Biology subjects

Bianchi, F.

Publications and source records attributed to Bianchi, F..

3 recordsLinked to original sources

bioRxiv2018

Enhanced axonal Neuregulin-1 type-III signaling ameliorates disease severity in a CMT1B mouse model

Charcot-Marie-Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) with heterogeneous pathogenesis and no available treatment. Axonal Neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here, we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain of function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor TACE/ADAM17, also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.

neuroscience↗

bioRxiv2018

In silico screening for ERα downmodulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

PurposeMost breast cancers (BCs) express estrogen receptor (ER) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI). Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ER intracellular content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ER content in BC cells.\n\nMethodsWe screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ER-expressing BC cells.\n\nResultsMitoxantrone and thioridazine induced ER downmodulation and prevented MCF-7 cell proliferation. Interestingly, while mitoxantrone was toxic for normal breast cells, thioridazine showed preferential activity toward BC cells. Thioridazine also reduced the ER content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ER-expressing BC cells.\n\nConclusionsWe suggest that the modulation of the ER intracellular concentration in BC cells can also be robustly exploited in in silico screenings to identify anti-BC drugs and further demonstrate a re-purposing opportunity for thioridazine in primary and metastatic ET-resistant BC treatment.

cancer biology↗

bioRxiv2017

Growth inhibition by amino acids in Saccharomyces cerevisiae

Amino acids are essential metabolites but can also be toxic when present at high levels intracellularly. Substrate-induced down-regulation of amino acid transporters in Saccharomyces cerevisiae is thought to be a mechanism to avoid this toxicity. It has been shown that unregulated uptake by the general amino acid permease Gap1 causes cells to become sensitive to amino acids. Here, we show that overexpression of eight other amino acid transporters (Agp1, Bap2, Can1, Dip5, Gnp1, Lyp1, Put4 or Tat2) also induces a growth defect when specific single amino acids are present at concentrations of 0.5-5 mM. We can now state that all proteinogenic amino acids, as well as the important metabolite ornithine, are growth inhibitory to S. cerevisiae when transported into the cell at high enough levels. Measurements of initial transport rates and cytosolic pH show that toxicity is due to amino acid accumulation and not to the influx of co-transported protons. The amino acid sensitivity phenotype is a useful tool that reports on the in vivo activity of transporters and has allowed us to identify new transporter-specific substrates.

cell biology↗