Drug repurposing for the treatment of HIV-Associated Neurocognitive Disorder by AI-based literature mining
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PROVIDER: PRJNA1121304 | ENA |
REPOSITORIES: ENA
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Project description:HIV-1 Associated Neurocognitive Disorder (HAND) is a common and clinically detrimental complication of HIV infection. Viral proteins including Tat, released from infected cells, cause neuronal toxicity. Substance abuse in HIV-infected patients greatly exacerbates the severity of neuronal damage. To repurpose small molecule inhibitors for anti-HAND therapy, we employed MOLIERE, an AI-based literature mining system that we developed. All human genes were analyzed and prioritized by MOLIERE to find previously unknown targets connected to HAND. The list was narrowed to those with known small molecule inhibitors developed for other applications and lacking systemic toxicity in animal models. We tested the activity of small molecules targeted against the proteins of five prioritized genes to protect against the combined neurotoxicity of HIV-Tat and cocaine in primary neuronal cultures. Four prevented Tat and cocaine toxicity. The compounds are: the FDA approved drugs Amlexanox and Tazemetostat (EPZ-6438), Itaconate and Senicapoc. Despite the disparate molecular targets of these drugs, analysis revealed a common mechanism of neuroprotection; namely that modulation of astrocyte and microglia status prevents the toxicity of Tat and cocaine.
2024-10-30 | GSE269380 | GEO
Project description:VS94 gene expression at different time-points in SAPI medium in absence and presence of AI-2 was studied. Autoinducer-2 (AI-2) is produced by many species of bacteria, including various commensal bacteria and is involved in inter-species communication. Since, pathogens encounter AI-2 once they enter the human gastro-intestinal tract; we studied the effects of presence of AI-2 on various phenotypes associated with infection and colonization of enterohemorrhagic Escherichia coli (EHEC) namely, chemotaxis, motility and attachment to HeLa cells. AI-2 attracted EHEC when observed in agarose plug assays and also increased EHEC motility by 1.44-fold. AI-2 also increased EHEC attachment to HeLa cells by 1.6-fold; hence, suggesting that exposure to AI-2 inside the gastro-intestinal tract can play an important role in EHEC colonization. We then investigated the global effects of AI-2 on EHEC gene expression using DNA microarrays at various time-points. We found that AI-2 controls virulence gene expression and several other groups of genes (flagellar genes, iron related genes, biofilm genes etc.) associated with virulence in a time-dependent manner. Hence, through these studies we have shown that AI-2 may be a key component in EHEC infection of human gastro-intestinal tract. Keywords: Time course
2008-03-21 | GSE9388 | GEO
Project description:Large-scale transcriptome and methylome data analyses obtained by high-throughput technologies have been enabling the identification of novel imprinted genes. We investigated genome-wide DNA methylation patterns in multiple human tissues, using a high-resolution microarray to uncover hemimethylated CpGs located in promoters overlapping CpG islands, aiming to identify novel candidate imprinted genes. Using our approach, we recovered ~30% of the known human imprinted genes, further 168 candidates were identified, 61 of which with at least three hemimethylated CpGs shared by more than two tissue types. Thirty-four of these candidate genes are members of the protocadherins cluster on 5q31.3; in mice, protocadherin genes have non-imprinted monoallelic randomic expression, which might be the case in humans. Among the remaining 27 genes, ZNF331 was recently validated as an imprinted gene, and six of them have been reported as candidates, supporting our prediction. Five candidates (CCDC166, ARC, PLEC, TONSL and VPS28) map to 8q24.3, and might constitute a novel imprinted cluster. Additionally, we performed a comprehensive compilation of known human and mice imprinted genes from literature and databases, and a comparison among high-throughput imprinting studies in humans. The screening for hemimethylated CpGs shared by multiple human tissues, together with the extensive review, appears as a useful approach to reveal candidate imprinted genes.
2017-09-26 | GSE103413 | GEO
Project description:Implantation is crucial for placental development which directly impacts fetal growth and pregnancy success with possible consequences on post-natal health. We postulated that early perturbations of the conceptus-maternal environment communication may alter the endometrium physiology that could account for the final reproductive outcome. Using cattle as an animal model, we compared gene expression profiles of the endometrial caruncular and intercaruncular areas during the critical period of implantation in three types of pregnancies: artificial insemination (AI), in vitro fertilization with embryo transfer (IVF-ET) or somatic cell nuclear transfer (SCNT). Less than 35% of the differentially expressed genes were found to be common between AI, IVF-ET, and SCNT conditions. Compared to AI, numerous biological functions and several canonical pathways and genes were found to be significantly affected in IVF-ET or SCNT, with a major impact on metabolism and immune function in SCNT. Our data show that the endometrium can fine-tune its physiology and could be considered as a biological sensor in response to pregnancy manipulations. Determining the limits of the endometrial plasticity should bring new insights on the contribution of the maternal compartment to the pregnancy outlet. Keywords: Fluorescence Microarray - Dye switch loop design
2009-11-01 | GSE14050 | GEO
Project description:Fiber diet plays a beneficial role in neurocognitive disorders, like dementia and Alzheimer’s Disease. However, insufficient fiber consumption in public increases the concern about public health, particularly about neurocognitive diseases. To survey the association between fiber dietary and neurocognitive performances, mice were subjected to normal-fiber diet or low-fiber diet during gestation, and the neurocognitive functions of the offspring were assessed. We found that maternal low-fiber diet impaired the cognitive functions, and the impairments can be reversed by butyrate, rather than propionate intake. Mechanism studies showed that HDAC4 might become the most potential mediator in butyrate-dependent neurocognitive improvement. Besides, using human maternal serum and paired umbilical cord blood samples, we demonstrated that the SCFA levels in offspring are positively correlated with levels in maternal serum. Those results provide a solid basis for not only maternal fiber diet regulates neurocognitive functions in offspring through altering SCFA levels, but clinical practice in SCFAs-dependent maternal intervention for offspring health.
2020-08-25 | GSE147022 | GEO
Project description:Implantation is crucial for placental development which directly impacts fetal growth and pregnancy success with possible consequences on post-natal health. We postulated that early perturbations of the conceptus-maternal environment communication may alter the endometrium physiology that could account for the final reproductive outcome. Using cattle as an animal model, we compared gene expression profiles of the endometrial caruncular and intercaruncular areas during the critical period of implantation in three types of pregnancies: artificial insemination (AI), in vitro fertilization with embryo transfer (IVF-ET) or somatic cell nuclear transfer (SCNT). Less than 35% of the differentially expressed genes were found to be common between AI, IVF-ET, and SCNT conditions. Compared to AI, numerous biological functions and several canonical pathways and genes were found to be significantly affected in IVF-ET or SCNT, with a major impact on metabolism and immune function in SCNT. Our data show that the endometrium can fine-tune its physiology and could be considered as a biological sensor in response to pregnancy manipulations. Determining the limits of the endometrial plasticity should bring new insights on the contribution of the maternal compartment to the pregnancy outlet. Keywords: Fluorescence Microarray - Dye switch loop design 44 samples
2009-10-31 | E-GEOD-14050 | biostudies-arrayexpress
Project description:Autoinducer 2 (AI-2), a widespread by-product of the LuxS-catalyzed S-ribosylhomocysteine cleavage reaction in the activated methyl cycle, has been suggested to serve as an intra- and interspecies signaling molecule, but in many bacteria AI-2 control of gene expression is not completely understood. Particularly, we have a lack of knowledge about AI-2 signaling in the important human pathogens Staphylococcus aureus and S. epidermidis. Here, to determine the role of LuxS and AI-2 in S. epidermidis, we analyzed genome-wide changes in gene expression in an S. epidermidis luxS mutant and after addition of AI-2 synthesized by over-expressed S. epidermidis Pfs and LuxS enzymes. Genes under AI-2 control included mostly genes involved in sugar, nucleotide, amino acid, and nitrogen metabolism, but also virulence-associated genes coding for lipase and bacterial apoptosis proteins. In addition, we demonstrate by liquid chromatography/mass-spectrometry of culture filtrates that the pro-inflammatory phenol-soluble modulin (PSM) peptides, key virulence factors of S. epidermidis, are under luxS/AI-2 control. Our results provide a detailed molecular basis for the role of LuxS in S. epidermidis virulence and suggest a signaling function for AI-2 in this bacterium. Keywords: wild type without glucose control vs luxS mutant vs luxS mutant with auto-inducer II
2008-10-10 | GSE9427 | GEO
Project description:Allelic imbalance (AI) region calls: start and end positions and the measured mBAF and LRR mean of each region after the BAF segmentation algorithm. Software: Illumina GenomeStudio;PennCNV v. 1.0.4;BAF segmentation v1.2.0.
| EGAD00010001926 | EGA
Project description:To characterize the molecular profile of the chorioamniotic membranes of preterm neonates with and without neurocognitive impairment at 18-24 months and (2) to determine if neonates who developed neurocognitive impairment can be identified at birth. Paired two-group design
2015-01-21 | E-GEOD-61822 | biostudies-arrayexpress
Project description:Salmonella enterica serovar Typhimurium is known to synthesize and respond to the cell signaling molecule, autoinducer-2 (AI-2). The luxS gene is involved in the synthesis of AI-2. We have previously shown that luxS controls a variety of bacterial processes in S. Typhimurium. In this study we identified the genes regulated by AI-2 using mRNA samples from isogenic luxS gene mutant of S. Typhimurium strain 87-26254 grown in LB media in the presence/absence of in vitro synthesized AI-2. In the presence of in vitro synthesized AI-2, 536 genes were significantly (p<0.05) regulated. Interestingly, in vitro synthesized AI-2 caused the down-regulation of 39 genes in Salmonella Pathogenicity Island-1 (SPI-1) including the transcriptional regulators hilA, hilD, and invF.
2015-07-31 | GSE23588 | GEO