GATA binding protein 2 mediates leptin inhibition of PPARγ1 expression in hepatic stellate cells and contributes to hepatic stellate cell activation

AbstractHepatic stellate cell (HSC) activation is a crucial step in the development of liver fibrosis. Peroxisome-proliferator activated receptor γ (PPARγ) exerts a key role in the inhibition of HSC activation. Leptin reduces PPARγ expression in HSCs and plays a unique role in promoting liver fibrosis. The present studies aimed to investigate the mechanisms underlying leptin regulation of PPARγ1 (a major subtype of PPARγ) in HSCs in vivo and in vitro. Results revealed a leptin response region in mouse PPARγ1 promoter and indicated that the region included a GATA binding protein binding site around position −2323. GATA binding protein-2 (GATA-2) could bind to the site and inhibit PPARγ1 promoter activity in HSCs. Leptin induced GATA-2 expression in HSCs in vitro and in vivo. GATA-2 mediated leptin inhibition of PPARγ1 expression by its binding site in PPARγ1 promoter in HSCs and GATA-2 promoted HSC activation. Leptin upregulated GATA-2 expression through β-catenin and sonic hedgehog pathways in HSCs. Leptin-induced increase in GATA-2 was accompanied by the decrease in PPARγ expression in HSCs and by the increase in the activated HSC number and liver fibrosis in vivo. Our data might suggest a possible new explanation for the promotion effect of leptin on liver fibrogenesis

Research of the induced voltage’s varying law of the pipe-type energy harvester tumbleweed rover

This paper introduces a novel tumbleweed rover design that employs a pipe-type energy harvester system to harvest electrical power from the wind indirectly. The critical parameters law of electromagnetic induction is studied firstly and then propose a preliminary model of the layout of harvesters. Simulates the motion of the harvester inside a spherical shell to achieve the performance of voltage generation and summarize the varying rules of induced voltage. Given the effect of centrifugal force, we further propose spring as a solution to support magnet to recover reciprocating motion in harvester. Finally, the experiments are implemented based on the simulated model to verify the dependability of the energy harvester and the validity of induced voltages’ varying rules

CYP-omega-hydroxylation-dependent metabolites of arachidonic acid inhibit the basolateral 10pS chloride channel in the rat thick ascending limb

Metabolites of arachidonic acid influence sodium chloride (NaCl) transport in the thick ascending limb. Because a 10pS Cl channel is the major type of chloride channel in the basolateral membrane of this nephron segment, we explored the effect of arachidonic acid on this channel in cell-attached patches. Addition of 5μmol arachidonic acid significantly decreased channel activity (a product of channel number and open probability) while linoleic acid had no effect. To determine if this was mediated by acachidonic acid per se or by its metabolites, we measured channel activity in the presence of the cyclooxygenase inhibitor indomethacin, the selective lipoxygenase inhibitor nordihydroguaiaretic acid, and the cytochrome P-450 (CYP)-ω-hydroxylation inhibitor 17-octadecynoic acid. Neither cyclooxygenase nor lipoxygenase inhibition had an effect on basal chloride channel activity; further they failed to abolish the inhibitory effect of arachidonate on the 10pS channel. However, inhibition of CYP-ω-hydroxylation completely abolished the effect of arachidonic acid. The similarity of the effects of 20-hydroxyeicosatetraenoic acid (20-HETE) and arachidonic acid suggests that the effect of arachidonic acid was mediated by CYP-ω-hydroxylation-dependent metabolites. We conclude that arachidonic acid inhibits the 10pS chloride channel in the basolateral membrane of the medullary thick ascending limb, an effect mediated by the CYP-ω-hydroxylation-dependent metabolite 20-HETE

MicroRNA-100-5p and microRNA-298-5p released from apoptotic cortical neurons are endogenous Toll-like receptor 7/8 ligands that contribute to neurodegeneration

Background: MicroRNA (miRNA) expression in the brain is altered in neurodegenerative diseases. Recent studies demonstrated that selected miRNAs conventionally regulating gene expression at the post-transcriptional level can act extracellularly as signaling molecules. The identity of miRNA species serving as membrane receptor ligands involved in neuronal apoptosis in the central nervous system (CNS), as well as the miRNAs' sequence and structure required for this mode of action remained largely unresolved. Methods. Using a microarray-based screening approach we analyzed apoptotic cortical neurons of C56BL/6 mice and their supernatant with respect to alterations in miRNA expression/presence. HEK-Blue Toll-like receptor (TLR) 7/8 reporter cells, primary microglia and macrophages derived from human and mouse were employed to test the potential of the identified miRNAs released from apoptotic neurons to serve as signaling molecules for the RNA-sensing receptors. Biophysical and bioinformatical approaches, as well as immunoassays and sequential microscopy were used to analyze the interaction between candidate miRNA and TLR. Immunocytochemical and -histochemical analyses of murine CNS cultures and adult mice intrathecally injected with miRNAs, respectively, were performed to evaluate the impact of miRNA-induced TLR activation on neuronal survival and microglial activation. Results: We identified a specific pattern of miRNAs released from apoptotic cortical neurons that activate TLR7 and/or TLR8, depending on sequence and species. Exposure of microglia and macrophages to certain miRNA classes released from apoptotic neurons resulted in the sequence-specific production of distinct cytokines/chemokines and increased phagocytic activity. Out of those miRNAs miR-100-5p and miR-298-5p, which have consistently been linked to neurodegenerative diseases, entered microglia, located to their endosomes, and directly bound to human TLR8. The miRNA-TLR interaction required novel sequence features, but no specific structure formation of mature miRNA. As a consequence of miR-100-5p- and miR-298-5p-induced TLR activation, cortical neurons underwent cell-autonomous apoptosis. Presence of miR-100-5p and miR-298-5p in cerebrospinal fluid led to neurodegeneration and microglial accumulation in the murine cerebral cortex through TLR7 signaling. Conclusion: Our data demonstrate that specific miRNAs are released from apoptotic cortical neurons, serve as endogenous TLR7/8 ligands, and thereby trigger further neuronal apoptosis in the CNS. Our findings underline the recently discovered role of miRNAs as extracellular signaling molecules, particularly in the context of neurodegeneration

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead