Observability of plant metabolic networks is reflected in the correlation of metabolic profiles.

Plant Physiol. 2016 Aug 26;

Authors: Schwahn K, Küken A, Kliebenstein DJ, Fernie AR, Nikoloski Z

Abstract
Understanding whether the functionality of a biological system can be characterized by measuring few selected components is key to targeted phenotyping techniques in systems biology. Methods from observability theory have proven useful in identifying sensor components that have to be measured to obtain information about the entire system. Yet, the extent to which the data profiles reflect the role of components in the observability of the system remains unexplored. Here we first identify the sensor metabolites in the model plant Arabidopsis thaliana by employing state-of-the-art genome-scale metabolic networks. By using metabolic data profiles from a set of seven environmental perturbations as well as from natural variability, we demonstrate that the data profiles of sensor metabolites are more correlated than those of non-sensor metabolites. This pattern was confirmed with in silico generated metabolic profiles from a medium-size kinetic model of plant central carbon metabolism. Altogether, due to the small number of identified sensors, our study implies that targeted metabolite analyses may provide the vast majority of relevant information about plant metabolic systems.

PMID: 27566166 [PubMed - as supplied by publisher]

Can a systems approach produce a better understanding of mood disorders?

Biochim Biophys Acta. 2016 Aug 24;

Authors: Plant N

Abstract
BACKGROUND: One in twenty-five people suffer from a mood disorder. Current treatments are sub-optimal with poor patient response and uncertain modes-of-action. There is thus a need to better understand underlying mechanisms that determine mood, and how these goes wrong in affective disorders. Systems biology approaches have yielded important biological discoveries for other complex diseases such as cancer, and their potential in affective disorders will be reviewed.
SCOPE OF REVIEW: This review will provide a general background to affective disorders, plus an outline of experimental and computational systems biology. The current application of these approaches in understanding affective disorders will be considered, and future recommendations made.
MAJOR CONCLUSIONS: Experimental systems biology has been applied to the study of affective disorders, especially at the genome and transcriptomic levels. However, data generation has been slowed by a lack of human tissue or suitable animal models. At present, computational systems biology has only be applied to understanding affective disorders on a few occasions. These studies provide sufficient novel biological insight to motivate further use of computational biology in this field.
GENERAL SIGNIFICANCE: In common with many complex diseases much time and money has been spent on the generation of large-scale experimental datasets. The next step is to use the emerging computational approaches, predominantly developed in the field of oncology, to leverage the most biological insight from these datasets. This will lead to the critical breakthroughs required for more effective diagnosis, stratification and treatment of affective disorders.

PMID: 27565355 [PubMed - as supplied by publisher]

Challenges in Measuring Cost and Value in Oncology: Making It Personal.

Value Health. 2016 Jul-Aug;19(5):520-4

Authors: Yu PP

Abstract
Oncology patients often find themselves facing an incurable disease with limited treatment options and increasing patient fragility. The importance of patient preferences and values increases in shared decision making especially when the cost of cancer care is continuing its steep rise. As our understanding of cancer systems biology increases, we are justifiably optimistic about therapeutic improvements but recognize that this has complicated the traditional Food and Drug Administration approval of drug indications based on organ-specific cancer for a particular drug. Dynamic and agile clinical guidelines that reflect a rapidly changing knowledge base for decision-making support are needed. The American Society of Clinical Oncology (ASCO) has been working on three initiatives to tackle these complex issues. The first initiative is ASCO's collaboration with other international organizations to create a framework to assess drugs for the World Health Organization's Essential Medicines List, including nongenerics. The second initiative aims to define clinically meaningful outcomes as precision medicine expands the definition of cancers, leading to increased demand for the use of targeted drugs as single agents or in combination. The third initiative is ASCO's value framework, published in 2015, focusing on patient-physician shared decision making. The framework incorporates three parameters: 1) the meaningfulness of the clinical benefit, 2) the toxicity of the treatment, and 3) the patient's financial out-of-pocket cost. ASCO is concerned about the rising cost of cancer care when the clinical complexity and the pace of change in oncology are accelerating, and it is committed to help improve patient outcomes and value in cancer care as well as to engage the broader health care community in a process of collaborative improvement.

PMID: 27565267 [PubMed - in process]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/08/27

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis.

Sci Rep. 2016;6:32083

Authors: Thomas SM, Purmal A, Pollastri M, Mensa-Wilmot K

Abstract
The protozoan parasite Trypanosoma brucei causes the fatal illness human African trypanosomiasis (HAT). Standard of care medications currently used to treat HAT have severe limitations, and there is a need to find new chemical entities that are active against infections of T. brucei. Following a "drug repurposing" approach, we tested anti-trypanosomal effects of carbazole-derived compounds called "Curaxins". In vitro screening of 26 compounds revealed 22 with nanomolar potency against axenically cultured bloodstream trypanosomes. In a murine model of HAT, oral administration of compound 1 cured the disease. These studies established 1 as a lead for development of drugs against HAT. Pharmacological time-course studies revealed the primary effect of 1 to be concurrent inhibition of mitosis coupled with aberrant licensing of S-phase entry. Consequently, polyploid trypanosomes containing 8C equivalent of DNA per nucleus and three or four kinetoplasts were produced. These effects of 1 on the trypanosome are reminiscent of "mitotic slippage" or endoreplication observed in some other eukaryotes.

PMID: 27561392 [PubMed - in process]

A Genome-wide Approach Validates that Thiopurine Methyltransferase Activity is a Monogenic Pharmacogenomic Trait.

Clin Pharmacol Ther. 2016 Aug 26;

Authors: Liu C, Yang W, Pei D, Cheng C, Smith C, Landier W, Hageman L, Chen Y, Yang JJ, Crews KR, Kornegay N, Karol SE, Wong FL, Jeha S, Sandlund JT, Ribeiro RR, Rubnitz JE, Metzger ML, Pui CH, Evans WE, Bhatia S, Relling MV

Abstract
We performed a genome-wide association study of primary erythrocyte TPMT activity in children with leukemia (n = 1026). Adjusting for age and ancestry, TPMT was the only gene that reached genome-wide significance (top hit rs1142345 or 719A>G, P = 8.6 × 10(-61) ). Additional genetic variants (besides the 3 SNPs rs1800462, rs1800460 and rs1142345 defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10(-11) ). Using 177 lymphoblastoid cell lines (LCLs), there were 251251 SNPs ranked higher than the top TPMT SNP (rs1142345 P = 6.8 × 10(-5) ), showing the limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic. This article is protected by copyright. All rights reserved.

PMID: 27564568 [PubMed - as supplied by publisher]

Overall energy conversion efficiency of a photosynthetic vesicle.

Elife. 2016;5

Authors: Sener M, Strumpfer J, Singharoy A, Hunter CN, Schulten K

Abstract
The chromatophore of purple bacteria is an intracellular spherical vesicle that exists in numerous copies in the cell and that efficiently converts sunlight into ATP synthesis, operating typically under low light conditions. Building on an atomic-level structural model of a low-light-adapted chromatophore vesicle from Rhodobacter sphaeroides, we investigate the cooperation between more than a hundred protein complexes in the vesicle. The steady-state ATP production rate as a function of incident light intensity is determined after identifying quinol turnover at the cytochrome bc1 complex (cytb⁢c1) as rate limiting and assuming that the quinone/quinol pool of about 900 molecules acts in a quasi-stationary state. For an illumination condition equivalent to 1% of full sunlight, the vesicle exhibits an ATP production rate of 82 ATP molecules/s. The energy conversion efficiency of ATP synthesis at illuminations corresponding to 1%-5% of full sunlight is calculated to be 0.12-0.04, respectively. The vesicle stoichiometry, evolutionarily adapted to the low light intensities in the habitat of purple bacteria, is suboptimal for steady-state ATP turnover for the benefit of protection against over-illumination.

PMID: 27564854 [PubMed - as supplied by publisher]

Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes: SIRT1 and its Gene Network in Impaired Insulin Secretion.

Rev Diabet Stud. 2016;13(1):17-34

Authors: Ali S, Nafis S, Kalaiarasan P, Rai E, Sharma S, Bamezai RN

Abstract
Type 2 diabetes (T2D) is a chronic metabolic disease which shows an exponential increase in all parts of the world. However, the disease is controllable by early detection and modified lifestyle. A series of factors have been associated with the pathogenesis of diabetes, and genes are considered to play a critical role. The individual risk of developing T2D is determined by an altered genetic background of the en-zymes involved in several metabolism-related biological mechanisms, including glucose homeostasis, insulin metab-olism, the glucose and ion transporters involved in glucose uptake, transcription factors, signaling intermediates of insulin signaling pathways, insulin production and secretion, pancreatic tissue development, and apoptosis. However, many candidate genes have shown heterogeneity of associations with the disease in different populations. A possible approach to resolving this complexity and under-standing genetic heterogeneity is to delineate the physiological phenotypes one by one as studying them in combination may cause discrepancies in association studies. A systems biology approach involving regulatory proteins, transcription factors, and microRNAs is one way to understand and identify key factors in complex diseases such as T2D. Our earlier studies have screened more than 100 single nucleotide polymorphisms (SNPs) belonging to more than 60 globally known T2D candidate genes in the Indian population. We observed that genes invariably involved in the activity of pancreatic β-cells provide susceptibility to type 2 diabetes (T2D). Encouraged by these results, we attempted to delineate in this review one of the commonest physiological phenotypes in T2D, namely impaired insulin secretion, as the cause of hyperglycemia. This review is also intended to explain the genetic basis of the pathophysiology of insulin secretion in the context of variations in the SIRT1 gene, a major switch that modulates insulin secretion, and a set of other genes such as HHEX, PGC-α, TCF7L2, UCP2, and ND3 which were found to be in association with T2D. The review aims to look at the genotypic and transcriptional regulatory relationships with the disease phenotype.

PMID: 27563694 [PubMed - in process]

Symptoms and medical conditions in 204 912 patients visiting primary health-care practitioners in India: a 1-day point prevalence study (the POSEIDON study).

Lancet Glob Health. 2015 Dec;3(12):e776-84

Authors: Salvi S, Apte K, Madas S, Barne M, Chhowala S, Sethi T, Aggarwal K, Agrawal A, Gogtay J

Abstract
BACKGROUND: India has one of the highest disease burdens in the world. A better understanding of what ails India will help policy makers plan appropriate health-care services and infrastructure development, design medical education curricula, and identify health research priorities that are relevant to the needs of the country. The POSEIDON study aimed to record the prevalence of symptoms and medical conditions for which patients visit a primary health-care practitioner in India.
METHODS: We randomly selected 12 000 general practitioners, general physicians, and paediatricians from 880 cities and towns and invited them to record demographic details, symptoms, and medical conditions for every patient they saw on Feb 1, 2011. A further 1225 practitioners volunteered to participate and their responses were included. We did simple descriptive analyses of prevalence rates and used χ(2) tests to study comorbid associations. Through application of systems biology methods, we visualised inter-relations between organ involvement of diseases and symptoms and deciphered how these associations change with age and gender.
FINDINGS: We included responses from 7400 health-care practitioners, which represented data for 204 912 patients, who presented with 554 146 reasons for visit. Fever (35·5%) was the most common presenting symptom. More than half of all patients presented with respiratory symptoms across all age groups and regions of India. Other common presentations were digestive system symptoms (25%), circulatory symptoms (12·5%), skin complaints (9%), and endocrine disorders (6·6%). Hypertension (14·52%), obstructive airways diseases (14·51%), and upper respiratory tract infections (12·9%) were the most common diagnoses reported. Of note was that 21·4% of all patients with hypertension reported by the primary health-care practitioners were younger than 40 years. Anaemia was the fourth most common disease reported by these health-care practitioners and was most common in women of menstrual age living outside metro cities.
INTERPRETATION: The POSEIDON study provides insight into the reasons that patients visit primary health-care practitioners in India; our results highlight important social and medical challenges in the developing world.
FUNDING: Chest Research Foundation, Council of Scientific and Industrial Research-Institute of Genomics and Integrated Biology (CSIR-IGIB), and Cipla Ltd.

PMID: 26566749 [PubMed - indexed for MEDLINE]

A systems biology approach to detect key pathways and interaction networks in gastric cancer on the basis of microarray analysis.

Mol Med Rep. 2015 Nov;12(5):7139-45

Authors: Guo L, Song C, Wang P, Dai L, Zhang J, Wang K

Abstract
The aim of the present study was to explore key molecular pathways contributing to gastric cancer (GC) and to construct an interaction network between significant pathways and potential biomarkers. Publicly available gene expression profiles of GSE29272 for GC, and data for the corresponding normal tissue, were downloaded from Gene Expression Omnibus. Pre‑processing and differential analysis were performed with R statistical software packages, and a number of differentially expressed genes (DEGs) were obtained. A functional enrichment analysis was performed for all the DEGs with a BiNGO plug‑in in Cytoscape. Their correlation was analyzed in order to construct a network. The modularity analysis and pathway identification operations were used to identify graph clusters and associated pathways. The underlying molecular mechanisms involving these DEGs were also assessed by data mining. A total of 249 DEGs, which were markedly upregulated and downregulated, were identified. The extracellular region contained the most significantly over‑represented functional terms, with respect to upregulated and downregulated genes, and the closest topological matches were identified for taste transduction and regulation of autophagy. In addition, extracellular matrix‑receptor interactions were identified as the most relevant pathway associated with the progression of GC. The genes for fibronectin 1, secreted phosphoprotein 1, collagen type 4 variant α‑1/2 and thrombospondin 1, which are involved in the pathways, may be considered as potential therapeutic targets for GC. A series of associations between candidate genes and key pathways were also identified for GC, and their correlation may provide novel insights into the pathogenesis of GC.

PMID: 26324226 [PubMed - indexed for MEDLINE]

Delivery of Alpha-1 Antitrypsin to Airways.

Ann Am Thorac Soc. 2016 Aug;13(Supplement_4):S346-S351

Authors: Griese M, Scheuch G

Abstract
Treatment with exogenous alpha-1 antitrypsin (AAT), a potent serine protease inhibitor, was developed originally for chronic obstructive pulmonary disease associated with AAT deficiency; however, other lung conditions involving neutrophilic inflammation and proteolytic tissue injury related to neutrophil elastase and other serine proteases may also be considered for AAT therapy. These conditions include bronchiectasis caused by primary ciliary dyskinesia, cystic fibrosis, and other diseases associated with an increased free elastase activity in the airways. Inhaled AAT may be a viable option to counteract proteolytic tissue damage. This form of treatment requires efficient drug delivery to the targeted pulmonary compartment. Aerosol technology meeting this requirement is currently available and offers an alternative therapeutic approach to systemic AAT administration. To date, early studies in humans have shown biochemical efficacy and have established the safety of inhaled AAT. However, to bring aerosol AAT therapy to patients, large phase 3 protocols in carefully selected patient populations (i.e., subgroups of patients with AAT deficiency, cystic fibrosis, or other lung diseases with bronchiectasis) will be needed with clinical end points in addition to the measurement of proteolytic activity in the airway. The outcomes likely will have to include lung function, lung structure assessed by computed tomography imaging, disease exacerbations, health status, and mortality.

PMID: 27564672 [PubMed - as supplied by publisher]

The Advantages of Adding Hyaluronic Acid or Mannitol to Hypertonic Saline Inhalation Treatment in Cystic Fibrosis.

J Aerosol Med Pulm Drug Deliv. 2016 Aug 26;

Authors: Cazzarolli C, Tartali C, Pradal U

PMID: 27563742 [PubMed - as supplied by publisher]

Targeting the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein for the Treatment of Cystic Fibrosis.

ACS Med Chem Lett. 2016 Aug 11;7(8):725-7

Authors: Abdel-Magid AF

PMID: 27563392 [PubMed]

Characterization of Staphylococcus aureus isolates from pediatric patients with cystic fibrosis.

World J Microbiol Biotechnol. 2016 Oct;32(10):162

Authors: Liu Y, Zhang J, Zhong D, Ji L, Yang J, Phillips J, Ji Y

Abstract
Staphylococcus aureus is one of the major respiratory pathogens associated with cystic fibrosis (CF) patients. In this study, we collected sputum and isolated fifty S. aureus isolates from CF patients with the median age of 9.5 years old. Then we determined the profiles of these isolates by antibiotic susceptibility testing, examining their cytotoxicity and ability to internalize into an epithelial cell line (A549), as well as multiple loci sequencing typing. Predominant CF S. aureus isolates were resistant to penicillin; however, these isolates were sensitive to various antibiotics, such as vancomycin and minocycline. Different CF S. aureus isolates showed distinct cytotoxic activities, and 90 % of CF S. aureus isolates possessed the enterotoxin genes, sea and hlg. Moreover, we found that multiple different CF S. aureus isolates appeared to have the distinct capacity of invading A549 cells. ST5 (14 %), ST30 (14 %), and ST8 (10 %) were prevalent ST types in these isolates. Further analysis revealed that ST5 and ST30 isolates were less toxic than ST8 and ST15 isolates, and that the ST5, ST15, ST59, and ST87 types of CF S. aureus were less capable of invading A549 cells. Our results suggest that the ST typing method may be useful in predicting cytotoxicity and the invading capacity of S. aureus isolates from patients with CF.

PMID: 27562596 [PubMed - in process]

Nano-based rescue of dysfunctional autophagy in chronic obstructive lung diseases.

Expert Opin Drug Deliv. 2016 Aug 26;:1-7

Authors: Vij N

Abstract
INTRODUCTION: ΔF508-CFTR (cystic fibrosis transmembrane conductance regulator) is a common CF-mutation that is known to induce oxidative-inflammatory stress through activation of reactive oxygen species (ROS), which induces autophagy-impairment resulting in accumulation of CFTR in aggresome-bodies. Cysteamine, the reduced form of cystamine, is a FDA-approved drug that has anti-oxidant, anti-bacterial, and mucolytic properties. This drug has been shown in a recent clinical trial to decrease lung inflammation and improve lung function in CF patients by potentially restoring autophagy and allowing CFTR to be trafficked to the cell membrane.
AREAS COVERED: The delivery of cysteamine to airway epithelia of chronic subjects prerequisite the need for a delivery system to allow rescue of dysfunctional autophagy.
EXPERT OPINION: We anticipate based on our ongoing studies that PLGA-PEG- or Dendrimer-mediated cysteamine delivery could allow sustained airway delivery over standard cysteamine tablets or delay release capsules that are currently used for systemic treatment. In addition, proposed nano-based autophagy induction strategy can also allow rescue of cigarette smoke (CS) induced acquired-CFTR dysfunction seen in chronic obstructive pulmonary disease (COPD)-emphysema subjects. The CS induced acquired-CFTR dysfunction involves CFTR-accumulation in aggresome-bodies that can be rescued by an autophagy-inducing antioxidant drug, cysteamine. Moreover, chronic CS-exposure generates ROS that induces overall protein-misfolding and aggregation of ubiquitinated-proteins as aggresome-bodies via autophagy-impairment that can be also be resolved by treatment with autophagy-inducing antioxidant drug, cysteamine.

PMID: 27561233 [PubMed - as supplied by publisher]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/08/26

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Establishment of human epithelial enteroids and colonoids from whole tissue and biopsy.

J Vis Exp. 2015;(97)

Authors: Mahe MM, Sundaram N, Watson CL, Shroyer NF, Helmrath MA

Abstract
The epithelium of the gastrointestinal tract is constantly renewed as it turns over. This process is triggered by the proliferation of intestinal stem cells (ISCs) and progeny that progressively migrate and differentiate toward the tip of the villi. These processes, essential for gastrointestinal homeostasis, have been extensively studied using multiple approaches. Ex vivo technologies, especially primary cell cultures have proven to be promising for understanding intestinal epithelial functions. A long-term primary culture system for mouse intestinal crypts has been established to generate 3-dimensional epithelial organoids. These epithelial structures contain crypt- and villus-like domains reminiscent of normal gut epithelium. Commonly, termed "enteroids" when derived from small intestine and "colonoids" when derived from colon, they are different from organoids that also contain mesenchyme tissue. Additionally, these enteroids/colonoids continuously produce all cell types found normally within the intestinal epithelium. This in vitro organ-like culture system is rapidly becoming the new gold standard for investigation of intestinal stem cell biology and epithelial cell physiology. This technology has been recently transferred to the study of human gut. The establishment of human derived epithelial enteroids and colonoids from small intestine and colon has been possible through the utilization of specific culture media that allow their growth and maintenance over time. Here, we describe a method to establish a small intestinal and colon crypt-derived system from human whole tissue or biopsies. We emphasize the culture modalities that are essential for the successful growth and maintenance of human enteroids and colonoids.

PMID: 25866936 [PubMed - indexed for MEDLINE]

Microbiome in the pathogenesis of cystic fibrosis and lung transplant-related disease.

Transl Res. 2016 Aug 4;

Authors: Cribbs SK, Beck JM

Abstract
Significant advances in culture-independent methods have expanded our knowledge about the diversity of the lung microbial environment. Complex microorganisms and microbial communities can now be identified in the distal airways in a variety of respiratory diseases, including cystic fibrosis (CF) and the posttransplantation lung. Although there are significant methodologic concerns about sampling the lung microbiome, several studies have now shown that the microbiome of the lower respiratory tract is distinct from the upper airway. CF is a disease characterized by chronic airway infections that lead to significant morbidity and mortality. Traditional culture-dependent methods have identified a select group of pathogens that cause exacerbations in CF, but studies using bacterial 16S rRNA gene-based microarrays have shown that the CF microbiome is an intricate and dynamic bacterial ecosystem, which influences both host immune health and disease pathogenesis. These microbial communities can shift with external influences, including antibiotic exposure. In addition, there have been a number of studies suggesting a link between the gut microbiome and respiratory health in CF. Compared with CF, there is significantly less knowledge about the microbiome of the transplanted lung. Risk factors for bronchiolitis obliterans syndrome, one of the leading causes of death, include microbial infections. Lung transplant patients have a unique lung microbiome that is different than the pretransplanted microbiome and changes with time. Understanding the host-pathogen interactions in these diseases may suggest targeted therapies and improve long-term survival in these patients.

PMID: 27559681 [PubMed - as supplied by publisher]

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner.

Thorax. 2016 Aug 24;

Authors: Garcia-Arcos I, Geraghty P, Baumlin N, Campos M, Dabo AJ, Jundi B, Cummins N, Eden E, Grosche A, Salathe M, Foronjy R

Abstract
BACKGROUND: The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells.
METHODS: Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot.
RESULTS: Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion.
CONCLUSIONS: Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use.

PMID: 27558745 [PubMed - as supplied by publisher]

Chenodeoxycholic Acid Requires Activation of EGFR, EPAC and Ca2+ to Stimulate CFTR-dependent Cl- Secretion in Human Colonic T84 Cells.

Am J Physiol Cell Physiol. 2016 Aug 24;:ajpcell.00168.2016

Authors: Domingue JC, Ao M, Sarathy J, Rao MC

Abstract
Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl(-) secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (AJP 305:C447-56, 2013); however, PKA signaling did not account for the entire CDCA response. Here we show that in human colonic T84 cells, CDCA's induction of CFTR activity, measured as changes in short-circuit current (Isc), is dependent on epidermal growth factor receptor (EGFR) activation, and does not involve the bile acid receptors TGR5 or FXR. CDCA activation of Cl(-) secretion does not require Src, mitogen activated protein kinases, or phosphoinositide-3 kinase downstream of EGFR, but does require an increase in cytosolic Ca(2+) In addition to PKA signaling, we found that the CDCA response requires a novel involvement of the exchange protein directly activated by cAMP (EPAC). EPAC is a known hub for cAMP and Ca(2+) cross talk. Downstream of EPAC, CDCA activates Rap2, and changes in [Ca(2+)]i were dependent on both EPAC and EGFR activation. This study establishes the complexity of CDCA signaling in the colonic epithelium, and shows the contribution of EGFR, EPAC and Ca(2+) in CDCA-induced activation of CFTR-dependent Cl(-) secretion.

PMID: 27558159 [PubMed - as supplied by publisher]