth and induced apoptosis,significantly downregulating Bcl-2 and cleaved-PARP while upregu-lating Bax expression(P＜0.05).Network pharma-cology analysis revealed 108 common targets of Brusa-tol and SCLC,with the top three core targets being ep-idermal growth factor receptor(EGFR),STAT3,and tumor necrosis factor(TNF).Molecular docking re-sults indicated strong binding affinity between bruceine D and these core targets.Western blot validation con-firmed that bruceine D suppressed the expression of STAT3 and p-STAT3.Conclusion Brusatol exerts anti-SCLC effects by inhibiting STAT3 to induce apop-tosis in SCLC cells.

Aim To investigate the effects of SAHA on the expression of P-gp and the pharmacokinetic pa-rameters of its substrate phenytoin sodium in rats under hypoxic environments.Methods Wistar rats were randomly divided into the normioxic group,the hypoxic model group,and the low-,medium-and high-dose vorinostat(SAHA)groups.Liver tissues were col-lected,and the expression levels of P-gp and HDAC5 were detected by Real-time PCR and Western blot.The morphological changes of liver tissues were ob-served by HE staining.Following intragastric adminis-tration of 50 mg·kg-1 phenytoin sodium to each group,blood samples were collected,and the plasma concentration of phenytoin sodium was determined u-sing UFLC-MS/MS to calculate pharmacokinetic pa-rameters.Results Compared with the normoxic group,the expression of HDAC5 in the liver tissues of hypoxia model rats increased,while the expression of P-gp decreased.After SAHA treatment,HDAC5 expression decreased,and P-gp expression increased.Among the SAHA groups,the medium-dose group showed the most significant effect,and HE staining re-sults indicated that this concentration did not cause damage to rat liver tissues.Compared with the normox-ic group,the AUC,Cmax,and T1/2 of phenytoin sodium in hypoxia model rats were significantly raised.After administration of the medium dose of SAHA,the AUC,Cmax,MRT,and T1/2 were significantly reduced,while CLZ/r was significantly increased.Conclusions Un-der hypoxic environments,the expression of P-gp in rat liver tissue is significantly downregulated,leading to increased systemic exposure of phenytoin,reduced clearance,and consequently elevated blood concentra-tions,raising the risk of central nervous system toxici-ty.In contrast,SAHA suppresses HDAC5 expression,thereby activating P-gp transcription and enhancing its efflux function.This results in decreased systemic ex-posure and improved clearance of phenytoin,signifi-cantly reducing drug accumulation in body and ulti-mately lowering the risk of adverse effects.

Aim To investigate the effect of Brusatol a-gainst small cell lung cancer(SCLC)and its potential mechanism.Methods CCK-8 assay and flow cytome-try were used to detect the cytotoxic effect of Brusatol on SCLC cells.Western blot was employed to measure the expression levels of apoptosis-related proteins,in-cluding cleaved poly(ADP-ribose)polymerase(cleaved-PARP),B-cell lymphoma 2(Bcl-2)and Bcl-2-associated X protein(Bax).Network pharma-cology databases were utilized to identify common tar-gets of Brusatol,SCLC,and apoptosis.Kyoto Encyclo-pedia of Genes and Genomes(KEGG)and Gene On-tology(GO)enrichment analyses were performed on the intersecting genes.Molecular docking simulations between Brusatol and core targets were conducted using the CB-DOCK2 online platform to calculate binding en-ergies and sites.Western blot was further applied to detect the expression levels of signal transducer and ac-tivator of transcription 3(STAT3)and phosphorylated-STAT3(p-STAT3).Results Brusatol inhibited SCLC cell growth and induced apoptosis,significantly downregulating Bcl-2 and cleaved-PARP while upregu-lating Bax expression(P＜0.05).Network pharma-cology analysis revealed 108 common targets of Brusa-tol and SCLC,with the top three core targets being ep-idermal growth factor receptor(EGFR),STAT3,and tumor necrosis factor(TNF).Molecular docking re-sults indicated strong binding affinity between bruceine D and these core targets.Western blot validation con-firmed that bruceine D suppressed the expression of STAT3 and p-STAT3.Conclusion Brusatol exerts anti-SCLC effects by inhibiting STAT3 to induce apop-tosis in SCLC cells.

RBM46 is a germ cell-specific RNA-binding protein required for gametogenesis, but the targets and molecular functions of RBM46 remain unknown. Here, we demonstrate that RBM46 binds at specific motifs in the 3'UTRs of mRNAs encoding multiple meiotic cohesin subunits and show that RBM46 is required for normal synaptonemal complex formation during meiosis initiation. Using a recently reported, high-resolution technique known as LACE-seq and working with low-input cells, we profiled the targets of RBM46 at single-nucleotide resolution in leptotene and zygotene stage gametes. We found that RBM46 preferentially binds target mRNAs containing GCCUAU/GUUCGA motifs in their 3'UTRs regions. In Rbm46 knockout mice, the RBM46-target cohesin subunits displayed unaltered mRNA levels but had reduced translation, resulting in the failed assembly of axial elements, synapsis disruption, and meiotic arrest. Our study thus provides mechanistic insights into the molecular functions of RBM46 in gametogenesis and illustrates the power of LACE-seq for investigations of RNA-binding protein functions when working with low-abundance input materials.
Animals ; Mice ; 3' Untranslated Regions/genetics* ; Cell Cycle Proteins/metabolism* ; Gametogenesis/genetics* ; Meiosis/genetics* ; Nuclear Proteins/genetics* ; RNA-Binding Proteins/genetics*

Objective: To analyze the mortality trend and characteristics of chronic obstructive pulmonary disease (COPD) among residents in China from 2004 to 2020. Methods: From the area, gender, region, and age dimensions, the Joinpoint regression model was used to analyze the trend of COPD mortality rate from 2004 to 2020, extracted from the China Death Surveillance Dataset. Results: From 2004 to 2020, the mortality rate and age-adjusted mortality rate of COPD showed a downward trend (AAPC=-3.68%, P<0.001; AAPC=-7.27%, P<0.001), which were consistent with urban and rural subpopulations (mortality rate: AAPC=-3.62%, P=0.009, AAPC=-3.23%, P=0.014; age-adjusted mortality rate: AAPC=-7.26%, P<0.001, AAPC=-6.78%, P<0.001). The mortality rate of COPD in rural was higher than that of urban subpopulations (P<0.001). Also, the mortality rate and age-adjusted mortality rate of COPD showed a downward trend in males and females (mortality rate: AAPC=-3.00%, P<0.001, AAPC=-4.37%, P<0.001; age-adjusted mortality rate: AAPC=-6.73%, P<0.001, AAPC=-8.11%, P<0.001), and the COPD mortality rate for male was generally higher than female (P<0.001). Meanwhile, the mortality rate of COPD in eastern, central and western regions also showed a downward trend (AAPC=-3.87%, P<0.001; AAPC=-3.12%, P<0.001; AAPC=-1.37%, P=0.001), and western regions were significantly higher than that in central (P<0.001) and eastern (P<0.001) regions. The mortality rate of COPD in the age group of Chinese people showed a downward trend in<45, 45-59, and≥60 years groups (AAPC=-9.48%, P<0.001; AAPC=-9.03%, P<0.001; AAPC=-5.91%, P<0.001). Among them,≥60 years groups was significantly higher than that in<45 (P<0.001) and 45-59 (P<0.001) years groups, and the decline rate was slowest. Conclusion: In China, the mortality rate of COPD decreases from 2004 to 2020, and more efforts are needed to reduce COPD mortality, especially in western regions, rural populations, males and the elderly.
Aged ; Female ; Humans ; Male ; Middle Aged ; Asian People ; China/epidemiology* ; Mortality ; Pulmonary Disease, Chronic Obstructive ; Rural Population ; Urban Population ; Adult

Objective: To analyze the mortality trend and characteristics of chronic obstructive pulmonary disease (COPD) among residents in China from 2004 to 2020. Methods: From the area, gender, region, and age dimensions, the Joinpoint regression model was used to analyze the trend of COPD mortality rate from 2004 to 2020, extracted from the China Death Surveillance Dataset. Results: From 2004 to 2020, the mortality rate and age-adjusted mortality rate of COPD showed a downward trend (AAPC=-3.68%, P<0.001; AAPC=-7.27%, P<0.001), which were consistent with urban and rural subpopulations (mortality rate: AAPC=-3.62%, P=0.009, AAPC=-3.23%, P=0.014; age-adjusted mortality rate: AAPC=-7.26%, P<0.001, AAPC=-6.78%, P<0.001). The mortality rate of COPD in rural was higher than that of urban subpopulations (P<0.001). Also, the mortality rate and age-adjusted mortality rate of COPD showed a downward trend in males and females (mortality rate: AAPC=-3.00%, P<0.001, AAPC=-4.37%, P<0.001; age-adjusted mortality rate: AAPC=-6.73%, P<0.001, AAPC=-8.11%, P<0.001), and the COPD mortality rate for male was generally higher than female (P<0.001). Meanwhile, the mortality rate of COPD in eastern, central and western regions also showed a downward trend (AAPC=-3.87%, P<0.001; AAPC=-3.12%, P<0.001; AAPC=-1.37%, P=0.001), and western regions were significantly higher than that in central (P<0.001) and eastern (P<0.001) regions. The mortality rate of COPD in the age group of Chinese people showed a downward trend in<45, 45-59, and≥60 years groups (AAPC=-9.48%, P<0.001; AAPC=-9.03%, P<0.001; AAPC=-5.91%, P<0.001). Among them,≥60 years groups was significantly higher than that in<45 (P<0.001) and 45-59 (P<0.001) years groups, and the decline rate was slowest. Conclusion: In China, the mortality rate of COPD decreases from 2004 to 2020, and more efforts are needed to reduce COPD mortality, especially in western regions, rural populations, males and the elderly.
Aged ; Female ; Humans ; Male ; Middle Aged ; Asian People ; China/epidemiology* ; Mortality ; Pulmonary Disease, Chronic Obstructive ; Rural Population ; Urban Population ; Adult

OBJECTIVE: To investigate the expression level of miR-181b in CD19+ B lymphocytes of patients with chronic lymphocytic leukemia (CLL), to analyze the relationship between its expression and the prognosis of CLL patients, and to predict the potential target gene of miR-181b in CLL by using bioinformatics. METHODS: Eight-four patients with CLL treated in People's Hospital of Xinjiang Uygur Autonomous Region from June 2013 to June 2018 were selected. and 20 healthy people were selected as control group. RNA was extracted from CD19+B lymphocytes of peripheral blood by magnetic bead sorting, the expression level of miR-181b was detected, and it's expression differences in different IPI groups were analyzed. The correlation between the expression level of miR-181b and PFS of CLL patients also was analyzed. miR-181b target genes were predicted by online database and literatures, and gene annotation analysis and relevant signal pathway analysis were performed for candidate target genes. RESULTS: The expression level of miR-181b in CLL patients was significantly lower than that in control group (P＜0.01); The expression level of miR-181b in the low-risk group was higher than that in high-risk group and extremely high-risk group (P＜0.05), but there was no statistical difference between low-risk group and medium-risk group (P=1.00). The expression level of miR-181b in medium-risk group was higher than that in high-risk group and extremely high-risk group (P＜0.05), but there was no difference between high-risk group and extremely high-risk group (P=1.00). ROC curve results showed that the area under the curve (AUC) was 0.792 (P＜0.01).When the expression level of miR-181b was at the threshold value of 0.279, it showed a better sensitivity (62.9%) and specificity (91.8%). Survival analysis results suggested that compared with the high expression group, the miR-181b low expression group had poor PFS (log rank: P=0.047). Prediction of miR-181b by using the starBase, targetscan and picTar database and its combination with literature reports indicated that CARD11, ZFP36L1, RUNX1, NR4A3, ATP1B1, PUM1 and PLAG1 related with blood diseases, and up-regulated CARD11 and ZFP36L1 participated in lymphoid tumor formation by promoting cell proliferation and inhibiting cell aging. CONCLUSION The expression level of miR-181b in CLL group are significantly lower than that in the controls group, and the low expression of miR-181b relates with poor prognosis of CLL patients. Through bioinformatics prediction and combined with literature reports, it is speculated that CARD11 and ZFP36L1 as target genes of miR-181b may be participated in the occurrence and development of CLL. Further experiments are needed to verify this result.
Apoptosis Regulatory Proteins ; Cell Proliferation ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; genetics ; MicroRNAs ; Prognosis

Objective To investigate the effect of cysteine protease inhibitor derived from S chistosoma japonicum(SjCys-tatin)on dextran sodium sulfate(DSS)-induced acute ulcerative colitis in mice.Methods Eighteen C57BL/6 mice were ran-domly divided into three groups:a control group treated with PBS(Group A),a DSS-induced-colitis group treated with PBS(Group B),and a DSS-induced-colitis group treated with SjCystatin(Group C).Colitis was induced in mice by giving 3％DSS orally for 7 days.During this period,the mice were daily injected with 10&mu;g of SjCystatin or PBS only as a control intraperitone-ally.The mice were monitored daily for their clinical manifestations and given scores based on disease activity index(DAI).The severity of colonic inflammation was monitored by the macroscopic score and pathological change.The cytokine profile including TNF-α,IL-4,IL-6 and IL-10 in the supernatants of colon homogenate was detected by ELISA.Results Compared with Group A(0.50 ± 0.28),the DAI score increased significantly in Group B(9.30 ± 1.30)(F=86.86,P<0.01),with remarkable path-ological damages seen in colon tissues.and the levels of TNF-α and IL-6 were(321.33±67.01)and(403.58 ±180.51)pg/mL.The DAI score significantly reduced in Group C(6.67±1.57)as compared to Group B(F=86.86,P<0.01),with improve-ments in the macroscopic and microscopic pathology in mouse colon specimens.As compared to Group B,the levels of TNF-α [(188.14 ± 40.14)pg/mL] and IL-6 [(209.71 ± 48.47)pg/mL] significantly decreased(F=17.46 and 9.89,both P<0.01).Con-clusion SjCystatin has a significantly inhibitory effect for alleviating DSS-induced acute ulcerative colitis in C57BL/6 mice.

The effect of high concentrations of testosterone on ovarian follicle development was investigated. Primary follicles and granulosa cells were cultured in vitro in media supplemented with a testosterone concentration gradient. The combined effects of testosterone and follicle-stimulating hormone (FSH) on follicular growth and granulosa cell gonadotropin receptor mRNA expression were also investigated. Follicle growth in the presence of high testosterone concentrations was promoted at early stages (days 1-7), but inhibited at later stage (days 7-14) of in vitro culture. Interestingly, testosterone-induced follicle development arrest was rescued by treatment with high concentrations of FSH (400 mIU/mL). In addition, in cultured granulosa cells, high testosterone concentrations induced cell proliferation, and increased the mRNA expression level of FSH receptor (FSHR), and luteinized hormone/choriogonadotropin receptor. It was concluded that high concentrations of testosterone inhibited follicle development, most likely through regulation of the FSH signaling pathway, although independently from FSHR downregulation. These findings are an important step in further understanding the pathogenesis of polycystic ovary syndrome.
Androgens ; pharmacology ; Animals ; Cell Proliferation ; drug effects ; Female ; Follicle Stimulating Hormone ; genetics ; metabolism ; pharmacology ; Gene Expression Regulation, Developmental ; Granulosa Cells ; cytology ; drug effects ; metabolism ; Mice ; Ovarian Follicle ; cytology ; drug effects ; growth & development ; metabolism ; Primary Cell Culture ; RNA, Messenger ; genetics ; metabolism ; Receptors, FSH ; genetics ; metabolism ; Receptors, Gonadotropin ; genetics ; metabolism ; Receptors, LH ; genetics ; metabolism ; Signal Transduction ; drug effects ; genetics ; Testosterone ; antagonists & inhibitors ; pharmacology