Pparg controls antifibrotic network
Scientists at the University of Tuebingen have identified a network of antifibrotic RNAs, and showed that this network was controlled by the transcription factor Pparg. Fibrosis, which is essentially the formation of inappropriate scar tissue, contributes to multiple diseases, and its molecular mechanisms are poorly understood. In their work, the authors began by identifying a Pparg-controlled network of eight miRNAs and 54 target genes that contributed to fibrosis of the tumor microenvironment in hepatocellular carcinoma. They then showed that the same network was active in breast and lung cancers, as well as two models of noncancerous liver fibrosis. The authors concluded that “we expand the antifibrotic function of Pparg to controlling the synthesis of an antifibrotic miRNA network. This network may serve as a therapeutic target in antifibrotic therapies.” They reported their findings in the Dec. 23, 2019, online issue of the Proceedings of the National Academy of Sciences.
Bacterial peptides can be gluten lookalikes
Scientists at Monash University have determined that several commensal bacterial species, including Pseudomonas fluorescens and Pseudomonas aeruginosa, were capable of activating immune responses that cross-reacted with gluten antibodies in T cells from celiac disease (CeD) patients. It has long been hypothesized that environmental microbes could set off such cross-reactive immune responses, but specific evidence has been lacking. In their work, the authors conducted structural screening of candidate bacterial peptides, and identified peptides with structural similarities to gluten epitopes that were capable of activating T cells. “Our data demonstrate that the prerequisites exist for the involvement of bacterial mimic peptides in the triggering of gluten-specific CD4+ T cells from CeD patients, but more data is required to causally link specific bacteria to CeD etiology,” the authors wrote. Furthermore, “the high frequency of mimic peptides in our sample set of candidate peptides suggests that bacteria probably contain a pool of mimic antigens that fit into the context of other autoimmune diseases. Ultimately, such knowledge may be used to prevent IMIDs in genetically predisposed individuals.” They reported their findings in the Dec. 23, 2019, online issue of Nature Structural and Molecular Biology.
Researchers at the University of Cambridge have identified the peptide hormone GDF15 as responsible for metformin’s effect on body weight. Metformin is something of an unassuming miracle drug. It has been used to treat diabetes for more than half a century, and modern epidemiology has shown both that it can also prevent the onset of type 2 diabetes, and that it causes weight loss that is likely responsible for some of its effects. Previous studies had noted an association of metformin with higher levels of circulating GDF15, which is a hormone that is released in response to cellular stress. In the new studies, the authors showed that GDF15 mediated metformin’s effects on weight loss, but that metformin continues to act as an insulin sensitizer in GDF15 knockout mice, separating the two effects. “In the work presented herein, we describe a body of data from humans, cells, organoids and mice that securely establish a major role for GDF15 in the mediation of metformin’s beneficial effects on energy balance,” the authors wrote. “Our observations represent a significant advance in our understanding of the action of metformin, one of the world’s most frequently prescribed drugs.” They reported their findings in the Dec. 25, 2019, online issue of Nature.
Viral infection may be second hit for familial ALS
Investigators at Cardiff University have gained new insights into how FUS-driven familial amyotrophic lateral sclerosis (ALS) develops. Roughly 10% of ALS cases are familial, and mutations in FUS are a major ALS driver within the familial subset. The authors showed that FUS-expressing cells were hypersensitive to toxicity caused by double-stranded DNA, which is a signal for viral infection, as well as by infection with certain viruses. “Our data suggest that the antiviral immune response is a plausible second hit for FUS proteinopathy,” the authors wrote. Their work appeared in the Dec. 24, 2019, issue of Cell Reports.
Oral compound ameliorates beta-thalassemia
A team at Vifor (International) Ltd. has identified an oral ferroportin inhibitor that was effective in animal models at improving the symptoms of beta-thalassemia. Caused by mutations in the beta-globin gene, beta-thalassemia leads to both anemia and iron overload, as cells try to compensate for iron deficiency by importing more iron. In their work, the team showed that the small-molecule drug VIT-2763 was as effective as the natural peptide hepcidin in inhibiting ferroportin. “Restricting iron availability by VIT-2763, the first clinical-stage oral ferroportin inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the mouse model of β-thalassemia intermedia,” the authors wrote. “The clinical development of [an] oral ferroportin inhibitor has the potential to provide a therapeutic option with dosing convenience for patients with β-thalassemia and other diseases with dysregulated iron homeostasis.” They reported their findings in the Dec. 9, 2019, issue of the Journal of Clinical Investigation.