Application of precision medicine in rare neurodegenerative diseases / 国际药学研究杂志

Technological development has paved the way for accelerated genomic discovery and brought precision medicine into view. Genetics, bioinformatics, molecular imaging and management provide tools for realizing the idea of precision medicine. The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to an individual’s molecular drivers of disease. It is very important for the implementation of precision medicine in rare neurodegenerative diseases, which are difficult to diagnose and treat. Precision medicine contributes to the identification of causative genes, the classification of genotypes and phenotypes of diseases, discovery of biomarkers with high sensitivity and specificity, and development of promising modified therapies. However, like the disadvantage encountered in other diseases, implementation of precision medicine in rare neurodegenerative diseases still confronts numerous challenges.

Effects of bone morphogenetic protein-7 therapy on E3 ubiquitin ligase expression in mouse liver with experimentally induced fibrosis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>This study explored the dynamic expression of the E3 ubiquitin-protein ligase gene, Arkadia, in response to carbon tetrachloride (CCl4)-induced liver fibrosis in a mouse model and investigated the differential expression that occurs following treatment with the anti-fibrotic bone morphogenetic protein-7 (BMP-7).</p><p><b>METHODS</b>Thirty healthy male imprinting control region (ICR) mice were randomly assigned to three groups: normal (control; n = 6), CCl4-induced model group (model; n = 18), and CCl4-induced model with BMP-7 treatment group (treatment; n = 6). The model group was further divided into three subgroups (n = 6 each) for analysis at 4, 8 and 12 weeks after fibrosis induction. Liver fibrosis was induced by hypodermic injections of 60% CCl4 /peanut oil (5 mL/kg) to the hind legs of mice two-times per week in alternating legs for a period of 12 weeks. At week 9, the treatment group of CCl4-induced mice were given an intraperitoneal injection of BMP-7 (300 pg/g) simultaneously with that day's hypodermic injection of 60% CCl4 /peanut oil, and then every other day for a period of four weeks. The pathological changes in liver tissues were observed after staining with hematoxylin-eosin (HE) and Masson's trichrome. Messenger RNA (mRNA) and protein expression of Arkadia in liver were evaluated using reverse transcription-polymerase chain reaction and immunohistochemistry and Western blotting, respectively.</p><p><b>RESULTS</b>Mouse models of liver fibrosis were successfully established by CCl4 exposure. Arkadia, Smad7 and TGF-beta1 mRNA levels were up-regulated in the model group in a time-dependent manner (vs. control group), and BMP-7 treatment led to significant down-regulation of the CCl4-induced expression of the three genes (vs. control group: F = 812.80, 451.46, and 998.96, respectively; P less than 0.01). At week 12, the mRNA levels of Arkadia, Smad7, and TGF-b1 were significantly lower in the BMP-7 treatment group than in the model group (t = 12.108, 18.737, and 16.364, respectively; P less than 0.01). Arkadia, Smad7, and TGF-b1 protein staining was weak in the portal area of control liver tissue. In contrast, the model group showed significantly stronger staining for all three proteins in the portal area and in the cytoplasm of liver cells. The staining of Arkadia, Smad7, and TGF-b1 proteins was significantly lower in the treatment group (vs. control group: F = 8.399, 609.690, and 900.561, respectively; P < 0.01). At week 12, the protein levels of Arkadia, Smad7, and TGF-b1 were significantly lower in the treatment group than in the model group (t = 23.438, 11.667, and 42.889, respectively; P < 0.01).</p><p><b>CONCLUSION</b>Arkadia expression gradually increased along with the development of liver fibrosis but was suppressed by treatment with the anti-fibrotic factor, BMP-7.</p>

Dynamic expression of tropomyosin 1 in rat model of hepatic fibrosis and hepatic stellate cells / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the dynamic expression of TPM1 in rat model of hepatic fibrosis and hepatic stellate cells induced by TGFβ1.</p><p><b>METHOD</b>Thirty male SD rats were divided into control group (n = 6) and model group (n = 24). The rat model of hepatic fibrosis was established by intraperitoneal injection of dimethylnitrosamine(DMN). The sera were collected from portal vein and liver tissues were taken from animals 2, 4, 6, 8 weeks HSC-T6 cells were cultured and induced 48 hours by 5 ng/ml TGF-β1. The pathological changes of liver were observed by Hematoxylin-Eosin and Masson Staining. Reverse Transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and Western-blotting were used to determine the mRNA and protein expressions of TPM1, TGFβ1 and α-SMA in rat models and HSC-T6 cells and the localization of TPM1 in rat models.</p><p><b>RESULTS</b>Rat models of hepatic fibrosis were successfully established. TPM1 was lowly stained in the wall of blood vessels in portal areas in normal livers, in fibrotic livers TPM1 was mainly stained along the fibrotic septum. The mRNA and protein expressions of TPM1 and α-SMA in rat models of hepatic fibrosis increased at the week 2 and peaked at week 6, which was statistical significance compared to control group, P < 0.05; TGF-β1 increased at week 2 and it was higher than the levels in other groups at week 4, which was statistical significance compared to control group P < 0.05; Correlation analysis showed that TPM1 positively correlated with α-SMA and TGF-β1, rs = 0.688, rs = 0.692, P < 0.01. In HSC-T6, the mRNA expressions of TPM1 and α-SMA increased after being induced by TGF -beta1. compare with control group, the differences were significant, P less than 0.05.</p><p><b>CONCLUSION</b>TPM1 may be playing an important role in the occurrence and development of liver fibrosis. Maybe it could become a potential therapeutic target for hepatic fibrosis.</p>

Expression of the keratin 10 related genes in buccal mucous membrane exfoliated cells and changes of liver function in coal-burning arsenism / 中国地方病学杂志

Objective To observe expression of the keratin 10 (K10), c-myc and cox2 in buccal mucous membrane exfoliated cells, and changes of liver function of coal-burning arsenism patients, in order to explorate coal-burning arsenic poison circumference biology symbol. Methods The buccal mucous membrane exfoliated cells were collected from both arsenism patients and normal controls. Real-time PCR was employed to detect the changes of K10, c-myc, cox2 genes expression in these cells. Simultaneously, circumference venous blood was extracted and examinated liver function. Results K10 was found obviously overexpressed in arsenism patients(3.60±0.94) compared to control(1.82±0.68), the difference had statistics significance(t=2.15, P<0.05), c-mye and cox2 did not found obviously changed(c-myc: 3.50±2.77,3.39±2.07; cox2:5.90±1.40,4.73±1.91; t=1.26,1.65, P> 0.05). The serum ALT of patients(25.83±2A5) obviously increased than control(36.86±1735, t=2.55, P<0.05). Conclusions Expression of K10 gene in buccal mucous membrane cells may be regarded as sensitive molecular markers for skin pathologic changes in arsenic patients. The liver is a sensitive target organ of inorganic arsenic.

Changes of plasma cytokines in patients with severe hepatitis treated with a probiotic preparation / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the changes of plasma cytokines in patients with severe hepatitis treated with a probiotic preparation.</p><p><b>METHODS</b>One hundred twelve patients with severe hepatitis treated with a basic regimen were randomly divided into a probiotic preparation treatment group and a control group. Their plasma cytokines such as tumor necrosis factor alpha, interleukin-2, interleukin-6, interleukin-10, were determined by conventional techniques.</p><p><b>RESULTS</b>Clinical symptoms of 84.5% of the treatment group were obviously improved. The treatment effectiveness in this group was better than that in the control group (X2=8.888). It showed that liver functions were significantly improved compared to those of the control group . After the probiotic preparation therapy, there were significant decreases in the concentrations of TNFa and IL-6. TNFa and IL-6 in the treatment group and in the control group were (109.4+/-14.7) pg/ml vs (128.7+/-18.8) pg/ml and (84.3+/-20.1) pg/ml vs (109.1+/-18.7) pg/ml respectively. However, the concentrations of IL-10 and IL-2 in the treatment group increased obviously: IL-2 was (59.8+/-12.2) pg/ml vs (47.1+/-6.7) pg/ml and IL-10 was (30.6+/-6.6) pg/ml vs (22.5+/-6.1) pg/ml.</p><p><b>CONCLUSION</b>The probiotic preparation treatment effectively reduces the TNFa and IL-6 and increases the concentrations of IL-10 and IL-2 in the blood of the patients with severe hepatitis.</p>

Expression of Bcl-2,Bax and proliferating cell nuclear antigen in the liver of rats with hepatic fibrosis and the effect of transforming growth factor-?1 vaccine on them / 中华传染病杂志

Objective To observe the expression of Bcl-2,Bax and proliferating cell nuclear antigen(PCNA) in liver of rats with hepatic fibrosis and the effects of transforming growth factor (TGF)-?1 vaccine on them.Methods Thirty healthy male Sprague-Dawley rats were assigned into 3 groups,named healthy control group(n=10),hepatic fibrosis group(n=10) and TGF-?1 vaccine treated group(n=10).The animal model with hepatic fibrosis was established by injecting solution dimethylnitrosamine (DMN) into abdominal cavity with concentration as 0.5% and dose as 0.2 mL/ 100 g.In TGF-?1 vaccine treated group,every rat was not only injected with DMN but also 150?g TGF-?1 vaccine protein.On the 42nd day,all rats were sacrificed.Then the blood and the liver tis- sues were collected.The expression levels of Bcl-2,Bax and PCNA in liver tissues were detected by S -P immunohistochemistry and observed by routine pathological evaluation.Alanine aminotransferase (ALT),aspartate aminotransferase(AST) and albumin(Alb) were determined by auto biochemical analytical tool.Serum levels of hyaluronic acid (HA),laminin(LN) were detected by radioimmunoas- say (RIA).Results The expression of Bax,which promoted apoptosis,directly correlated with pathological grade in liver of rats,while the expression of Bcl-2 and Bcl-2/Bax,which protected a gainst apoptosis,inversely correlated with pathological grade in liver of rats.The expression levels of TGF-?1 and Bax in healthy control group were significantly lower than those of fibrosis group,how ever,the expression levels of Bcl-2 were comparable between these two groups.As compared with fi- brosis group,the expression of TGF-?1 was significantly lower while the expression of Bcl-2 was sig nificantly higher in TGF-?1 vaccine treated group.However,the expression of Bax was comparable between these two groups.The expression level of PCNA of fibrosis group was significantly higher than that of healthy control group but dramatically lower than that of TGF-?1 vaccine treated group (Both P

Status and drug resistance surveillance of enterococcus infection in patients with severe hepatitis / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To analyze the infection status and the drug resistance of enterococci in patients with severe hepatitis to guide future treatment.</p><p><b>METHODS</b>All bacteria from infected patients with severe hepatitis were cultured with BacT/Alert120 automation instrument (Aksu) and identified with Vitek-AMS60 (Biomerieux). Drug sensitivities of the isolated enterococci were tested with 11 antibacterial agents.</p><p><b>RESULTS</b>Among the 112 isolated enterococci, Enterococcus faecalis was the most preponderant bacterium, and the second was E. faecium. Their isolation rates were 79.5% and 14.3%, respectively. 57.1% of all the enterococci were found in the ascetic fluid of patients with severe hepatitis. Fifty-eight (51.8%) isolated enterococci were found to be high level aminoglycoside resistant (HLAR), 19 (17.0%) enterococci were ampicillin-resistant enterococcus (ARE) and 7 (6.3%) were both HLAR and ARE. The susceptive rates of the enterococci to vancomycin and teicoplanin were very high, namely 96.4% and 100%, respectively. No vancomycin or teicoplanin resistant enterococci were found, but 4 enterococci were mildly sensitive to vancomycin.</p><p><b>CONCLUSION</b>Enterococcus faecalis is the most prevalent species isolated in severe hepatitis patients infected with enterococcal infection. From our study, vancomycin and teicoplanin are the drugs of first choice to treat those infections.</p>

Study on the polymorphisms and promoter methylation and expression of the glutathione S-transferases P1 gene in hepatocellular carcinoma / 中华消化杂志

Objective To study the relationships between hepatocellular carcinoma (HCC) and the polymorphisms,promoter methylation,and expression of glutathione S-transferases P1 gene (GST) P1 gene.Methods Using methylation-special PCR (MSP),the methylated status of CpG islands of GSTP1 gene in tumor tissues of 53 HCC and its adjacent nontumor tissues were studied.The enzyme activities of GSTP1 were evaluated by ultraviolet colormetry.And using PCR-RFLP,the genetic polymorphisms of the GSTP1 genes of 74 healthy controls and 53 HCC patients were studied.Results The diffe-rences of the frequency of GSTP1 Ile/Ile,Ile/Val and Val/Val genotypes between HCC patients and the normal controls did not reach statistical significance (X~2=0.84,v=2,P=0.656).The frequency of methyla- tion of CpG islands of GSTP1 gene was significantly higher among the HCC tumor tissues when com- pared to the corresponding nontumor tissues (X~2=19.08,P＜0.001),and significantly higher in stageⅢ-Ⅳcases when compared to the stageⅠ-Ⅱcases (X~2=4.84,P=0.028).GSTP1 enzyme activities of cytoplasm in tumor cells were lower significantly than that in the adjacent nontumor tissues (t=2.49, P=0.014),and significantly higher in stageⅠ-Ⅱcases when compared to the stageⅢ-Ⅳcases (t= 2.31,P=0.025).On the other hand,the GSTP1 enzyme activities of cytoplasm in tumor cells with methylated status of GSTP1 gene were significantly lower than that in tumor cells with unmethylation (t=3.50,P=0.001).Conclusion GSTP1 inactivation via CpG island hypermethylation may contrib- ute to the pathogenesis of HCC.