JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis

Li Xie,Hui Chen,Li Zhang,Yue Ma,Yuan Zhou,Yong-Yu Yang,Chang Liu,Yu-Li Wang,Ya-Jun Yan,Jia Ding,Xiao Teng,Qiang Yang,Xiu-Ping Liu,Jian Wu 대한간학회 2024 Clinical and Molecular Hepatology(대한간학회지) Vol.30 No.2

Background/Aims: Cholestatic liver diseases including primary biliary cholangitis (PBC) are associated with active hepatic fibrogenesis, which ultimately progresses to cirrhosis. Activated hepatic stellate cells (HSCs) are the main fibrogenic effectors in response to cholangiocyte damage. JCAD regulates cell proliferation and malignant transformation in nonalcoholic steatoheaptitis-associated hepatocellular carcinoma (NASH-HCC). However, its participation in cholestatic fibrosis has not been explored yet. Methods: Serial sections of liver tissue of PBC patients were stained with immunofluorescence. Hepatic fibrosis was induced by bile duct ligation (BDL) in wild-type (WT), global JCAD knockout mice (JCAD-KO) and HSC-specific JCAD knockout mice (HSC-JCAD-KO), and evaluated by histopathology and biochemical tests. In situ-activated HSCs isolated from BDL mice were used to determine effects of JCAD on HSC activation. Results: In consistence with staining of liver sections from PBC patients, immunofluorescent staining revealed that JCAD expression was identified in smooth muscle α-actin (α-SMA)-positive fibroblast-like cells and was significantly up-regulated in WT mice with BDL. JCAD deficiency remarkably ameliorated BDL-induced hepatic injury and fibrosis, as documented by liver hydroxyproline content, when compared to WT mice with BDL. Histopathologically, collagen deposition was dramatically reduced in both JCAD-KO and HSC-JCAD-KO mice compared to WT mice, as visualized by Trichrome staining and semi-quantitative scores. Moreover, JCAD deprivation significantly attenuated in situ HSC activation and reduced expression of fibrotic genes after BDL. Conclusions: JCAD deficiency effectively suppressed hepatic fibrosis induced by BDL in mice, and the underlying mechanisms are largely through suppressed Hippo-YAP signaling activity in HSCs.

Decoupling Analysis of Interaction between Tunnel Surrounding Rock and Support in Xigeda Formation Strata

Ping Zhou,Feicong Zhou,Jiayong Lin,Jinyi Li,Yifan Jiang,Bao Yang,Zhijie Wang 대한토목학회 2021 KSCE JOURNAL OF CIVIL ENGINEERING Vol.25 No.12

The Xigeda Formation has the characteristics of poor cementation, variable structure, and softening in water. It is prone to lead to failure of the initial support structures, arch collapse, and even roof fall. The key to the problem lies in the exploration of the interaction between surrounding rock and support. Therefore, based on the constraint loss theory of the tunnel face space effect, this paper constructively introduces multiple dependent variables, including the intermediate principal stress, the dilatancy of the surrounding rock, the timeliness of the shotcrete support stiffness, and the water content of the Xigeda formation, to decouple the whole process of the interaction between the surrounding rock and support, and discusses the influence of each variable. The research results show that: i) there is a critical support point in the tunnel under the influence of the unified strength theoretical parameter b and water content, and when the unified strength theoretical parameter b is constant, the critical distance of the support will decrease with the increase of the water content; ii) from the perspective of deformation control, the stress of support structure will increase with the increase of dilatancy angle of Xigeda surrounding rock; iii) considering the hardening characteristics of shotcrete, the initial support stiffness of Xigeda tunnel increases nonlinearly, and the whole process of stress and deformation can be divided into four stages; iv) the combined support structure of section steel and grille has little difference in the deformation control effect of the surrounding rock and the stress of the support structure, but the combined support structure of the grille steel frame is more sensitive to the hardening parameters.

Association Between XRCC5, 6 and 7 Gene Polymorphisms and the Risk of Breast Cancer: A HuGE Review and Meta-analysis

Zhou, Li-Ping,Luan, Hong,Dong, Xi-Hua,Jin, Guo-Jiang,Man, Dong-Liang,Shang, Hong Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.8

Objective: Non-homologous end joining (NHEJ) is a pathway for repairing DNA double-strand breaks. Recent publications indicated that XRCC5, XRCC6 and XRCC7 genes may participate in the pathogenesis of breast cancer. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to investigate associations between XRCC5, XRCC6 and XRCC7 genetic polymorphisms in the NHEJ pathway and breast cancer risk. Methods: Studies focusing on the relationship between genetic polymorphisms in XRCC5, XRCC6 and XRCC7 genes and susceptibility to breast cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers. The meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software. The odds ratio (OR) with 95% confidence interval (95%CI) was calculated based on the extracted data. Results: According to the inclusion criteria, we final included seven studies with a total of 2,864 breast cancer cases and 3,060 healthy controls. Meta-analysis results showed that rs3835 (G>A) and rs828907 (G>T) in XRCC5 gene, and rs132793 (G>A) in XRCC6 gene might increase the risk of breast cancer, while rs132788 G>T and rs6002421 (A>G) might be protective factors. However, there was no relationship between XRCC7 genetic polymorphisms and the risk of breast cancer. Conclusion: This meta-analysis suggests that the rs3835 G>A and rs828907 G>T in XRCC5 gene, rs6002421 (A>G), rs132788 (G>T) and rs132793 (G>A) in XRCC6 gene might be risk factors for breast cancer, while the rs132788 (G>T) and rs6002421 (A>G) in XRCC6 gene might be protective.

Genetic Variants of CYP2D6 Gene and Cancer Risk: A HuGE Systematic Review and Meta-analysis

Zhou, Li-Ping,Luan, Hong,Dong, Xi-Hua,Jin, Guo-Jiang,Man, Dong-Liang,Shang, Hong Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.7

Objective: Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. A large number of single nucleotide polymorphisms (SNPs) in the CYP2D6 gene have been reported to associate with cancer susceptibility. However, the results are controversial. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to summarize the evidence for associations. Methods: Studies focusing on the relationship between CYP2D6 gene polymorphisms and susceptibility to cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers and the meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software. Odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated. Results: According to the inclusion criteria, forty-three studies with a total of 7,009 cancer cases and 9,646 healthy controls, were included in the meta-analysis. The results showed that there was a positive association between heterozygote (GC) of rs1135840 and cancer risk (OR=1.92, 95%CI: 1.14-3.21, P=0.01). In addition, we found that homozygote (CC) of rs1135840 might be a protective factor for cancer (OR=0.58, 95%CI: 0.34-0.97, P=0.04). Similarly, the G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 had negative associations with cancer risk (OR=0.69, 95%CI: 0.48-0.99, P=0.04; OR=0.60, 95%CI: 0.38-0.94, P=0.03; OR=0.50, 95%CI: 0.26-0.95, P=0.03; respectively). Conclusion: This meta-analysis suggests that CYP2D6 gene polymorphisms are involved in the pathogenesis of various cancers. The heterozygote (GC) of rs1135840 in CYP2D6 gene might increase the risk while the homozygote (CC) of rs1135840, G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 might be protective factors.

Lack of Association Between LIG4 Gene Polymorphisms and the Risk of Breast Cancer: A HuGE Review and Meta-analysis

Zhou, Li-Ping,Luan, Hong,Dong, Xi-Hua,Jin, Guo-Jiang,Man, Dong-Liang,Shang, Hong Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.7

Objective: Non-homologous end joining (NHEJ) is one of the pathways of repair of DNA double-strand breaks. A number of genes involved in NHEJ have been implicated as breast cancer susceptibility genes such as LIG4. However, some studies have generated conflicting results. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to investigate association between LIG4 gene polymorphisms in the NHEJ pathway and breast cancer risk. Methods: Studies focusing on the relationship between LIG4 gene polymorphisms and susceptibility to breast cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers and the meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software, calculating odds ratios (ORs) with 95% confidence intervals (95%CIs). Results: According to the inclusion criteria, we final included seven studies with a total of 10,321 breast cancer cases and 10,160 healthy controls in the meta-analysis. The results showed no association between LIG4 gene polymorphisms (rs1805386 T>C, rs1805389 C>T, rs1805388 C>T and rs2232641 A>G) and breast cancer risk, suggesting that the mutant situation of these SNPs neither increased nor decreased the risk for breast cancer. In the subgroup analysis by Hardy-Weinberg equilibrium (HWE) and ethnicity, we also found no associations between the variants of LIG4 gene and breast cancer risk among HWE, non-HWE, Caucasians, Asians and Africans. Conclusion: This meta-analysis suggests that there is a lack of any association between LIG4 gene polymorphisms and the risk of breast cancer.

Association of Functional Polymorphisms of the XRCC4 Gene with the Risk of Breast Cancer: A Meta-analysis

Zhou, Li-Ping,Luan, Hong,Dong, Xi-Hua,Jin, Guo-Jiang,Ma, Dong-Liang,Shang, Hong Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.7

Objective: X-ray cross-complementing group 4 (XRCC4) is a major repair gene for DNA double-strand breaks (DSB) in the non-homologous end-joining (NHEJ) pathway. Several potentially functional polymorphisms of the XRCC4 gene have been implicated in breast cancer risk, but individually published studies showed inconclusive results. The aim of this meta-analysis was to investigate the association between XRCC4 polymorphisms and the risk of breast cancer. Methods: The MEDLINE, EMBASE, Web of science and CBM databases were searched for all relevant articles published up to June 20, 2012. Potential associations were assessed with comparisons of the total mutation rate (TMR), complete mutation rate (CMR) and partial mutation rate (PMR) in cases and controls. Statistical analyses were performed using RevMan 5.1.6 and STATA 12.0 software. Results: Five studies were included with a total of 5,165 breast cancer cases and 4,839 healthy controls. Meta-analysis results showed that mutations of rs2075686 (C>T) and rs6869366 (G>T) in the XRCC4 gene were associated with increased risk of breast cancer, while rs2075685 (G>T) and rs10057194 (A>G) might decrease the risk of breast cancer. However, rs1805377 (A>G), rs1056503 (G>T), rs28360317 (ins>del) and rs3734091 (A>G) polymorphisms of XRCC4 gene did not appear to have an influence on breast cancer susceptibility. Conclusion: Results from the current meta-analysis suggest that the rs2075685 (G>T) and rs6869366 (G>T) polymorphisms of the XRCC4 gene might increase the risk of breast cancer, whereas rs2075685 (G>T) and rs10057194 (A>G) might be protective factors.

Knockdown of GCF2/LRRFIP1 by RNAi Causes Cell Growth Inhibition and Increased Apoptosis in Human Hepatoma HepG2 Cells

Li, Jing-Ping,Cao, Nai-Xia,Jiang, Ri-Ting,He, Shao-Jian,Huang, Tian-Ming,Wu, Bo,Chen, De-Feng,Ma, Ping,Chen, Li,Zhou, Su-Fang,Xie, Xiao-Xun,Luo, Guo-Rong Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.6

Background: GC-binding factor 2 (GCF2) is a transcriptional regulator that represses transcriptional activity of the epidermal growth factor receptor (EGFR) by binding to a specific GC-rich sequence in the EGFR gene promoter. In addition to this function, GCF2 has also been identified as a tumor-associated antigen and regarded as a potentially valuable serum biomarker for early human hepatocellular carcinoma (HCC) diagnosis. GCF2 is high expressed in most HCC tissues and cell lines including HepG2. This study focused on the influence of GCF2 on cell proliferation and apoptosis in HepG2 cells. Materials and Methods: GCF2 expression at both mRNA and protein levels in HepG2 cells was detected with reverse transcription (RT) PCR and Western blotting, respectively. RNA interference (RNAi) technology was used to knock down GCF2 mRNA and protein expression. Afterwards, cell viability was analyzed with a Cell Counting Kit-8 (CCK-8), and cell apoptosis and caspase 3 activity by flow cytometry and with a Caspase 3 Activity Kit, respectively. Results: Specific down-regulation of GCF2 expression caused cell growth inhibition, and increased apoptosis and caspase 3 activity in HepG2 cells. Conclusions: These primary results suggest that GCF2 may influence cell proliferation and apoptosis in HepG2 cells, and also provides a molecular basis for further investigation into the possible mechanism at proliferation and apoptosis in HCC.

Preparation and In Vitro Release of Ramose Chitosan-Based-5-Fluorouracil Microspheres

Li, He-Ping,Li, Hui,Wang, Zhou-Dong,Zhang, Juan-Juan,Deng, Man-Feng,Chen, San-Long Korean Chemical Society 2013 대한화학회지 Vol.57 No.1

In order to construct a controlled release system of drugs and to reduce toxic side effects of 5-fluorouracil, the novel ramose chitosan-based-5-fluorouracil microspheres (CS-FU-MS) were prepared. Firstly, using chitosan (CS) as carriers and 5-fluorouracil (5-FU) as a model drug, ramose chitosan-based-5-fluorouracil (CS-FU) was efciently synthesized by chemical crosslinking method through microwave irradiation, drug loading was 10.6%; Secondly, CS-FU-MS were prepared by CS-FU self-assembled under the dialysis conditions and the free 5-FU was encapsulated further at the same time. The size dispersivity of particles is uniform, and the average diameter of the CS-FU-MS was $4{\mu}m$. The drug encapsulation efficiency was 76.1%, and the drug loading was increased to 26.22%. CS-FU-MS maintain the zero-order release time in PBS (pH = 7.4) and HCl/KCl (pH = 1.2) dialysis medium was 40h and 34h respectively, and the cumulative release were 58.89% and 79.33% in 182 h. The results showed that CS-FU-MS have excellent sustained release properties.

Cinobufacin Suppresses Cell Proliferation via miR-494 in BGC-823 Gastric Cancer Cells

Zhou, Rong-Ping,Chen, Gang,Shen, Zhi-Li,Pan, Li-Qun Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.3

Cinobufacin is used clinically to treat patients with many solid malignant tumors. However, the mechanisms underlying action remain to be detailed. Our study focused on miRNAs involved in cinobufacin inhibition of GC cell proliferation. miRNA microarray analysis and real time PCR identified miR-494 as a significant cinobufacin-associated miRNA. In vivo, ectopic expression of miR-494 inhibited the proliferation and induced apoptosis of BGC-823 cells on CCK-8 and flow cytometry analysis. Further study verified BAG-1 (anti-apoptosis gene) to bea target of miR-494 by luciferase reporter assay and Western blotting. In summary, our study demonstrated that cinobufacin may inhibit the proliferation and promote the apoptosis of BGC-823 cells. Cinobufacin-associated miR-494 may indirectly be involved in cell proliferation and apoptosis by targeting BAG-1, pointing to use as a potential molecular target of cinobufacin in gastric cancer therapy.

Synthesis and Characterization of Lactobionic Acid Grafted Phenylalanyl-Glycyl-Chitosan

Li, He-Ping,Li, Shan,Wang, Zhou-Dong,Qin, Long Korean Chemical Society 2011 대한화학회지 Vol.55 No.6

In order to enhance the target action of chitosan-based drug, this paper firstly prepared phenylalanyl-glycylchitosan (Phe-Gly-CS) by grafting the key intermediate, bromoacetyl-phenylalanine (BA-Phe) onto chitosan. Then the target sugar molecule, lactobionic acid (LA), was grafted to Phe-Gly-CS and the topic compound lactobionic acid grafted phenylalanyl-glycyl-chitosan (Phe-Gly-CS-LA) was finally obtained in a yield of 78.8%. The product were characterized by FTIR, MS and 1H NMR. The preparing condition of BA-Phe was optimized as follows: the best pH was 10-11, the optimum temperature was $-4^{\circ}C$, the reaction time was 1.5 h.