C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation

Hypertrophy is a prominent feature of damaged podocytes in diabetic kidney disease (DKD). mTORC1 hyperactivation leads to podocyte hypertrophy, but the detailed mechanism of how mTORC1 activation occurs under pathological conditions is not completely known. Moreover, reduced nephrin tyrosine phosphorylation has been observed in podocytes under pathological conditions, but the molecular mechanism linking nephrin phosphorylation and pathology is unclear so far. In this study, we observed a significant increase in C1-Ten level in diabetic kidney and in high glucose-induced damaged podocytes. C1-Ten acts as a protein tyrosine phosphatase (PTPase) at the nephrin-PI3K binding site and renders PI3K for IRS-1, thereby activating mTORC1. Furthermore, C1-Ten causes podocyte hypertrophy and proteinuria by increasing mTORC1 activity in vitro and in vivo. These findings demonstrate the relationship between nephrin dephosphorylation and the mTORC1 pathway, mediated by C1-Ten PTPase activity. We suggest that C1-Ten contributes to the pathogenesis of DKD by inducing podocyte hypertrophy under high glucose conditions.111Ysciescopu

Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition

Resveratrol (RSV) is a natural polyphenol that has a beneficial effect on health, and resveratrol-induced autophagy has been suggested to be a key process in mediating many beneficial effects of resveratrol, such as reduction of inflammation and induction of cancer cell death. Although various resveratrol targets have been suggested, the molecule that mediates resveratrol-induced autophagy remains unknown. Here, we demonstrate that resveratrol induces autophagy by directly inhibiting the mTOR-ULK1 pathway. We found that inhibition of mTOR activity and presence of ULK1 are required for autophagy induction by resveratrol. In line with this mTOR dependency, we found that resveratrol suppresses the viability of MCF7 cells but not of SW620 cells, which are mTOR inhibitor sensitive and insensitive cancer cells, respectively. We also found that resveratrol-induced cancer cell suppression occurred ULK1 dependently. For the mechanism of action of resveratrol on mTOR inhibition, we demonstrate that resveratrol directly inhibits mTOR. We found that resveratrol inhibits mTOR by docking onto the ATP-binding pocket of mTOR (i.e., it competes with ATP). We propose mTOR as a novel direct target of resveratrol, and inhibition of mTOR is necessary for autophagy inductionopen

KaPPA-View4: a metabolic pathway database for representation and analysis of correlation networks of gene co-expression and metabolite co-accumulation and omics data

Correlations of gene-to-gene co-expression and metabolite-to-metabolite co-accumulation calculated from large amounts of transcriptome and metabolome data are useful for uncovering unknown functions of genes, functional diversities of gene family members and regulatory mechanisms of metabolic pathway flows. Many databases and tools are available to interpret quantitative transcriptome and metabolome data, but there are only limited ones that connect correlation data to biological knowledge and can be utilized to find biological significance of it. We report here a new metabolic pathway database, KaPPA-View4 (http://kpv.kazusa.or.jp/kpv4/), which is able to overlay gene-to-gene and/or metabolite-to-metabolite relationships as curves on a metabolic pathway map, or on a combination of up to four maps. This representation would help to discover, for example, novel functions of a transcription factor that regulates genes on a metabolic pathway. Pathway maps of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and maps generated from their gene classifications are available at KaPPA-View4 KEGG version (http://kpv.kazusa.or.jp/kpv4-kegg/). At present, gene co-expression data from the databases ATTED-II, COXPRESdb, CoP and MiBASE for human, mouse, rat, Arabidopsis, rice, tomato and other plants are available

Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.</p

From the Dish to the Real World: Modeling Interactions between the Gut and Microorganisms in Gut Organoids by Tailoring the Gut Milieu

The advent of human intestinal organoid systems has revolutionized the way we understand the interactions between the human gut and microorganisms given the host tropism of human microorganisms. The gut microorganisms have regionality (i.e., small versus large intestine) and the expression of various virulence factors in pathogens is influenced by the gut milieu. However, the culture conditions, optimized for human intestinal organoids, often do not fully support the proliferation and functionality of gut microorganisms. In addition, the regional identity of human intestinal organoids has not been considered to study specific microorganisms with regional preference. In this review we provide an overview of current efforts to understand the role of microorganisms in human intestinal organoids. Specifically, we will emphasize the importance of matching the regional preference of microorganisms in the gut and tailoring the appropriate luminal environmental conditions (i.e., oxygen, pH, and biochemical levels) for modeling real interactions between the gut and the microorganisms with human intestinal organoids.11Nsciescopu

Approaching precision medicine by tailoring the microbiota

Accumulating evidence has revealed the link between the microbiota and various human diseases. Advances in high-throughput sequencing technologies have identified some consistent disease-associated microbial features, leading to the emerging concept of microbiome-based therapeutics. However, it is also becoming clear that there are considerable variations in the microbiota among patients with the same disease. Variations in the microbial composition and function contribute to substantial differences in metabolic status of the host via production of a myriad of biochemically and functionally different microbial metabolites. Indeed, compelling evidence indicates that individuality of the microbiome may result in individualized responses to microbiome-based therapeutics and other interventions. Mechanistic understanding of the role of the microbiota in diseases and drug metabolism would help us to identify causal relationships and thus guide the development of microbiome-based precision or personalized medicine. In this review, we provide an overview of current efforts to use microbiome-based interventions for the treatment of diseases such as cancer, neurological disorders, and diabetes to approach precision medicine.11Nsciescopu

Nueve Canciones, by Gisela Hernández Gonzalo

Gisela Hernández Gonzalo (1912−1971) was a Cuban composer. Aware of the political necessity, she established ties with the Castro government in return for recognition of her activities as a music teacher and composer. She was also a member of the nationalistic Grupo Minorista that led a movement to incorporate Afro-Cuban sounds into larger forms of music. Hernández taught music at the Hubert de Blanck Conservatory, and with Olga De Blanck Martín, director of the conservatory, she developed a music education system that made significant changes in Mexican music education. With de Blanck, she also co-founded Ediciones de Blanck publishing and became instrumental in publishing critical editions of Ignacio Cervantes’ music. Hernandez often used Afro-Cuban elements in her compositions including the Nueves Canciones, song collection and the Triptico, song cycle