PPAR is a member of the nuclear receptor family for which agonist ligands have anti-growth effects. However, clinical studies using PPAR ligands as a monotherapy failed to show a beneficial effect. Here we have studied the effects of PPAR activation with chemotherapeutic agents in current use for specific cancers. We observed a striking synergy between rosiglitazone and platinum-based drugs in several different cancers both in vitro and using transplantable and chemically induced spontaneous tumor models. The effect appears to be due in part to PPAR-mediated downregulation of metallothioneins, proteins that have been shown to be involved in resistance to platinum-based therapy. These data strongly suggest combining PPAR agonists and platinum-based drugs for the treatment of certain human cancers
Synergy between PPARgamma ligands and platinum-based drugs in cancer.
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View Samples3T3-L1 adipocytes were treated inhibitors against the glutathione and thioredoxin cycling pools for several time-points (2-24 h).
The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes.
Cell line, Treatment
View Samples3T3-L1 adipose cells were grown, differentiated and insulin resistance was stimulated by addition of Glucose Oxidase.
The transcriptional response to oxidative stress is part of, but not sufficient for, insulin resistance in adipocytes.
Specimen part
View SamplesMitochondrial defects are associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as diabetes and neurodegeneration. In lower organisms, genetic retrograde signaling programs have been identified that promote cellular and organism survival in the face of mitochondrial dysfunction. Here, we characterized the transcriptional component of the human mitochondrial retrograde response in an inducible model of mitochondrial dysfunction.
Mitochondrial dysfunction remodels one-carbon metabolism in human cells.
Cell line
View SamplesThe Fulani ethnic group is relatively protected from Plasmodium falciparum malaria, however a genetic basis for this is unknown. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani, compared to a sympatric ethnic group, the Mossi. When we compared uninfected and infected individuals in Fulani and Mossi, a strong transcriptional response was only detected in the monocyte fraction of Fulani, and this was not related to differences in DNA methylation. Overall design: RNA sequencing analysis of CD14+ (monocyte) and CD14- (predominantly lymphocyte), and DNA-methylation analysis of CD14+ (monocyte) fractions of PBMCs, from of Fulani and Mossi individuals, uninfected or infected with P.falciparum. This Series represents the RNA-Seq dataset.
Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria.
Subject
View SamplesGut-draining mesenteric lymph nodes (mLNs) play a key role in peripheral tolerance towards food and commensal antigens by providing an optimal microenvironment for efficient de novo induction of Foxp3+ regulatory T cells (Tregs). We recently identified mLN stromal cells as critical cellular players in this process and demonstrated that their tolerogenic properties are imprinted by microbiota. Here, we show that this imprinting process already takes place in the neonatal phase and renders the mLN stromal cell compartment resistant to inflammatory perturbations later in life. Utilizing LN transplantation, RNA-seq and single-cell RNA-seq allowed identification of stably imprinted expression signatures in mLN fibroblastic stromal cells. We dissected common stromal cell subsets across gut-draining mLNs and skin-draining LNs with location-specific immunomodulatory functions, such as subset-specific expression of Aldh1a2/3. Accordingly, mLN stromal cells shaped resident dendritic cells to attain high Treg-inducing capacity in a Bmp2-dependent manner. Thus, crosstalk between mLN stromal and resident dendritic cells provides a robust feedback mechanism for the maintenance of intestinal tolerance. Overall design: Transcriptomic analysis of fibroblastic stromal cells of skin-draining and intestinal-draining lymph nodes from endogenous and transplanted lymph nodes at the popliteal fossa.
Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes.
Cell line, Subject
View SamplesGut-draining mesenteric lymph nodes (mLNs) play a key role in peripheral tolerance towards food and commensal antigens by providing an optimal microenvironment for efficient de novo induction of Foxp3+ regulatory T cells (Tregs). We recently identified mLN stromal cells as critical cellular players in this process and demonstrated that their tolerogenic properties are imprinted by microbiota. Here, we show that this imprinting process already takes place in the neonatal phase and renders the mLN stromal cell compartment resistant to inflammatory perturbations later in life. Utilizing LN transplantation, RNA-seq and single-cell RNA-seq allowed identification of stably imprinted expression signatures in mLN fibroblastic stromal cells. We dissected common stromal cell subsets across gut-draining mLNs and skin-draining LNs with location-specific immunomodulatory functions, such as subset-specific expression of Aldh1a2/3. Accordingly, mLN stromal cells shaped resident dendritic cells to attain high Treg-inducing capacity in a Bmp2-dependent manner. Thus, crosstalk between mLN stromal and resident dendritic cells provides a robust feedback mechanism for the maintenance of intestinal tolerance. Overall design: Transcriptomic analysis of resident dendritic cells of skin-draining and intestinal-draining lymph nodes from endogenous and lymph nodes transplanted to the popliteal fossa.
Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes.
Cell line, Subject
View SamplesGut-draining mesenteric lymph nodes (mLNs) play a key role in peripheral tolerance towards food and commensal antigens by providing an optimal microenvironment for efficient de novo induction of Foxp3+ regulatory T cells (Tregs). We recently identified mLN stromal cells as critical cellular players in this process and demonstrated that their tolerogenic properties are imprinted by microbiota. Here, we show that this imprinting process already takes place in the neonatal phase and renders the mLN stromal cell compartment resistant to inflammatory perturbations later in life. Utilizing LN transplantation, RNA-seq and single-cell RNA-seq allowed identification of stably imprinted expression signatures in mLN fibroblastic stromal cells. We dissected common stromal cell subsets across gut-draining mLNs and skin-draining LNs with location-specific immunomodulatory functions, such as subset-specific expression of Aldh1a2/3. Accordingly, mLN stromal cells shaped resident dendritic cells to attain high Treg-inducing capacity in a Bmp2-dependent manner. Thus, crosstalk between mLN stromal and resident dendritic cells provides a robust feedback mechanism for the maintenance of intestinal tolerance. Overall design: Transcriptomic analysis of migratory dendritic cells of skin-draining and intestinal-draining lymph nodes from endogenous and lymph nodes transplanted to the popliteal fossa.
Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes.
Specimen part, Subject
View SamplesThe Mesio-Temporal Lobe Epilepsy (MTLE) syndrome is the most common form of intractable epilepsies. It is characterized by the recurrence of focal seizures occurring in mesio-temporal limbic structures and is often associated with hippocampal sclerosis and drug resistance.
Glial responses during epileptogenesis in Mus musculus point to potential therapeutic targets.
Sex, Specimen part
View Samples