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Assessment of bearing capacity of interfering strip footings located near sloping surface considering artificial neural network technique

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Journal of Mountain Science 2018年第12期15卷 2766-2780页

作者： Rana ACHARYYA Arindam DEY Department of Civil Engineering Indian Institute of Technology Guwahati

The bearing capacity of interfering footings located near the slope face suffers from reduced bearing capacity due to the formation of the curtailed passive zone. Depending upon the position of the footing, their spacing and steepness of the slope different extents of bearing capacity reduction can be exhibited. A series of finite element investigation has been done with the aid of Plaxis 3 D v AE.01 to elucidate the influence of various geotechnical and geometrical parameters on the ultimate bearing capacity of interfering surface strip footings located at the crest of the natural soil slope. Based on the large database obtained from the numerical simulation, a6-8-1 Artificial Neural Network architecture has been considered for the assessment of the ultimate bearing capacity of interfering strip footings placed on the crest of natural soil slope. Sensitivity analyses have been conducted to establish the relative significance of the contributory parameters, which exhibited that for the stated problem, apart from shear strength parameters, the setback ratio and spacing of footing are the prime contributory parameters.

关键词： interfering strip footing Natural slope Finite element simulation Artificial Neural Network Sensitivity analysis Prediction model

Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma

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World Journal of Gastroenterology 2015年第42期21卷 12022-12041页

作者： Jaleh Varshosaz Maryam Farzan Department of Pharma-ceutics Faculty of Pharmacy and Novel Drug Delivery Systems Research Centre Isfahan University of Medical Sciences

Hepatocellular carcinoma(HCC) is the 5th most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorablesystemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs(si RNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and si RNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited sideeffects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is overexpressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and nonviral si RNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic si RNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein, ganglioside GM1 cell surface ligand, epidermal growth

关键词： Small interfering RNA Targeted delivery Nanopartic

Small interfering RNA-mediated inhibition of hepatitis G virus gene expression in human hepatoma cell Huh-7

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Science China(Life Sciences) 2005年第1期48卷 61-69页

作者： CAO Mingmei REN Hao ZHAO Ping PAN Wei ZHAO Lanjuan QI Zhongtian Department of Microbiology Second Military Medical University Shanghai200433 China Department of Microbiology Second Military Medical University Shanghai200433 China Department of Microbiology Second Military Medical University Shanghai200433 China Department of Microbiology Second Military Medical University Shanghai200433 China Department of Microbiology Second Military Medical University Shanghai200433 China Department of Microbiology Second Military Medical University Shanghai200433 China

The RNA interference (RNAi) phenomenon is a recently observed process in which the introduction of a double-stranded, small interfering RNA (siRNA) into a cell causes the specific degradation of a homologous single-stranded RNA. It represents an exciting new technology that could have therapeutic applications for the treatment of viral infections. Since hepatitis G virus (HGV) genome is a positive-sense single-stranded RNA, the replication of HGV does not lead to an integrated DNA genome, suggesting a particularly attractive target for RNAi study that could eliminate viral RNA from infected cells. The eukaryotic expression vector pVAX.EH containing the cDNA sequences of the entire HGV structural genes and hygromycin resistance gene downstream from the encephalomyocarditis virus (ECMV) internal ribosome entry site (IRES)was constructed and transfected into human hepatoma cell Huh-7. The modified cleavage products of the structural proteins of HGV expressed in hygromycin-resistant cell line Huh-7-EH were confirmed by RT-PCR and Western blot methods. Two specific HGV E2 siRNAs (1-E2siRNA, 2-E2 siRNA) synthesized with T7 RNA polymerase by transcription in vitro were transfected into the Huh-7-EH cells. With the analyses of Western blot and the formation of hygromycin-resistant colonies, the inhibitions of expression of HGV structural protein by two HGV E2siRNAs were detected and found lasting at least one week. The inhibition of 2-E2 siRNA was stronger and only 1% of the cells treated with 2-E2 siRNA formed hygromycin-resistant colonies.These results support that specific HGV 2-E2 siRNAs mediate the degradation of mRNA spanning from HGV structural gene cDNA to hygromycin resistance gene in a majority of cells. In conclusion, the Huh-7-EH cells expressing HGV structural proteins stably can be used as a cell model for studying the replication of HGV and RNAi and the enlargement of RNAi may exist, in mammalian cells.

关键词： RNA interference, small interfering RNA, hepatitis G virus, structural gene, cell model.

Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA

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Chinese Medical Journal 2020年第6期133卷 679-686页

作者： Yan-Ying Liu Shi-Yao Wang Ying-Ni Li Wen-Jie Bian Lin-Qi Zhang Yu-Hui Li Li Long Xia Liu Xue-Wu Zhang Zhan-Guo Li Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis(BZ0135) Peking University People's HospitalBeijing 100044China Center of Clinical Immunology Peking UniversityBeijing 100044China

Background:Fibroblast-like synoviocytes(FLSs),resident mesenchymal cells of synovial joints,play an important role in the pathogenesis of rheumatoid arthritis(RA).Dickkopf-1(DKK-1)has been proposed to be a master regulator of bone remodeling in inflammatory arthritis.Here,potential impairation on the activity of FLSs derived from RA to small interfering RNAs(siRNAs)targeting DKK-1 was investigated.Methods:siRNAs targeting DKK-1 were transfected into FLSs of patients with RA.Interleukin(IL)-1β,IL-6,IL-8,matrix metalloproteinase(MMP)2,MMP3,MMP9,transforming growth factor(TGF)-pi,TGF-β2 and monocyte chemoattractant protein(MCP)-1 levels in the cell culture supernatant were detected by enzyme-linked immunosorbent assay(ELISA).Invasion assay and 3H incorporation assay were utilized to investigate the effects of siRNAs targeting DKK-1 on FLSs invasion and cell proliferation,respectively.Western blotting was performed to analyze the expression of nuclear factor(NF)-kB,interleukin-1 receptor-associared kinase(IRAK)1,extracellular regulated protein kinases(ERK)1,Jun N-terminal kinase(JNK)and p-catenin in FLSs.Results:DKK-1 targeting siRNAs inhibited the expression of DKK-1 in FLSs(P<0.01).siRNAs induced a significant reduction of the levels of IL-6,IL-8,MMP2,MMP3 and MMP9 in FLSs compared to the control group(P<0.05).DKK-1 targeting siRNAs inhibited the proliferation and invasion of FLSs(P<0.05).Important molecules of pro-inflammatory signaling in FLSs,including IRAKI and ERK1,were decreased by the inhibition of DKK-1 in FLSs.In contrast,β-catenin,a pivotal downstream molecule of the Wnt signaling pathway was increased.Conclusions:By inhibiting DKK-1,we were able to inhibit the proliferation,invasion and pro-inflammatory cytokine secretion of FLSs derived from RA,which was mediated by the ERK or the IRAK-1 signaling pathway.These data indicate the application of DKK-1 silencing could be a potential therapeutic approach to RA.

关键词： Dickkopf-1 Fibroblast-like synoviocytes Rheumatoid arthritis small interfering RNAs

Blocking effects of siRNA on VEGF expression in human colorectal cancer cells

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World Journal of Gastroenterology 2010年第9期16卷 1086-1092页

作者： Yu Yin,Li-Yu Cao,Wen-Qing Wu,Hao Li,Yan Jiang,Hong-Fu Zhang,Department of Pathology,Anhui Medical University,Hefei 230032,Anhui Province,China Wen-Qing Wu,Department of Pathology,Anhui Provincial Hospital,Hefei 230001,Anhui Province,China Department of Pathology Anhui Medical University Hefei 230032 Anhui Province China.

AIM:To investigate the expression of vascular endothelial cell growth factor (VEGF) and its receptors Fmslike tyrosine kinase 1 (FLT-1) and fetal liver kinase 1 (FLK-1) in colorectal carcinoma (CRC),and the blocking effects of small interfering RNAs (siRNAs) on VEGF expression in human colorectal cancer HCT116 cells.METHODS:Immunohistochemical staining for VEGF,FLT-1 and FLK-1 proteins was performed in 82 cases of CRC and 14 normal colorectal mucosae.A siRNA targeting VEGF was synthesized and transfected into HCT116 cells using lipofectamine 2000.Immunocytochemical staining and Western blotting analyses were performed to detect the expression of VEGF protein.The suppressive effect of the siRNA on cell proliferation was detected using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltertrazolium bromide (MTT) assay.Cellular apoptosis was detected using flow cytometry (FCM).RESULTS:The expression of VEGF,FLT-1 and FLK-1 in tumor tissues was significantly higher than that in normal tissues (P=0.008,P=0.000,P=0.000).The expression of VEGF was positively correlated with both lymph node metastasis and clinical stage (P=0.009 and P=0.025,respectively).Immunocytochemistry showed that the expression of VEGF was weakly positive and Western blotting indicated a significant reduction in VEGF-siRNA cell protein levels.VEGF-siRNA cell growth inhibition was assessed by the MTT assay,and the tumor cell proliferation rate was significantly different at 24,48,and 72 h after transfection.FCM results showed that the VEGF-siRNA group had an apparent aneuploid peak.CONCLUSION:VEGF,FLT-1 and FLK-1 are associated with colorectal carcinogenesis.siRNA silencing of the VEGF gene suppresses proliferation,and induces apoptosis in HCT116 cells.The results suggest that VEGF may be a new gene therapy target for colorectal cancer.

关键词： Colorectal carcinoma Vascular endothelial cell growth factor Fms-like tyrosine kinase 1 Fetal liver kinase 1 Small interfering RNA

Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2013年第6期14卷 451-459页

作者： Ning SONG Yan WANG Xiao-dong GU Zong-you CHEN Liu-bin SHI Department of General Surgery Huashan HospitalFudan University

Eukaryotic initiation factor subunit c(eIF3c) has been identified as an oncogene that is over-expressed in tumor cells and,therefore,is a potential therapeutic target for gene-based cancer treatment.This study was focused on investigating the effect of small interfering RNA(siRNA)-mediated eIF3c gene knockdown on colon cancer cell survival.The eIF3c gene was observed to be highly expressed in colon cancer cell models.The expression levels of the gene in eIF3c siRNA infected and control siRNA infected cells were compared via real-time polymerase chain reaction(PCR) and western blotting analysis.Cell proliferation levels were analyzed employing 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide(MTT) and colony formation assays.Furthermore,the effects of eIF3c gene knockdown on the cell cycle and apoptosis were analyzed using flow cytometry.The results showed that suppression of eIF3c expression significantly(P<0.001) reduced cell proliferation and colony formation of RKO colon cancer cells.The cell cycle was arrested by decreasing the number of cells entering S phase.Further,apoptosis was induced as a result of eIF3c knockdown.Collectively,eIF3c deletion effectively reduced the survival of colon cancer cells and could be used as a therapeutic tool for colon cancer therapy.

关键词： Eukaryotic initiation factor subunit c(eIF3c) Colon cancer RKO cells Small interfering RNA(siRNA)

VEGF-specific siRNAs modified with 2′-deoxy effectively suppress VEGF expression and inhibit growth of nasopharyngeal carcinoma xenograft in a mouse model

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Science China(Life Sciences) 2008年第2期51卷 104-110页

作者： CHEN ShanYi1, GAO GuoFeng1, CHEN Wei1, Lü Qing2, TANG Shen2, HUA Zhong2, YE WenBin2, GU DaYong2, WANG ShaYan1 & ZHANG YaOu2 1 Shenzhen People’s Hospital, Clinical Medical College of Jinan University, Shenzhen 518020, China 2 Life Science Division, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China Shenzhen People’s Hospital Clinical Medical College of Jinan University Shenzhen China Life Science Division Graduate School at Shenzhen Tsinghua University Shenzhen China

Vascular endothelial growth factor (VEGF) is up-regulated in the vast majority of human tumors. The up-regulation of VEGF not only plays important roles in tumor angiogenesis, but also provides a target for tumor treatment with small interfering RNA (siRNA) that targets VEGF; however, it is unclear whether a quite high up-regulation of VEGF will affect the efficiency of RNA interference strategies targeting VEGF. A high level expression of VEGF was found in CNE cells from a nasopharyngeal carcinoma cell line. In this study, we investigate whether VEGF-specific siRNAs can effectively suppress VEGF expression in CNE cells, and study the methods for the use of VEGF-specific siRNAs as potential therapeutic agents. CNE cells with high VEGF expression induced by hypoxia were transfected with VEGF-specific siRNAs. The expression of VEGF was effectively suppressed by VEGF-specific siRNAs, measured by ELISA, Western blot analysis and RT-PCR. Furthermore, experiments in nude mice bearing nasopharyngeal carcinoma xenograft were initiated 5 d after injection of CNE cells. VEGF-specific siRNAs were modified with 2′-deoxy, then injected into the tumors, and a liposome-mediated siRNA transfection system and ultrasound exposure were used to help delivery of the siRNAs. Tumor growth was reduced significantly after 3 weeks' treatment. These studies suggest that VEGF-specific siRNAs still can effectively suppress VEGF expression even in tumor cell lines with a relatively high level of VEGF expression, such as CNE, and VEGF-specific siRNAs modified with 2′-deoxy can be used as potential agents for tumor therapy.

关键词： small interfering RNA vascular endothelial growth factor (VEGF) nasopharyngeal carcinoma 2′-deoxy modification ultrasound

Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery

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Asian Journal of Pharmaceutical Sciences 2018年第2期13卷 163-172页

作者： Wanling Liang Alan Y.L.Chan Michael Y.T.Chow Fiona F.K.Lo Yingshan Qiu Philip C.L.Kwok Jenny K.W.Lam Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong Advanced Drug Delivery Group Faculty of Pharmacy The University of Sydney

The therapeutic potential of small nucleic acids such as small interfering RNA(siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation.In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids.Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope(SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5 μm, and the aerosol performance study using next generation impactor(NGI) showed an emitted fraction(EF) and fine particle fraction(FPF) of 91% and 28% respectively. This formulation(5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4%and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

关键词： Inhalation Pulmonary delivery Small interfering RNA Spray freeze drying

Targeting long non-coding RNA MALAT1 alleviates retinal neurodegeneration in diabetic mice

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International Journal of Ophthalmology(English edition) 2020年第2期13卷 213-219页

作者： Yu-Lan Zhang Han-Ying Hu Zhi-Peng You Bing-Yang Li Ke Shi Department of Ophthalmology the Second Affiliated HospitalNanchang UniversityNanchang 330006Jiangxi ProvinceChina

●AIM:To observe the effect of inhibiting long non-coding RNA(lncRNA)metastasis-associated lung adenocarcinoma transcript 1(MALAT1)on diabetic neurodegeneration.●METHODS:Thirty-six 8-week-old C57 BL/6 mice were randomly divided into normal control,diabetic control,diabetic scrambled small interfering RNAs(siRNAs)and diabetic MALAT1-siRNA groups.After diabetic induction with streptozocin intraperitoneally-injection,the diabetic M A L AT 1-s i R N A g ro u p w a s i n t r av i t r e a l l y i n j e c te d with 1μL 20μmol/L MALAT1 siRNA,and the diabetic scrambled siRNA group was injected with the same amount of scrambled siRNA.Electroretinography was performed to examine photoreceptor functions 16 wk after diabetes induction.MALAT1 expression was detected via real time polymerase chain reaction.Cone morphological changes were examined using immunofluorescence.Rod morphological changes were examined by determining outer nuclear layer(ONL)thickness.●RESULTS:The upregulation of retinal MALAT1 expression was detected in the diabetic control mice,while MALAT1 expression in the diabetic MALAT1-siRNA mice was decreased by 91.48%compared to diabetic control mice.The diabetic MALAT1-siRNA and diabetic control mice showed lower a-wave and b-wave amplitudes than did the normal control mice in scotopic and photopic electroretinogram,while the diabetic MALAT1-siRNA mice showed higher amplitudes than diabetic control mice.Morphological examination revealed that ONL thickness in the diabetic MALAT1-siRNA and diabetic control mice was lower than normal control mice.However,ONL thickness was greater in the diabetic MALAT1-siRNA mice than diabetic control mice.Moreover,the diabetic control mice performed a sparser cone cell arrangement and shorter outer segment morphology than diabetic MALAT1-siRNA mice.●CONCLUSION:Inhibiting retinal MALAT1 results in mitigative effects on the retinal photoreceptors,thus alleviating diabetic neurodegeneration.

关键词： long non-coding RNA MALAT1 small interfering RNA diabetic retinopathy neurodegeneration