Effects of Losartan and Irbesartan administration on brain angiotensinogen mRNA levels

Losartan, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'(1H-tetrazol-5-yl)-biphenil-4-yl)methyl] imidazole, and Irbesartan, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non -1-en-4-one, are two angiotensin AT1 receptor antagonists largely used in human health care as antihypertensive agents. Their ability to cross the blood-brain barrier and to influence the central renin-angiotensin system are widely investigated, but how this brain system responds to the subchronic and chronic block of the angiotensin AT1 receptor is still unknown. Normotensive rats were intragastrically implanted for 7- and 30-day administration, with a dose of 3 and 30 mg/kg body weight. Treatments were shown to influence, in a dose-, time- and brain-area-dependent manner, angiotensinogen mRNA levels in scanned areas. This study showed a general up-regulation of angiotensinogen mRNA expression after 7 days and a widespread down-regulation or basal level of expression after a 30-day administration of two angiotensin AT1 receptor antagonists

The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells

Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome

Hypericum perforatum methanolic extract inhibits growth of human prostatic carcinoma cell line orthotopically implanted in nude mice.

The antiproliferative effect of serotonin-reuptake inhibitors (SSRI) and serotonin antagonists has been demonstrated in prostate tumors. Since Hypericum perforatum components act as serotonin-reuptake inhibitors and exert cytotoxic effects on several human cancer cell lines, in this work we analyzed the effect of a treatment with Hypericum perforatum extract (HPE) on the growth of human prostate cancer cells in vitro and in vivo. This study highlighted a significant reduction of tumor growth and number of metastasis suggesting that this natural compound may be useful in the treatment of prostate cancer

Interaction between ASIP and MC1R in Black and Brown Alpaca

Animal fibres from South American camelids and other fibre or wool bearing species provide important products for use by the human population. The contemporary context includes the competition with petrocarbon-based artificial fibres and concern about excessive persistence of these in the natural environment. Animal fibres present highly valuable characteristics for sustainable production and processing as they are both natural and renewable. On the other hand, their use is recognised to depend on availability of appropriate quality and quantity, the production of which is underpinned by a range of sciences and processes which support development to meet market requirements. This collection of papers combines international experience from South and North America, China and Europe. The focus lies on domestic South American camelids (alpacas, llamas) and also includes research on sheep and goats. It considers latest advances in sustainable development under climate change, breeding and genetics, reproduction and pathology, nutrition, meat and fibre production and fibre metrology. Publication of this book is supported by the Animal Fibre Working Group of the European Federation of Animal Science (EAAP). ‘Advances in Fibre Production Science in South American Camelids and other Fibre Animals’ addresses issues of importance to scientists and animal breeders, textile processors and manufacturers, specialised governmental policy makers and students studying veterinary, animal and applied biological sciences

Interaction of ASP and MC1R in black and brown alpaca.

Alpaca coat colour is a relevant feature both for breeders than textile industries. Agouti (ASP) and Extension (MC1R) are genes known to be involved in coat colour through pigmentation pathways by regulating type, amount and distribution of eumelanin and pheomelanin pigments in melanocytes. In alpaca genotype of ASP and MC1R genes have already been analysed distinctly, but their epistatic interaction have not been evaluated. In this study have been assessed their segregation more insights on black and brown phenotypes. In several mammals MC1R is epistatic over ASP, id est recessive allele in Agouti (a) and dominant allele in Extension locus (E) produces black phenotype. That is confirmed in alpaca where black coat has aH/aΔ57 and aH/ahT genotype on agouti and E/E or E/e genotype on MC1R locus. Otherwise ASP and MC1R in Brown/Red Brown, have a dominant profile at least in one allele as A/A, A/ahT on Agouti and E/e on Extension. Genotype and phenotype comparison clears that receptor and ligand are in concordance to produce pheomelanin and eumelanin in alpaca. Segregation analysis of 12 alpaca families genotyped by coat color, confirm the dominance of brown over black and could be helpful for coat colour classification and genotyping

Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro and in vivo model

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells treated with the fatty acid sodium oleate (fatty dHepaRG) recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG cells and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging-dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting

Alpaca FGF5: Hypothetical Post-Transcriptional Readthrough Regulation in Skin Biopsies

Animal fibres from South American camelids and other fibre or wool bearing species provide important products for use by the human population. The contemporary context includes the competition with petrocarbon-based artificial fibres and concern about excessive persistence of these in the natural environment. Animal fibres present highly valuable characteristics for sustainable production and processing as they are both natural and renewable. On the other hand, their use is recognised to depend on availability of appropriate quality and quantity, the production of which is underpinned by a range of sciences and processes which support development to meet market requirements. This collection of papers combines international experience from South and North America, China and Europe. The focus lies on domestic South American camelids (alpacas, llamas) and also includes research on sheep and goats. It considers latest advances in sustainable development under climate change, breeding and genetics, reproduction and pathology, nutrition, meat and fibre production and fibre metrology. Publication of this book is supported by the Animal Fibre Working Group of the European Federation of Animal Science (EAAP). ‘Advances in Fibre Production Science in South American Camelids and other Fibre Animals’ addresses issues of importance to scientists and animal breeders, textile processors and manufacturers, specialised governmental policy makers and students studying veterinary, animal and applied biological sciences

Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer’s disease patients, possible biomarkers for early diagnosis

Alzheimer's disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid-beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure; therefore, the actual challenge is to define new biomarkers and non-invasive technologies to measure neuropathological changes in vivo at pre-symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non-invasive rapid detection of AD biomarkers. Here, we report the presence of amyloid beta plaques, tau tangles, neurodegeneration and detrimental astrocyte and microglia activation according to a disease associated microglia phenotype (DAM). Thus, we propose the human retina as a useful site for the detection of cellular and molecular changes associated with Alzheimer's disease

Genome-wide identification of direct HBx genomic targets

Background: The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. Results: ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Conclusions: Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication

In polycistronic Qβ RNA, single-strandedness at one ribosome binding site directly affects translational initiations at a distal upstream cistron

In Qβ RNA, sequestering the coat gene ribosome binding site in a putatively strong hairpin stem structure eliminated synthesis of coat protein and activated protein synthesis from the much weaker maturation gene initiation site, located 1300 nucleotides upstream. As the stability of a hairpin stem comprising the coat gene Shine–Dalgarno site was incrementally increased, there was a corresponding increase in translation of maturation protein. The effect of the downstream coat gene ribosome binding sequence on maturation gene expression appeared to have occurred only in cis and did not require an AUG start codon or initiation of coat protein synthesis. In all cases, no structural reorganization was predicted to occur within Qβ RNA. Our results suggest that protein synthesis from a relatively weak translational initiation site is greatly influenced by the presence or absence of a stronger ribosome binding site located elsewhere on the same RNA molecule. The data are consistent with a mechanism in which multiple ribosome binding sites compete in cis for translational initiations as a means of regulating protein synthesis on a polycistronic messenger RNA