Ras

Activated macrophages have a greater ability of phagocytosis against pathogens that is mediated by large-scale actin rearrangement. However, molecular machineries that conduct this task have not been fully identified. Here, we demonstrate an unanticipated role of TAGLN2, a 22-kDa actin-binding protein, in Toll-like receptor (TLR)-stimulated phagocytosis. TAGLN2 was greatly induced in macrophages in response to lipopolysaccharide (LPS), a ligand for TLR4, partly via the NF-κB pathway. TAGLN2-deficient macrophages (TAGLN2 (-/-)) showed defective phagocytic functions of IgM- and IgG-coated sheep red blood cells as well as bacteria...

METHODS: Female Wistar rats were exposed to filtered air (F) or to concentrated fine particulate matter (P) for 15 days. After mating, the rats were divided into four groups and again exposed to F or P (FF, FP, PF, PP) beginning on day 6 of pregnancy. At embryonic day 19, the placenta was collected. The placental structure, the protein and gene expression of TGFβ1, VEGF-A, and its receptor Flk-1 and RAS were evaluated by indirect ELISA and quantitative real-time PCR. RESULTS: Exposure to P decreased the placental mass, size, and surface area as well as the TGFβ1, VEGF-A and Flk-1 content...

The effects of angiotensin-converting enzyme (ACE) inhibition by an antihypertensive drug, captopril, and milk casein-derived ACE-inhibiting bioactive tripeptide isoleucine-proline-proline (Ile-Pro-Pro), on local renin-angiotensin system (RAS) and glucocorticoid production in the intestine were studied in the dextran sodium sulfate induced colitis in mice. Mice received water or 3% dextran sodium sulfate with or without either 15.7 mg/l captopril or 833 mg/l Ile-Pro-Pro for 7 days. Captopril and Ile-Pro-Pro were found to have distinct effects on local renin-angiotensin system and mRNA expression of glucocorticoid synthesis components in colon in vitro...

Chronic kidney disease (CKD) has become a major public health problem in Brazil and worldwide. There are many causes of CKD, being the congenital anomalies of the kidney and urinary tract and the glomerular diseases very common in pediatric patients, while diabetic nephropathy, CKD due to chronic arterial hypertension and glomerular diseases are predominant in adult patients. Many endogenous mediators have been related to the pathophysiology of CKD, being relevant the effects of the renin-angiotensin system (RAS) and the immune-inflammatory mediators including cytokines...

Spatiotemporal control is a common mechanism that modulates activity and function of signal transducers in the signaling network. We identified acetylation of CNK1 (connector enhancer of kinase suppressor of Ras-1) as a late step in the activation of CNK1 signaling, accompanied with prolonged stimulation of extracellular signal-regulated kinase (ERK). We identified the acetyltransferase CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)-binding protein and the deacetylase SIRT2 (sirtuin type 2) as novel binding partners of CNK1, modulating the acetylation state of CNK1...

The ATP7A protein is a ubiquitously expressed copper-translocating P-type ATPase that controls cytoplasmic copper concentrations by mediating cellular copper egress. In vitro studies have previously demonstrated that ATP7A abundance in various tumor cell lines is correlated with increased resistance to cisplatin, a widely-used chemotherapy agent. However, to date no studies have examined a role for ATP7A in tumor growth or cisplatin sensitivity in vivo. In this study, we deleted ATP7A in H-RAS transformed tumorigenic mouse embryonic fibroblasts (MEF(RAS)7A-)...

Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. While the molecular mechanisms of RAS GEF catalysis have been unveiled, how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here, we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro, and for PDGF activation of RAC and RAC-dependent actin remodeling and cell migration...

Objective-Not all patients with type 2 diabetes achieve the recommended glycated hemoglobin A1c (A1C) levels after adequate titration of basal insulin (BI). Current intensification approaches include addition of rapid-acting insulin (RAI) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA), but it is not clear which strategy results in better long-term outcomes. Methods-This retrospective analysis of health insurance claims data in the US MarketScan database compared glycemic control and healthcare resource utilization and costs 12 months after adding GLP-1 RA to BI vs adding RAI or increasing BI doses...

Reliable characterization of wetting properties is essential for the development and optimization of superhydrophobic surfaces. Here, the dynamics of superhydrophobicity is studied including droplet friction and wetting transitions by using droplet oscillations on micropillared surfaces. Analyzing droplet oscillations by high-speed camera makes it possible to obtain energy dissipation parameters such as contact angle hysteresis force and viscous damping coefficients, which indicate pinning and viscous losses, respectively...

BK polyomavirus (BKPyV) is a human pathogen first isolated in 1971. BKPyV infection is ubiquitous in the human population, with over 80% of adults worldwide being seropositive for BKPyV. BKPyV infection is usually asymptomatic; however, BKPyV reactivation in immunosuppressed transplant patients causes two diseases, polyomavirus-associated nephropathy and hemorrhagic cystitis. To establish a successful infection in host cells, BKPyV must travel in retrograde transport vesicles to reach the nucleus. To make this happen, BKPyV requires the cooperation of host cell proteins...

BACKGROUND: RAS protein interactions have predominantly been studied in the context of the RAF and PI3kinase oncogenic pathways. Structural modeling and X-ray crystallography have demonstrated that RAS isoforms bind to canonical downstream effector proteins in these pathways using the highly conserved switch I and II regions. Other non-canonical RAS protein interactions have been experimentally identified, however it is not clear whether these proteins also interact with RAS via the switch regions...

Renal Artery Stenosis (RAS) is an important cause of treatment-resistant hypertension. Uncontrolled hypertension with RAS can cause progressive chronic kidney disease (CKD) leading to end-stage kidney disease. Therapeutic revascularisation can be helpful in appropriate circumstances where pharmaceutical intervention has failed and significant renovascular disease contributes to resistant hypertension. We present an interesting case of a Caucasian male with peripheral vasculopathy, abdominal aortic aneurysm (AAA), single functioning kidney and ostial RAS caused by stent struts from an endovascular AAA stent graft...

PURPOSE: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. EXPERIMENTAL DESIGN: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed...

The Renin-Angiotensin System (RAS) has emerged as being related to vascular disease. Recently the RAS has been associated with obesity, diabetes, and even cancer. This review focuses on the therapeutic potential of angiotensin converting enzyme (ACE) inhibitors for Oral Squamous Cell Carcinoma (OSCC). Considering the limited literature, Bioinformatics analyses was performed to identify possible effects of ACE inhibitors in OSCC. The current review intends to more fully explore the potential benefits of ACE inhibitors for OSCC patients...

OBJECTIVE: To compare the influence of rural background, rural intent at medical school entry, and Rural Clinical School (RCS) participation on the likelihood of later participation in rural practice. DESIGN: Analysis of linked data from the Medical School Outcomes Database Commencing Medical Students Questionnaire (CMSQ), routinely collected demographic information, and the Australian Health Practitioner Regulation Agency database on practice location. SETTING AND PARTICIPANTS: University of Western Australia medical students who completed the CMSQ during 2006-2010 and were practising medicine in 2016...

Prenatal hypoxia is associated with growth restriction and adverse cardiovascular outcomes. Here, we describe renal and cardiovascular outcomes in ageing mouse offspring prenatally exposed to hypoxia (12% O2) from embryonic day 14.5 until birth. At 12 months of age, both male and female offspring exposed to prenatal hypoxia had elevated mean arterial pressure. Glomerular number was reduced by 25% in hypoxia-exposed male, but not female, offspring and this was associated with increased urinary albumin excretion, glomerular hypertrophy and renal fibrosis...

OBJECTIVES: Genetic variability in NS5A is associated to different levels of resistance to the currently licensed NS5A inhibitors. The aim of this study was to detect NS5A inhibitor resistance associated substitutions (RASs) in HCV genotype 1 (GT1) patients naïve to direct acting HCV antivirals. METHODS: Amplification, Sanger sequencing and phylogenetic analysis of the HCV NS5A region were performed on plasma obtained from 122 consecutive patients with HCV chronic infection attending four different clinics in Italy...

Hepatocyte growth factor (HGF)/MET signaling is implicated in the development of colorectal cancer (CRC) and possesses therapeutic value for various types of cancer. However, inhibition of MET alone has been demonstrated to have limited efficacy. The present study examined the combined inhibition of MET and SRC kinase activity in colon cancer cells. Furthermore, the role of the HGF/MET pathway in ligand-dependent and -independent activation was demonstrated. The single inhibition of MET by knockdown small interfering RNA or inhibitor indicated a limited anti-viability effects without inhibiting the basal phosphorylation levels of SRC, protein kinase B (AKT) or extracellular signal-regulated kinase (ERK)...

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations...

BACKGROUND: The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). MATERIAL AND METHODS: A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy...