In silico feedback for in vivo regulation of a gene expression circuit

The main functions of lamins are their mechanical and structural roles as major building blocks of the karyoskeleton. They are also involved in chromatin structure regulation, gene expression, intracellular signalling pathway modulation and development. All essential lamin functions seem to depend on their capacity for assembly or disassembly after the receipt of specific signals, and after specific, selective and precisely regulated interactions through their various domains. Reversible phosphorylation of lamins is crucial for their functions, so it is important to understand how lamin polymerization and interactions are modulated, and which sequences may undergo such modifications. This review combines experimental data with results of our in silico analyses focused on lamin phosphorylation in model organisms to show the presence of evolutionarily conserved sequences and to indicate specific in vivo phosphorylations that affect particular functions.

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Computational Drug Repositioning and Experimental Validation of Ivermectin in Treatment of Gastric Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.625991 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanne-Line Rabben ◽

Gøran Troseth Andersen ◽

Aleksandr Ianevski ◽

Magnus Kringstad Olsen ◽

Denis Kainov ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Cell Proliferation ◽

Mouse Model ◽

Signaling Pathways ◽

In Silico ◽

Drug Repositioning ◽

Human And Mouse

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches.Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice).Results: GC gene expression “signature” and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/β-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/β-catenin signaling pathway in “dose-depended” manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/β-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways.Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.

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Computational drug repositioning of bortezomib to reverse metastatic effect ofGALNT14in lung cancer

10.1101/394163 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ok-Seon Kwon ◽

Haeseung Lee ◽

Hyeon-Joon Kong ◽

Ji Eun Park ◽

Wooin Lee ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

In Silico ◽

Large Scale ◽

Cancer Metastasis ◽

Drug Repositioning ◽

Expression Patterns ◽

Lung Cancer Metastasis

AbstractAlthough many molecular targets for cancer therapy have been discovered, they often show poor druggability, which is a major obstacle to develop targeted drugs. As an alternative route to drug discovery, we adopted anin silicodrug repositioning (in silicoDR) approach based on large-scale gene expression signatures, with the goal of identifying inhibitors of lung cancer metastasis. Our analysis of clinicogenomic data identified GALNT14, an enzyme involved in O-linked N-acetyl galactosamine glycosylation, as a putative driver of lung cancer metastasis leading to poor survival. To overcome the poor druggability of GALNT14, we leveraged Connectivity Map approach, anin silicoscreening for drugs that are likely to revert the metastatic expression patterns. It leads to identification of bortezomib (BTZ) as a potent metastatic inhibitor, bypassing direct inhibition of poorly druggable target, GALNT14. The anti-metastatic effect of BTZ was verifiedin vitroandin vivo. Notably, both BTZ treatment andGALNT14knockdown attenuated TGFβ-mediated gene expression and suppressed TGFβ-dependent metastatic genes, suggesting that BTZ acts by modulating TGFβ signalingTaken together, these results demonstrate that ourin silicoDR approach is a viable strategy to identify a candidate drug for undruggable targets, and to uncover its underlying mechanisms.

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First insights into the molecular basis association between promoter polymorphisms of the IL1B gene and Helicobacter pylori infection in the Sudanese population: computational approach

10.21203/rs.3.rs-60531/v3 ◽

2020 ◽

Author(s):

Abeer Babiker Idris ◽

Einas Babiker Idris ◽

Amany Eltayib Ataelmanan ◽

Ali Elbagir Ali Mohamed ◽

Bashir M. Osman Arbab ◽

...

Keyword(s):

Gene Expression ◽

In Silico ◽

Expression Patterns ◽

Regulatory Region ◽

Regulatory Elements ◽

Computer Algorithms ◽

Promoter Polymorphisms ◽

H Pylori

Abstract Background: Helicobacter pylori (H. pylori) infects nearly half of the world’s population with a variation in incidence among different geographic regions. Genetic variants in the promoter regions of the IL1B gene can affect cytokine expression and creates a condition of hypoacidity which favors the survival and colonization of H. pylori. Therefore, the aim of this study was to characterize the polymorphic sites in the 5’- region [-687_+297] of IL1B in H. pylori infection using in silico tools.Results: A total of five nucleotide variations were detected in the 5’-regulatory region [-687_+297] of IL1B which led to the addition or alteration of transcription factor binding sites (TFBSs) or composite regulatory elements (CEs). Genotyping of IL1B-31 C>T revealed a significant association between -31T and susceptibility to H. pylori infection in the studied population (P=0.0363). Comparative analysis showed conservation rates of IL1B upstream [−368_+10] region above 70% in chimpanzee, rhesus monkey, a domesticated dog, cow and rat.Conclusions: In H. pylori-infected patients, three detected SNPs (-338, -155 and -31) located in the IL1B promoter were predicted to alter TFBSs and CE, which might affect the gene expression. These in silico predictions provide insight for further experimental in vitro and in vivo studies of the regulation of IL1B expression and its relationship to H. pylori infection. However, the recognition of regulatory motifs by computer algorithms is fundamental for understanding gene expression patterns.

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Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature in castration-resistant prostate cancer by in silico screening

Prostate Cancer and Prostatic Diseases ◽

10.1038/s41391-021-00426-0 ◽

2021 ◽

Author(s):

Hiroshi Hongo ◽

Takeo Kosaka ◽

Yoko Suzuki ◽

Mototsugu Oya

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

In Silico ◽

Antitumor Effect ◽

Resistant Cell ◽

Potential Candidate ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Candidate Drug

Abstract Background The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC. Methods We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models. Results We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression. Conclusions Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.

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Probiogenomics of Lactobacillus delbrueckii subsp. lactis CIDCA 133: In Silico, In Vitro, and In Vivo Approaches

Microorganisms ◽

10.3390/microorganisms9040829 ◽

2021 ◽

Vol 9 (4) ◽

pp. 829

Author(s):

Luís Cláudio Lima de Jesus ◽

Mariana Martins Drumond ◽

Flávia Figueira Aburjaile ◽

Thiago de Jesus Sousa ◽

Nina Dias Coelho-Rocha ◽

...

Keyword(s):

Gene Expression ◽

In Silico ◽

Genomic Analysis ◽

Probiotic Strain ◽

Lactobacillus Delbrueckii ◽

Cytoplasmic Proteins ◽

Genomic Approach ◽

Lactobacillus Delbrueckii Subsp

Lactobacillus delbrueckii subsp. lactis CIDCA 133 (CIDCA 133) has been reported as a potential probiotic strain, presenting immunomodulatory properties. This study investigated the possible genes and molecular mechanism involved with a probiotic profile of CIDCA 133 through a genomic approach associated with in vitro and in vivo analysis. Genomic analysis corroborates the species identification carried out by the classical microbiological method. Phenotypic assays demonstrated that the CIDCA 133 strain could survive acidic, osmotic, and thermic stresses. In addition, this strain shows antibacterial activity against Salmonella Typhimurium and presents immunostimulatory properties capable of upregulating anti-inflammatory cytokines Il10 and Tgfb1 gene expression through inhibition of Nfkb1 gene expression. These reported effects can be associated with secreted, membrane/exposed to the surface and cytoplasmic proteins, and bacteriocins-encoding genes predicted in silico. Furthermore, our results showed the genes and the possible mechanisms used by CIDCA 133 to produce their beneficial host effects and highlight its use as a probiotic microorganism.

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