Integrated analysis of mRNA and miRNA expression in response to interleukin-6 in hepatocytes

Lukowski, Samuel W.; Fish, Richard J.; Martin-Levilain, Juliette; Gonelle‐Gispert, Carmen; Bühler, Léo H.; Maechler, Pierre; Dermitzakis, Emmanouil T.; Neerman-Arbez, Marguerite

doi:10.1016/j.dib.2015.05.023

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…This assay was designed to allow ~100% of control cells to express the S protein following 48 h of infection, allowing robust detection of antiviral activity as reduction of S protein abundance. We validated this IF assay by treating 229E-infected cells with the nucleoside analogue prodrug remdesivir 27 (Fig. S1), showing that this BSL2-based screening system allows for the safe and straightforward identification of novel antiviral compounds.…”

Section: Resultsmentioning

confidence: 97%

“…Antivirals targeting SARS-CoV-2 such as remdesivir have modest clinical benefits 27 , indicating a need for more effective antivirals to complement anti-inflammatory therapy approaches for the treatment of COVID-19. As the timeline for development of new drugs is ~10 years 28 , and given the current dire need for effective antiviral agents, the identification of new drugs with antiviral activity cannot provide antiviral therapies in time to address the current pandemic.…”

Section: Introductionmentioning

confidence: 99%

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Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

Sugiyama

Cui

Karimzadeh

et al. 2021

Preprint

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The COVID-19 pandemic has led to an urgent need for the identification of new antiviral drug therapies that can be rapidly deployed to treat patients with this disease. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of COVID-19. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cell-based experimental assessment reveals several clinically-relevant repurposing drug candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

Sugiyama

Cui

Karimzadeh

et al. 2021

Preprint

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Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia

Grimaldi

Karaca

Latini

et al. 2017

Human Molecular Genetics

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Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome gives rise to unregulated protein-induced insulin secretion from pancreatic beta-cells, fasting hypoglycemia and elevated plasma ammonia levels. Mutations associated with HI/HA were identified in the Glud1 gene, encoding for glutamate dehydrogenase (GDH). We aimed at identifying the molecular causes of dysregulation in insulin secretion and ammonia production conferred by the most frequent HI/HA mutation Ser445Leu. Following transduction with adenoviruses carrying the human GDH-wild type or GDH-S445L-mutant gene, immunoblotting showed efficient expression of the transgenes in all the investigated cell types. Enzymatic activity tested in INS-1E beta-cells revealed that the mutant was much more sensitive to the allosteric activator ADP, rendering it highly responsive to substrates. INS-1E cells expressing either the wild type or mutant GDH responded similarly to glucose stimulation regarding mitochondrial activation and insulin secretion. However, at basal glucose glutamine stimulation increased mitochondrial activity and insulin release only in the mutant cells. In mouse and human islets, expression of mutant GDH resulted in robust elevation of insulin secretion upon glutamine stimulation, not observed in control islets. Hepatocytes expressing either the wild type or mutant GDH produced similar levels of ammonia when exposed to glutamine, although alanine response was strongly elevated with the mutant form. In conclusion, the GDH-S445L mutation confers hyperactivity to this enzyme due to higher sensitivity to ADP allosteric activation. This renders beta-cells responsive to amino acid stimulation, explaining protein-induced hypoglycemia secondary to non-physiological insulin release. Hepatocytes carrying mutant GDH produced more ammonia upon alanine exposure, which underscores hyperammonemia developed by the patients.

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Hepatocytes as Immunological Agents

Crispe

2016

The Journal of Immunology

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Hepatocytes are targeted for infection by a number of major human pathogens, including Hepatitis B Virus, Hepatitis C Virus and malaria. However, hepatocytes are also immunological agents in their own right. In systemic immunity, they are central in the acute-phase response, which floods the circulation with defensive proteins during diverse stresses including ischemia, physical trauma and sepsis. They express a variety of innate immune receptors and when challenged with Pathogen- or Damage-Associated Molecular Patterns, can deliver cell-autonomous innate immune responses that may result in host defense, or in immunopathology. Important human pathogens have evolved mechanisms to subvert these responses. Finally, hepatocytes talk directly to T cells, resulting in a bias towards immune tolerance.

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Integrated analysis of mRNA and miRNA expression in response to interleukin-6 in hepatocytes

Cited by 3 publications

References 10 publications

Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

Identification of the molecular dysfunction caused by glutamate dehydrogenase S445L mutation responsible for hyperinsulinism/hyperammonemia

Hepatocytes as Immunological Agents

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