New opportunities for kinase drug repurposing and target discovery.

Br J Cancer. 2018 Mar 16;:

Authors: Knapp S

Abstract
Protein kinases are major drug targets for oncology. The large size of the kinome, active site conservation and the influence of activation states on drug binding complicates the analysis of their cellular mode of action. In a recent article in Science, Klaeger et al. analysed cellular targets of 243 drug candidates providing a large repository of data for drug repurposing.

PMID: 29545596 [PubMed - as supplied by publisher]

Therapeutic Effect of Quinacrine, an Anti-protozoan Drug, by Selective Suppression of p-CHK1/2 in p53-negative Malignant Cancers.

Mol Cancer Res. 2018 Mar 15;:

Authors: Park S, Oh AY, Cho JH, Yoon MH, Woo TG, Kang S, Lee HY, Jung Y, Park BJ

Abstract
Quinacrine (QNC), anti-protozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest anti-tumor effects of QNC through suppression of NF-κB and activation of p53. This study, demonstrates the anti-cancer effect of QNC via a novel pathway through the elimination of check point kinase 1/2 (Chk1/2) under p53 inactivated conditions. Inhibition of p53, by PFT-α or siRNA, promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 by QNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G2/M phase. QNC increases the binding between p-Chk1/2 and β-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed anti-tumor effects in a Villin-Cre;p53+/LSL-R172H intestinal cancer mouse model system as well as HCT116 p53-/- xenografts.
IMPLICATIONS: Quinacrine has been used for the past over 70 years without obvious side-effects, as such it is a plausible drug candidate for relapsed cancers, small-cell lung cancer, breast cancer as well as various p53-inactivated human malignancies.

PMID: 29545477 [PubMed - as supplied by publisher]

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CYP2D6 Pharmacogenetics Testing and Post-Cesarean Section Pain Scores-a Preliminary Study.

Pain Med. 2018 Mar 12;:

Authors: Ribeiro C, Quinta R, Raposo A, Valentim A, Albuquerque J, Grazina M

Abstract
Objective: Prospective observational study to analyze CYP2D6 pharmacogenetics in 55 Portuguese adult parturients undergoing elective cesarean section and to investigate the association between CYP2D6 alleles and pain score.
Methods: DNA was extracted from peripheral blood by standard methods. Genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number determination with TaqMan probes by real-time polymerase chain reaction (PCR). Allele duplications were confirmed (long PCR and PCR-restriction fragment length polymorphism). Theoretical metabolic profiles prediction was based on genetic data and activity scores. Association was investigated between genotypes and predicted phenotypes with pain scores. Statistical analysis was performed by using a χ2 test, and significance was set at P < 0.05.
Results: The percentage of poor, intermediate, extensive, and ultrarapid metabolizers found were 9%, 38%, 46%, and 7%, respectively. The results reveal a positive association between alleles *4, *10, and pain.
Conclusions: A positive association was found between predicted reduced or null activity of CYP2D6 and increased pain. It can be hypothesized that if CYP2D6 activity is reduced, tyramine metabolism will decrease, resulting in reduced formation of endogenous dopamine. Consequently, activation of the signal transduction pathways that controls pain and analgesic effect may be reduced, leading to an increase in pain. Therefore, we would recommend CYP2D6 genotyping to anticipate the needs for analgesia, which will help to adjust opioid dose and maximize clinical efficacy while reducing side effects.

PMID: 29546421 [PubMed - as supplied by publisher]

Association between HLA-B Alleles and Carbamazepine-Induced Maculopapular Exanthema and Severe Cutaneous Reactions in Thai Patients.

J Immunol Res. 2018;2018:2780272

Authors: Sukasem C, Chaichan C, Nakkrut T, Satapornpong P, Jaruthamsophon K, Jantararoungtong T, Koomdee N, Sririttha S, Medhasi S, Oo-Puthinan S, Rerkpattanapipat T, Klaewsongkram J, Rerknimitr P, Tuchinda P, Chularojanamontri L, Tovanabutra N, Puangpetch A, Aekplakorn W

Abstract
The HLA-B∗15:02 allele has been reported to have a strong association with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Thai patients. The HLA-B alleles associated with carbamazepine-induced maculopapular exanthema (MPE) and the drug reaction with eosinophilia and systemic symptoms (DRESS) among the Thai population have never been reported. The aim of the present study was to carry out an analysis of the involvement of HLA-B alleles in carbamazepine-induced cutaneous adverse drug reactions (cADRs) in the Thai population. A case-control study was performed by genotyping the HLA-B alleles of Thai carbamazepine-induced hypersensitivity reaction patients (17 MPE, 16 SJS/TEN, and 5 DRESS) and 271 carbamazepine-tolerant controls. We also recruited 470 healthy Thai candidate subjects who had not taken carbamazepine. HLA-B∗15:02 showed a significant association with carbamazepine-induced MPE (P = 0.0022, odds ratio (OR) (95% confidence interval [CI]) = 7.27 (2.04-25.97)) and carbamazepine-induced SJS/TEN (P = 4.46 × 10-13; OR (95% CI) = 70.91(19.67-255.65)) when compared with carbamazepine-tolerant controls. Carbamazepine-induced SJS/TEN also showed an association with HLA-B∗15:21 allele (P = 0.013; OR (95% CI) = 9.54 (1.61-56.57)) when compared with carbamazepine-tolerant controls. HLA-B∗58:01 allele was significantly related to carbamazepine-induced MPE (P = 0.007; OR (95% CI) = 4.73 (1.53-14.66)) and DRESS (P = 0.0315; OR (95% CI) = 7.55 (1.20-47.58)) when compared with carbamazepine-tolerant controls. These alleles may serve as markers to predict carbamazepine-induced cADRs in the Thai population.

PMID: 29546073 [PubMed - in process]

Porokeratotic eccrine and hair follicle nevus: a report of two cases and review of the literature.

An Bras Dermatol. 2017;92(5 Suppl 1):121-125

Authors: Agulló-Pérez AD, Resano-Abarzuza MÁ, Córdoba-Iturriagagoitia A, Yanguas-Bayona JI

Abstract
Porokeratotic eccrine and hair follicle nevus is a very rare non-hereditary disorder of keratinization with eccrine and hair follicle involvement with only 9 cases described in the literature. In 2009 the term porokeratotic anexial ostial nevus was proposed to comprehend porokeratotic eccrine and hair follicle nevus and a related and more common process without follicular involvement: porokeratotic eccrine ostial and dermal duct nevus Recent findings suggest that both entities may be produced by a mutation in GJB2 gene, which is associated to KID syndrome. Herein we report 2 cases of porokeratotic eccrine and hair follicle nevus and review the existing cases in the Spanish and English literature.

PMID: 29267468 [PubMed - indexed for MEDLINE]

Osteoma cutis: rare painful tumor in atypical location.

An Bras Dermatol. 2017;92(5 Suppl 1):113-114

Authors: Sánchez MEG, Martínez MLM, Mena JLA, Martín LIO

Abstract
Osteoma cutis or cutaneous ossification is a rare entity characterized by the formation of bone in the skin. We present an isolated primary osteoma cutis located on the palm, an atypical location.

PMID: 29267465 [PubMed - indexed for MEDLINE]

Lymphocytoma cutis on the inguinal region: report of a rare case of benign lymphoproliferative disorder.

An Bras Dermatol. 2017;92(5 Suppl 1):98-100

Authors: Rosa WSC, Girão RJS, Carvalho IMS, Vargas LMML

Abstract
Lymphocytoma cutis, or benign reactive lymphoid hyperplasia, is an inflammatory skin lesion that mimics clinically and histologically malignant lymphoma. Most cases are idiopathic, but they may also be triggered by multiple factors, such as insect bites, tattoos, injections and herpes zoster. Clinically, the lesions are erythematous, soft papules, plaques or nodules, usually located on the upper limbs and face. The diagnosis is mainly based on histopathology and immunohistochemistry. Corticosteroid injections, cryosurgery, PUVA therapy, radiotherapy and surgery can be therapeutic options in cases requiring immediate treatment. To demonstrate an atypical presentation of this tumor, a case lymphocytoma skin on the groin will be reported, describing its diagnosis and treatment.

PMID: 29267460 [PubMed - indexed for MEDLINE]

Uncommon Cranial Meningioma: Key Imaging Features on Conventional and Advanced Imaging.

Clin Neuroradiol. 2017 Jun;27(2):135-144

Authors: Zakhari N, Torres C, Castillo M, Nguyen TB

Abstract
Given the high incidence of intracranial meningiomas encountered in clinical practice, it is not uncommon to find rare subtypes of meningioma, with unusual imaging findings. These commonly represent a diagnostic challenge. In this article, we review the imaging appearance of typical meningioma on conventional and advanced imaging as well as the key imaging features of multiple uncommon subtypes: cystic, microcystic, lipomatous, chordoid, angiomatous, intraosseous, extracranial, atypical/malignant, and tumor-to-tumor metastasis (also known as collision tumors). Some of these uncommon subtypes, however, demonstrate imaging features that may allow for a more specific diagnosis, or features, which can influence patient's management.

PMID: 28466126 [PubMed - indexed for MEDLINE]

Transepithelial Fluid and Salt Re-Absorption Regulated by cGK2 Signals.

Int J Mol Sci. 2018 Mar 16;19(3):

Authors: Chang J, Ding Y, Zhou Z, Nie HG, Ji HL

Abstract
Transepithelial fluid and salt re-absorption in epithelial tissues play an important role in fluid and salt homeostasis. In absorptive epithelium, fluid and salt flux is controlled by machinery mainly composed of epithelial sodium channels (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR), Na⁺/H⁺ exchanger (NHE), aquaporin, and sodium potassium adenosine triphosphatase (Na⁺/K⁺-ATPase). Dysregulation of fluid and salt transport across epithelium contributes to the pathogenesis of many diseases, such as pulmonary edema and cystic fibrosis. Intracellular and extracellular signals, i.e., hormones and protein kinases, regulate fluid and salt turnover and resolution. Increasing evidence demonstrates that transepithelial fluid transport is regulated by cyclic guanosine monophosphate-dependent protein kinase (cGK) signals. cGK2 was originally identified and cloned from intestinal specimens, the presence of which has also been confirmed in the kidney and the lung. cGK2 regulates fluid and salt through ENaC, CFTR and NHE. Deficient cGK2 regulation of transepithelial ion transport was seen in acute lung injury, and cGK2 could be a novel druggable target to restore edematous disorder in epithelial tissues.

PMID: 29547542 [PubMed - in process]

Prediction of Mortality in Adolescents with Cystic Fibrosis-Corrigendum.

Med Sci Sports Exerc. 2018 Apr;50(4):880

Authors:

PMID: 29547500 [PubMed - in process]

Involvement Of TLR4 and PPAR-α Receptors in Host Response and NLRP3 Inflammosome Activation, Against Pulmonary Infection with Pseudomosas Aeruginosa.

Shock. 2018 Mar 15;:

Authors: Gugliandolo E, Fusco R, Ginestra G, D'amico R, Bisignano C, Mandalari G, Cuzzocrea S, Di Paola R

Abstract
BACKGROUND: Colonization with Pseudomonas aeruginosa (PA), the most common pathogen isolated mainly in patients with cystic fibrosis, is particularly difficult to eradicate and is associated with acceleration of decline in lung function and with poorer prognosis. PA LPS is recognized by toll like receptors 4 (TLR4) and has been shown to induce lung inflammation in vivo. In addition, regulation of this process is essential for proper pathogen clearance and to prevent excessive inflammatory response resulting in tissue damage. One potential regulator of these process are the peroxisome proliferator-activated receptors (PPARs), and in particular PPARα Thus, the purpose of the present study was to evaluate the the effects of the absence of TLR4 and PPARα receptors in the pulmonary innate immunity response to PA and in the consequent inflammatory response and in the activation of the macromolecular complex of the NLRP3 inflamosome.
METHODS: To evaluate the involvement of TLR4 and PPARα in a PA infection, we used TLR4 KO and PPARα KO mice who received an intratracheal (i.t.) administration of 50 μl of PA strain (106 CFU), thus evaluating if these mice were profoundly susceptible to PA compared to WT mice.
RESULTS: The results of the present study showed that administration of PA worsened the pathophysiology of PA lung disease in TLR4 and PPARα KO mice compared to WT.
CONCLUSIONS: The present study demonstrated that TLR4 and PPARα receptors would mediate the earliest control of bacterial replication as well as proinflammatory responses to PA infections, and in particular that PPARα receptors are needed to prevent an excessive inflammatory response, as in the control of the inflammosome complex NLP3 activation.

PMID: 29547450 [PubMed - as supplied by publisher]

[Anaerobic bacteria, the unknown members of the lung microbiota].

Med Sci (Paris). 2018 Mar;34(3):253-260

Authors: Guilloux CA, Lamoureux C, Héry-Arnaud G

Abstract
Lungs were considered as sterile for a long time. However, it is now evident that the lungs of healthy people are colonized by microorganisms. Among the bacteria present in the pulmonary microbiota, a significant proportion is anaerobic (strict or facultative). Even though interest in the pulmonary microbiota is increasing, few studies have focused on these unknowns that represent the lung resident anaerobic bacteria. This review describes the biodiversity of anaerobes in physiological conditions, and in different chronic respiratory diseases (cystic fibrosis, COPD, asthma). It also explains anaerobes' roles in the barrier flora effect, in inflammation, or as potential biomarkers in disease progression.

PMID: 29547112 [PubMed - in process]

Transmission and lineage displacement drive rapid population genomic flux in cystic fibrosis airway infections of a Pseudomonas aeruginosa epidemic strain.

Microb Genom. 2018 Mar 16;:

Authors: Williams D, Fothergill JL, Evans B, Caples J, Haldenby S, Walshaw MJ, Brockhurst MA, Winstanley C, Paterson S

Abstract
Pseudomonas aeruginosa chronic infections of cystic fibrosis (CF) airways are a paradigm for within-host evolution with abundant evidence for rapid evolutionary adaptation and diversification. Recently emerged transmissible strains have spread globally, with the Liverpool Epidemic Strain (LES) the most common strain infecting the UK CF population. Previously we have shown that highly divergent lineages of LES can be found within a single infection, consistent with super-infection among a cross-sectional cohort of patients. However, despite its clinical importance, little is known about the impact of transmission on the genetic structure of these infections over time. To characterize this, we longitudinally sampled a meta-population of 15 genetic lineages within the LES over 13 months among seven chronically infected CF patients by genome sequencing. Comparative genome analyses of P. aeruginosa populations revealed that the presence of coexisting lineages contributed more to genetic diversity within an infection than diversification in situ. We observed rapid and substantial shifts in the relative abundance of lineages and replacement of dominant lineages, likely to represent super-infection by repeated transmissions. Lineage dynamics within patients led to rapid changes in the frequencies of mutations across suites of linked loci carried by each lineage. Many loci were associated with important infection phenotypes such as antibiotic resistance, mucoidy and quorum sensing, and were repeatedly mutated in different lineages. These findings suggest that transmission leads to rapid shifts in the genetic structure of CF infections, including in clinically important phenotypes such as antimicrobial resistance, and is likely to impede accurate diagnosis and treatment.

PMID: 29547097 [PubMed - as supplied by publisher]

Unexpected diversity in the mobilome of a Pseudomonas aeruginosa strain isolated from a dental unit waterline revealed by SMRT Sequencing.

Genome. 2018 Mar 16;:

Authors: Vincent AT, Charette SJ, Barbeau J

Abstract
The Gram-negative bacterium Pseudomonas aeruginosa is found in several habitats, both natural and human-made, and is particularly known for its recurrent presence as a pathogen in the lungs of patients suffering from cystic fibrosis, a genetic disease. Given its clinical importance, several major studies have investigated the genomic adaptation of P. aeruginosa in lungs and its transition as acute infections become chronic. However, our knowledge about the diversity and adaptation of the P. aeruginosa genome to non-clinical environments is still fragmentary, in part due to the lack of accurate reference genomes of strains from the numerous environments colonized by the bacterium. Here, we used PacBio long-read technology to sequence the genome of PPF-1, a strain of P. aeruginosa isolated from a dental unit waterline. Generating this closed genome was an opportunity to investigate genomic features that are difficult to accurately study in a draft genome (contigs state). It was possible to shed light on putative genomic islands, some shared with other reference genomes, new prophages, and the complete content of insertion sequences. In addition, four different group II introns were also found, including two characterized here and not listed in the specialized group II intron database.

PMID: 29546998 [PubMed - as supplied by publisher]

[Rectal prolapse as an unusual presentation of celiac disease. Report of two cases].

Rev Chil Pediatr. 2017 Dec;88(6):798-802

Authors: Errázuriz G

Abstract
INTRODUCTION: Rectal prolapse (RP) is related to an increase of intra-abdominal pressure, pelvic floor disease or anal sphincter. The most common causes of RP are constipation, cystic fibrosis, whooping cough and dysenteric diarrhea. However, celiac disease is not considered among the pathologies re lated to RP.
OBJECTIVE: To present a scarcely described association between RP and celiac disease.
CLINICAL CASES: We presented 2 preschoolers in whom the reason for consultation was RP, whose study was focused on as prolonged diarrhea, due to the antecedent of pasty consistency of stools. The tests showed elevated anti-tissue transglutaminase (anti-tTG) antibody titers, and duodenal biopsies with villous atrophy and increased intraepithelial lymphocytes, consistent with celiac disease. Both had an excellent response to the gluten-free diet, with rapid normalization of depositions, without presenting any episodes of RP after treatment. Both with normal staturo-ponderal development and anti-tTG-negative controls at the annual 5-year follow-up.
CONCLUSIONS: Although the association between RP and celiac disease has not been described yet, it should be considered in diagnosis and treatment.

PMID: 29546932 [PubMed - in process]

Folate supplementation in people with sickle cell disease.

Cochrane Database Syst Rev. 2018 Mar 16;3:CD011130

Authors: Dixit R, Nettem S, Madan SS, Soe HHK, Abas AB, Vance LD, Stover PJ

Abstract
BACKGROUND: Sickle cell disease (SCD) is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with SCD, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with SCD, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating SCD.
OBJECTIVES: To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with SCD.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 17 November 2017.
SELECTION CRITERIA: Randomised, placebo-controlled trials of folate supplementation for SCD.
DATA COLLECTION AND ANALYSIS: Four review authors assessed We used the standard Cochrane-defined methodological procedures.Four review authors independently assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. The quality of the evidence was assessed using GRADE.
MAIN RESULTS: One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with SCD. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children).Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/L and values below 5 µg/L (low-quality evidence). In the folic acid group, values above 18 µg/L were observed in 33 of 41 (81%) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/L, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year (low-quality evidence). It is important to note that none of the raw data for the outcomes listed above were available for analysis.The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio (RR) 0.99 (95% confidence interval (CI) 0.85 to 1.15) (low-quality evidence); major infections, RR 0.89 (95% CI 0.47 to 1.66) (low-quality evidence); dactylitis, RR 0.67 (95% CI 0.35 to 1.27) (low-quality evidence); acute splenic sequestration, RR 1.07 (95% CI 0.44 to 2.57) (low-quality evidence); or episodes of pain, RR 1.16 (95% CI 0.70 to 1.92) (low-quality evidence). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05).Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups.The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low.There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet).
AUTHORS' CONCLUSIONS: One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with SCD was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear.If further trials were conducted, these may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to SCD-related morbidity. Such trials should include people with SCD of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow-up, than the trial currently included in this review. However, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

PMID: 29546732 [PubMed - as supplied by publisher]

Increased intracellular Cl- concentration promotes ongoing inflammation in airway epithelium.

Mucosal Immunol. 2018 Mar 15;:

Authors: Zhang YL, Chen PX, Guan WJ, Guo HM, Qiu ZE, Xu JW, Luo YL, Lan CF, Xu JB, Hao Y, Tan YX, Ye KN, Lun ZR, Zhao L, Zhu YX, Huang J, Ko WH, Zhong WD, Zhou WL, Zhong NS

Abstract
Airway epithelial cells harbor the capacity of active Cl- transepithelial transport and play critical roles in modulating innate immunity. However, whether intracellular Cl- accumulation contributes to relentless airway inflammation remains largely unclear. This study showed that, in airway epithelial cells, intracellular Cl- concentration ([Cl-]i) was increased after Pseudomonas aeruginosa lipopolysaccharide (LPS) stimulation via nuclear factor-κB (NF-κB)-phosphodiesterase 4D (PDE4D)-cAMP signaling pathways. Clamping [Cl-]i at high levels or prolonged treatment with LPS augmented serum- and glucocorticoid-inducible protein kinase 1 (SGK1) phosphorylation and subsequently triggered NF-κB activation in airway epithelial cells, whereas inhibition of SGK1 abrogated airway inflammation in vitro and in vivo. Furthermore, Cl--SGK1 signaling pathway was pronouncedly activated in patients with bronchiectasis, a chronic airway inflammatory disease. Conversely, hydrogen sulfide (H2S), a sulfhydryl-containing gasotransmitter, confers anti-inflammatory effects through decreasing [Cl-]i via activation of cystic fibrosis transmembrane conductance regulator (CFTR). Our study confirms that intracellular Cl- is a crucial mediator of sustained airway inflammation. Medications that abrogate excessively increased intracellular Cl- may offer novel targets for the management of airway inflammatory diseases.

PMID: 29545647 [PubMed - as supplied by publisher]

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.

Eur Respir J. 2018 Mar 15;:

Authors: Dittrich AS, Kühbandner I, Gehrig S, Rickert-Zacharias V, Twigg M, Wege S, Taggart CC, Herth F, Schultz C, Mall MA

Abstract
Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We, therefore, determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and 8 healthy controls using novel lipidated Foerster resonance energy transfer (FRET) reporters and correlated with free NE activity, neutrophil counts, IL-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with FEV1% predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with FRCpleth% predicted (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

PMID: 29545279 [PubMed - as supplied by publisher]

Comparison of ex vivo and in vitro intestinal cystic fibrosis models to measure CFTR-dependent ion channel activity.

J Cyst Fibros. 2018 Mar 13;:

Authors: Zomer-van Ommen DD, de Poel E, Kruisselbrink E, Oppelaar H, Vonk AM, Janssens HM, van der Ent CK, Hagemeijer MC, Beekman JM

Abstract
BACKGROUND: New functional assays using primary human intestinal adult stem cell cultures can be valuable tools to study epithelial defects in human diseases such as cystic fibrosis.
METHODS: CFTR-mediated ion transport was measured in rectal organoid-derived monolayers grown from subjects with various CFTR mutations and compared to donor-matched intestinal current measurements (ICM) in rectal biopsies and forskolin-induced swelling of rectal organoids.
RESULTS: Rectal organoid-derived monolayers were generated within four days. Ion transport measurements of CFTR function using these monolayers correlated with ICM and organoid swelling (r = 0.73 and 0.79 respectively). Culturing the monolayers under differentiation conditions enhanced the detection of mucus-secreting cells and was accompanied by reduced CFTR function.
CONCLUSIONS: CFTR-dependent intestinal epithelial ion transport properties can be measured in rectal organoid-derived monolayers of subjects and correlate with donor-matched ICM and rectal organoid swelling.

PMID: 29544685 [PubMed - as supplied by publisher]