Objective To study whether the protective effects of fenofibrate on insulin resistance in mice of nonal-coholic fatty liver disease(NAFLD) are related to endoplasmic reticulum stress (ERS). Methods Male C57BL/6 mice were fed with high-calorie and high-cholesterol diet ( HCD) to induce a model of NAFLD, then one of those two groups from HCD was treated with fenofibrate 40 mg/( kg · d ) for 2 weeks ( HCF ) . Glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to analyze the improvement on insulin resistance. The serum levels of triglyceride ( TG) , total cholesterol ( TC) , high density lipoprotein-cholesterol ( HDL-C) , low density lip-oprotein-cholesterol ( LDL-C) , alanine aminotransferase ( ALT) and aspartic transaminase ( AST) were detected. The pathological changes of livers were detected with HE and Oil Red O staining, the mRNA and protein expression of peroxisome proliferator-activated receptorα( PPARα) , glucose regulated protein 78 ( GRP78 ) and transcription factors GADD153 ( CHOP) were detected with real-time quantification PCR and Western blot analysis respectively. Results Compared with the SCD mice, the HCD mice showed significant insulin resistance, higher serum levels of TG, TC and LDL-C (P<0. 01, P<0. 05), lower serum level of HDL-C (P<0. 01), micro-and macrovesicular steatosis, ballooned hepatocytes and infiltration of inflammatory cells were observed in the liver, the expressions of PPARα and GRP78 at mRNA and protein levels were decreased (P<0. 05), however, the expressions of CHOP at mRNA and protein levels were increased ( P<0 . 05 ) . Fenofibrate intervention significantly improved insulin resist-ance and decreased the serum level of TG ( P<0. 05 ) . Fenofibrate also alleviated hepatic steatosis and inflammato-ry infiltration, and increased the mRNA and protein expressions of PPARα and GRP78, decreased the mRNA and protein expression of CHOP ( P<0 . 05 ) . Conclusion Fenofibrate significantly improves insulin resistance and de-creases the serum level of TG in NAFLD mice, which may be related to activating PPARα and relieving ERS.

Objective To study the influences of fenofibrate on oxidative stress and endoplasmic reticulum stress in livers of hyperlipidemic rats. Methods Male SD rats were fed with high-fat diet for 12 weeks to induce a model of hyperlipidemia, then divided into control group, high-fat diet group with another four-week high-fat diet and fenofibrate group, in which rats were treated with fenofibrate [100 mg / (kg·d)] for 4 weeks. Then improvement of insulin resistance was detected in rats with GTT and ITT experiment. The serum levels of glucose (GLU), fasting insulin (FINS),triglyceride (TG) and total cholesterol (TC) were detected. The pathological changes of livers were detected with Oil Red O staining. The oxidative stress indices such as T-SOD, Mn-SOD, GSH and T-AOC were detected with liver homogenate. The expression of GRP78 was detected with real-time quantification RT-PCR and Western blot analysis respectively. Results Compared with rats with high-fat-diet, rats after fenofibrate treatment showed obviously improved insulin resistance, lower serum level of TG, TC and FINS (P < 0.05), decreased number and size of lipid droplets in liver tissue sections. T-SOD level in liver homogenate was significantly increased (P < 0.05), while GSH and T-AOC levels increased but had no obvious differences when compared with control group (P > 0.05). The expression of GRP78 at mRNA and protein levels were increased significantly after fenofibrate treatment (P < 0.05). Conclusions Fenofibrate has significant effects on improving insulin resistance and lipid regulation, which might be related to decreased oxidative stress and subsequent endoplasmic reticulum stress.

Objective To survey on satisfaction degree of preventive medicine undergraduates on tutorial system and to improve the effects of tutorial system.Methods Totally 73 students of preventive medicine,who would graduate in 2012,were asked to fill the questionnaires by themselves.Main contents of questionnaires include effects,satisfaction score,expectations and reality benefits,requirements for the tutors and problems of the tutorial system.Chi-square was used to test the differences between expectations and reality benefits and the significance level was set as P ＜ 0.05.Results More than half of the students thought that the effect of tutorial system was general while 43.8％students thought good and excellent.Percentages of satisfaction score over 50,over 80 and over 90 were 75.3％,41.1％ and 12.3％,respectively.Statistical analysis shown that the real benefits from research activities were more than expectation (P ＜ 0.001),while the real benefits from tutor's academic encouragement,job guidance and life values were lower than expectation (P =0.026,P =0.003,P =0.010).Students expected to have more opportunities with the professors in the future.However,there were 17.8％ students hardly attended the activities of tutorial system,in which lack of understanding of tutorial system was the main reason and without enough time was another reason.Conclusions Students basically satisfies with tutorial system and the satisfaction degree needs to be improved.Roles of tutorial system should be fully strengthened by the management department,tutors and students.

OBJECTIVETo find out the distributive features of some metabolic genes polymorphisms in Han population of south area of China.

METHODSStudy population was obtained from the controls of a community based case-control study, which included 290 blood relatives (inner control) and 404 non-blood relatives (outer control).

RESULTSFrequencies of CYP1A1, GSTM1 and GSTT1 polymorphisms had no significant difference among confounding factors, such as sex, living areas, stomach cancer family history and history of tobacco smoking etc. Some controls showed significant difference in age group and alcohol drinking which would be adjusted in analysis of the relationship between polymorphisms and cancers. CYP1A1 Ile/Val and Val/Val genotypes were 33.43% and 5.62% respectively, which were similar to other results from Chinese and Japanese, but higher than those from Caucasians in American, Europe and African-Americans. GSTM1 null allele frequency was 53.48% in our population, which showed difference even among Chinese in different areas. GSTT1 null allele frequency was 45.78%, which was significantly higher than that in Caucasians and African-American.

CONCLUSIONThe frequencies of CYP1A1 Ile/Val, Val/Val and GSTT1 null in Han population in south area of China are significantly higher than those in other races, while the ethnic difference of frequency of GSTM1 null is less.

China ; Cytochrome P-450 CYP1A1 ; genetics ; DNA ; genetics ; Female ; Gene Frequency ; Genotype ; Geography ; Glutathione Transferase ; genetics ; Humans ; Male ; Polymorphism, Genetic

OBJECTIVETo study the relationship between polymorphism of inducible Nitric Oxide Synthase (iNOS) gene and the susceptibility of intestinal type stomach cancer and stomach cardia cancer in Chinese people.

METHODSA community-based case-control study was designed. Ninety-three intestinal type of stomach cancer and 50 stomach cardia cancer patients with endoscopy and pathology diagnosis were identified as cases. Two hundred and forty-six controls served as controls.

RESULTSC-->T polymorphism was found in exon 16 of iNOS gene, which changed the coding amino acid from serine to leucine, and formed a recognition site identified by Tsp 509 I restriction enzyme (we called it C-->T polymorphism). The T allele gene frequency in the control group was 13.21%. No statistically significant difference was found between C-->T polymorphism alone and the increased susceptibility to intestinal stomach cancer or stomach cardia cancer. A significant type 2 multiplicative interaction was found in increasing both the risk of intestinal stomach cancer and stomach cardia cancer when both C-->T polymorphism and tobacco smoking exposure existed. An additive interaction model, which showed statistically significant difference, was found to increase only the risk of stomach cardia cancer when CagA antibody shared negative but C-->T polymorphism occurred.

CONCLUSIONC-->T polymorphism of iNOS gene was considered as one of the possible susceptible genes, which specifically increased the risk of tobacco-related but CagA negative types of intestinal stomach cancer and stomach cardia cancer.

Antibodies, Bacterial ; blood ; Antigens, Bacterial ; immunology ; Bacterial Proteins ; immunology ; Genetic Predisposition to Disease ; Humans ; Nitric Oxide Synthase ; genetics ; Nitric Oxide Synthase Type II ; Polymorphism, Genetic ; Stomach Neoplasms ; genetics

Objective:To study the protective effect of Mongolian medicine Bateri-7 on radiation-induced intestinal injury in mice.Methods:C57BL/6J male mice were randomly divided into control group, irradiation group and irradiation plus drug administration group, with 10 or 15 mice in each group. For irradiation group, the mice were given a single dose of 12 Gy 60Co γ-rays with total body irradiation. For drug treatment, the mice were gavaged with Bateri-7 (530 mg/kg) 7 d before irradiation until 3 d after IR. At 6 h and 24 h after irradiation, the Tunel positive cells in intestine were detected immunohistochemically. At 3.5 d after irradiation, the structure of intestinal villi was observed by HE staining, and the BrdU and Ki67 positive cells were detected immunohistochemically. The expression levels of IL-6, TNF-α and Cxcl-5 were detected by qPCR. The FITC-dextran in peripheral blood was also determined. Results:The survival of irradiated mice was significantly increased by Bateri-7 ( χ2= 5.84, P < 0.05), but there was no significant difference in weight between two groups ( P > 0.05). The villi length of small intestine in the irradiation plus drug group was significantly longer than that in the irradiation group ( t = 20.24, P < 0.05), and there was no significant difference in the depth of intestinal crypt between two groups ( P > 0.05). At 6 and 24 h after irradiation, the number of Tunel positive cells in intestinal crypts in the irradiation plus drug group was significantly reduced in comparison with the irradiation group ( t = 3.52, 2.90, P < 0.05). At 3.5 d after irradiation, the level of FITC-dextran in serum and the expressions of IL-6, TNF-α and Cxcl-5 in small intestine of mice in the irradiation plus drug group were significantly lower than those in the irradiation group, respectively( t = 6.92, 7.01, 7.18, 13.16, P < 0.05). The number of BrdU and Ki67 positive cells in the crypt of mice in the irradiation plus drug group was higher than that of the irradiation group ( t = 3.91, 2.57, P < 0.05). Conclusions:Mongolian medicine Bateri-7 can effectively alleviate irradiation-induced intestinal injury of mice, which may have a good preventive and therapeutic effect on radiation enteritis.

Objective:To explore the correlation between the index of hemodynamics in perinatal period and retinopathy of prematurity(ROP), so as to provide basis for the better prevention and treatment of ROP.Methods:From May 2017 to April 2019, the preterm infants were admitted to the Neonatal Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University at birth and were hospitalized for more than 2 weeks, gestational age ≤ 35 weeks and birth weight ≤ 2 500 g. They were selected as the study objects.The perinatal data including heart rate, blood pressure, patent ductus arteriosus, ventricular septal defect, and NT-proBNP level on the 1 st, 7 th and 14 th day, respectively after birth were collected.They were divided into ROP group and non ROP group according to the results of the retinopathy screening report.The influencing factors of ROP were screened out by univariate analysis and multivariate regression analysis. Results:A total of 1 119 subjects were included, 105 infants with ROP were detected, and the prevalence of ROP was 9.4%.Among them, 12 cases of pre-threshold lesion type 1 and threshold lesions required treatment, accoun-ting for 1.07% of screened preterm infants .Univariate analysis and multivariate regression analysis revealed that gestational age, birth weight, total oxygen therapy time, and intrauterine growth restriction were all factors affecting ROP, and 2 hemodynamic related indicators, such as the level of NT-proBNP in plasma on the 14 th day after birth, and placenta previa or abruption were also related to ROP( OR=0.604, 0.647, 1.276, 2.361, 1.688 and 2.506, respectively, all P<0.05). Conclusion:The hemodynamic changes in perinatal period may be involved in the formation of ROP, and it is necessary to further clarify its mechanism.

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl₄. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6C^high macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl₄-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl₄-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

OBJECTIVES: To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. METHODS: Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was used for analysis. Differentially expressed genes were screened with the criteria of false discovery rate<0.05 and l o g 2 F C >1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for differentially expressed genes. Genes encoding transcription factors were further screened for differential expression genes. Then, the expression of these genes during renal fibrosis was verified using unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis model and a public gene expression dataset (GSE104954). RESULTS: After TGF-β1 treatment for 6, 12 and 24 h, 552, 1209 and 1028 differentially expressed genes were identified, respectively. GO analysis indicated that these genes were significantly enriched in development, cell death, and cell migration. KEGG pathway analysis showed that in the early stage of TGF-β1 induction (TGF-β1 treatment for 6 h), the changes in Hippo, TGF-β and Wnt signaling pathways were observed, while in the late stage of TGF-β1 induction (TGF-β1 treatment for 24 h), the changes of extracellular matrix-receptor interaction, focal adhesion and adherens junction were mainly enriched. Among the 291 up-regulated differentially expressed genes treated with TGF-β1 for 6 h, 13 genes (Snai1, Irf8, Bhlhe40, Junb, Arid5a, Vdr, Lef1, Ahr, Foxo1, Myc, Tcf7, Foxc2, Glis1) encoded transcription factors. Validation in a cell model showed that TGF-β1 induced expression of 9 transcription factors (encoded by Snai1, Irf8, Bhlhe40, Junb, Arid5a, Vdr, Lef1, Myc, Tcf7), while the expression levels of the other 4 genes did not significantly change after TGF-β1 treatment. Validation results in UUO-induced mouse renal fibrosis model showed that Snai1, Irf8, Bhlhe40, Junb, Arid5a, Myc and Tcf7 were up-regulated after UUO, Vdr was down-regulated and there was no significant change in Lef1. Validation based on the GSE104954 dataset showed that IRF8 was significantly overexpressed in the renal tubulointerstitium of patients with diabetic nephropathy or IgA nephropathy, MYC was highly expressed in diabetic nephropathy, and the expressions of the other 7 genes were not significantly different compared with the control group. CONCLUSIONS TGF-β1 induces differentially expressed genes in renal fibroblasts, among which Irf8 and Myc were identified as potential targets of chronic kidney disease and renal fibrosis.
Mice ; Animals ; Humans ; Transforming Growth Factor beta1/metabolism* ; Diabetic Nephropathies/pathology* ; Transcriptome ; Signal Transduction ; Kidney ; Ureteral Obstruction/pathology* ; Fibrosis ; Interferon Regulatory Factors ; Transforming Growth Factor beta/metabolism* ; DNA-Binding Proteins/metabolism* ; Transcription Factors/metabolism*