In silico prediction and validation of potential therapeutic genes in pancreatic β-cells associated with type 2 diabetes.

Exp Ther Med. 2020 Nov;20(5):60

Authors: Zhou DY, Mou X, Liu K, Liu WH, Xu YQ, Zhou D

Abstract
Diabetes mellitus is becoming a major health burden worldwide. Pancreatic β-cell death is a characteristic of type 2 diabetes (T2D), but the underlying mechanisms of pancreatic β-cell death remain unknown. Therefore, the aim of the present study was to identify potential targets in the pancreatic islet of T2D. The GSE20966 dataset was obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by using the GEO2R tool. The Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analysis of DEGs were further assessed using the Database for Annotation, Visualization and Integrated Discovery. Furthermore, protein-protein interaction (PPI) networks were constructed for the up- and downregulated genes using STRING databases and were then visualized with Cytoscape. The body weight, fasting blood glucose (FBG), pancreatic index and biochemistry parameters were measured in db/db mice. Moreover, the morphology of the pancreas was detected by hematoxylin and eosin staining, and hub genes were assessed using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. In total, 570 DEGs were screened, including 376 upregulated and 194 downregulated genes, which were associated with 'complement activation, classical pathway', 'proteolysis', 'complement activation' and 'pancreatic secretion pathway'. It was found that the body weight, FBG, alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, blood urea nitrogen, creatinine, fasting serum insulin, glucagon and low-density lipoprotein cholesterol levels were significantly higher in db/db mice, while high-density lipoprotein cholesterol levels and the pancreatic index were significantly decreased. Furthermore, albumin, interleukin-8, CD44, C-C motif chemokine ligand 2, hepatocyte growth factor, cystic fibrosis transmembrane conductance regulator, histone cluster 1 H2B family member n, mitogen-activated protein kinase 11 and neurotrophic receptor tyrosine kinase 2 were identified as hub genes in PPI network. RT-qPCR and western blotting results demonstrated the same expression trend in hub genes as found by the bioinformatics analysis. Therefore, the present study identified a series of hub genes involved in the progression of pancreatic β-cell, which may help to develop effective therapeutic strategy for T2D.

PMID: 32952650 [PubMed]

Reliability of impulse oscillometry parameters in healthy children and in children with cystic fibrosis.

Int J Clin Pract. 2020 Sep 21;:e13715

Authors: Maba R, Assumpção M, Parazzi PLF, Ribeiro JD, Roesler H, Schivinski C

Abstract
Impulse oscillometry system (IOS) is an instrument developed to evaluate the mechanical lung properties. It has been reported that to analyze the exam in a proper way it is necessary to carry out more than one measure. However, studies addressing the standardization are still scarce. The objective was to determine within trial reliability of three measures in IOS parameters in healthy children and children with cystic fibrosis (CF). Weight, height, body mass index, forced spirometric and the oscillometric parameters (resistance, respiratory impedance, respiratory reactance, and resonance frequency) data were collected, in a way that all participants performed three IOS measures. To evaluate the reproducibility was used the intraclass correlation coefficient [two-way mixed model, absolute agreement definition, ICC]. The response stability was appraised using the standard error of measurements (SEM) in three repetitions of the IOS in the healthy children group (HCG) and in the cystic fibrosis group (CFG). 95 subjects participated, in each group with a mean age of 10.89 ± 2.21 years old in the HCG and 9.73 ±2.43 years old in the CFG, having been 41 and 43 boys and 54 and 52 girls, in the respectively group. In both groups, all IOS parameters evaluated in the three measures presented an ICC of 0.9, which is a high reproducibility. CONCLUSION: the IOS parameters are reproducible for healthy children and CF children in three measures. However, according to the population studied, the performance of only one measure is sufficient to assess respiratory mechanics, whereas the SEM were low, except for Fres, in both groups.

PMID: 32955781 [PubMed - as supplied by publisher]

Hypoglycaemia in cystic fibrosis during an extended oral glucose tolerance test.

Pediatr Pulmonol. 2020 Sep 21;:

Authors: Armaghanian N, Hetherington J, Parameswaran V, Chua EL, Markovic TP, Brand-Miller J, Steinbeck K

Abstract
BACKGROUND: Hypoglycaemia in cystic fibrosis (CF) in the absence of glucose lowering therapies, has long been identified as an important issue in the management of CF. There is currently still no unifying hypothesis for its aetiology.
AIM: The aims of this study were to perform a three hour OGTT in participants with CF and 1) document glucose, insulin, glucagon, GLP-1 and GIP release patterns within varying glucose tolerance groups during the OGTT; 2) determine the prevalence of hypoglycaemia during the OGTT and 3) define any association between hypoglycaemia and patterns of insulin, glucagon, GLP-1 and GIP release.
METHOD: Eligible participants attending an adult CF clinic completed a three hour OGTT. Hypoglycaemia on OGTT was defined as mild (glucose 3.4-3.9mmol/L), moderate (glucose 3.1- 3.3mmol/L) and severe (glucose ≤ 3mmol/L). Hormones were measured at fasting, 30, 60, 120 and 180 minutes.
RESULTS: Twenty-four participants completed the study, of which seven had normal glucose tolerance (NGT), twelve had abnormal glucose tolerance (AGT) and five had cystic fibrosis related diabetes (CFRD). All participants had a delayed insulin response compared to normative data. All glucose tolerance groups showed appropriate and similar suppression of fasting glucagon. Four participants (17%) had mild hypoglycaemia, 3 (13%) had moderate hypoglycaemia and eight (33%) had severe hypoglycaemia. No participant with CFRD demonstrated hypoglycaemia. Of the 19 participants without CFRD, 15 (79%) experienced hypoglycaemia. Participants with hypoglycaemia had greater peak glucose and insulin responses than those that did not have hypoglycaemia, and this approached significance (p=0.0625 for glucose and p=0.0862 for insulin). No significant mean differences between GLP-1 and GIP release were found. There was no relationship between hypoglycaemia and modulator therapy.
CONCLUSION: Post-prandial hypoglycaemia was unmasked by the extension of an OGTT to three hours. Delayed and abnormal insulin release, and ineffective counter-regulatory action of glucagon may have a role in its aetiology. This article is protected by copyright. All rights reserved.

PMID: 32955169 [PubMed - as supplied by publisher]

Isolation and first draft genome sequence of a linezolid-dependent Staphylococcus aureus clinical strain.

Future Microbiol. 2020 Aug;15:1123-1129

Authors: García-Angulo VA, Herve B, Melo J, Sanhueza C, la Fuente S, Aguirre LL, Baysdorfer C, Ulloa MT

Abstract
Background: Antibiotic-dependent pathogenic bacteria are sporadically isolated from patients that received prolonged antibiotic treatments. Evolution of antibiotics dependence and its clinical implications are scarcely studied. Materials & methods: A linezolid-dependent Staphylococcus aureus strain was isolated from a cystic fibrosis patient. A draft genome sequence was obtained and searched for known antibiotics resistance determinants and virulence factors. Results: The genome was assembled into 79 contigs for a total of 2.83 Mbp. This strain is a sequence type 5 methicillin-resistant Staphylococcus aureus with a type I SCCmec cassette also conserving the Panton-Valentine leukocidin. The G2576T substitution, conferring linezolid resistance, was harbored by all five copies of the 23S rRNA. Conclusion: The linezolid-dependent strain is related to a strain circulating in Latin America that acquired a mutation conferring linezolid resistance.

PMID: 32954844 [PubMed - in process]

Cystic Fibrosis and COVID-19: Care Considerations.

Respir Med Case Rep. 2020 Sep 16;:101226

Authors: Mirza AA, Rad EJ, Mohabir PK

Abstract
The coronavirus disease 2019 (COVID-19) pandemic has demanded large scale changes in patient care. People with cystic fibrosis have unique considerations, including underlying lung disease and routine aerosolizing therapies, but there is insufficient evidence to create comprehensive practice guidelines. We share a case of a patient with CF and COVID-19 as well as alterations to routine CF care at a large academic center. Key considerations include accessible COVID-19 screening, augmented infection control practices, and rapid integration of telemedicine.

PMID: 32953446 [PubMed - as supplied by publisher]

The coughing body: etiquettes, techniques, sonographies and spaces.

Biosocieties. 2020 Sep 15;:1-19

Authors: Brown N, Nettleton S, Buse C, Lewis A, Martin D

Abstract
With newfound relevance in the context of Covid-19, we focus on the coughing body, building on an in-depth qualitative study of three UK lung infection clinics treating people with cystic fibrosis. Conceptually we take our cue from Norbert Elias and the way something as physiologically fundamental as coughing becomes the focus of etiquette and technique, touching also on themes central to Mary Douglas' anthropology of pollution. This is explored through four themes. First, we show how coughing becomes a matter of biopolitical citizenship expressed through etiquettes that also displace pollution anxieties to surroundings. Second, coughing is a question of being assisted to cough through the mediation of professional skills, interventions and devices. Third, coughing is seen to be central to the sonographic soundscape of the healthcare environment whereby people learn to recognise (and sometimes misrecognise) each other through the 'sound' of the cough. Finally, coughing properly can be seen to have both a 'time and a place' including the retreat of the cough from public space into risky confined spaces. Our conclusion speculates on the way these insights shed light on aspects of life that, until the Covid-19 pandemic, lay largely hidden.

PMID: 32952594 [PubMed - as supplied by publisher]

Infant spirometry as a predictor of lung function at early childhood in cystic fibrosis patients.

J Cyst Fibros. 2020 Sep 17;:2116

Authors: Pollak M, Shaw M, Balkovec S, Wilson D, Kowalik K, Subbarao P, Ratjen F

Abstract
BACKGROUND: Infant pulmonary function testing using the raised volume rapid thoracoabdominal compression (RVRTC) technique requires sedation and is time consuming. Many cystic fibrosis (CF) centers do not have access to equipment and the utility of routine testing remains to be determined. We aimed to assess whether RVRTC tests performed during infancy predict spirometry at early school age.
METHODS: The RVRTC-based forced expiratory flow measures in infants were compared to the first adequately performed spirometry at school age. All tests were carried out during routine clinic visits and expressed as age related z-scores; only test occasions where patients were considered stable were included in the analysis.
RESULTS: 47 patients had useable infant RVRTC as well as matching school age spirometry data. There was weak correlation between infant FEV0.5 and early school age FEV1 (R = 0.29, p = 0.05). Four infants had significantly low zFEV0.5 (zFEV0.5 < -1.96), of which one of those remained under that limit at childhood. Changes in spirometry between infancy and early childhood were negatively correlated to baseline FEV0.5 (R = 0.61 p<0.001) reflecting that the change was driven by where individuals started off with. There was no difference in clinical characteristics between those improving, those with stable or deteriorating in lung function.
CONCLUSION: Infant RVRTC measures were not predictive of pulmonary function in early school age, likely due to the high proportion of measures of forced expiratory flows within the normal range at both time points.

PMID: 32952083 [PubMed - as supplied by publisher]

Does newborn screening improve early lung function in cystic fibrosis?

Paediatr Respir Rev. 2020 Aug 20;:

Authors: Davies G

Abstract
Despite evidence showing an improvement in nutritional outcomes following diagnosis by newborn screening (NBS) for cystic fibrosis (CF), the impact on pulmonary outcomes has been less clear. In this review the approaches to measurement of early lung function and knowledge gained from NBS CF cohorts will be described. Studies which have compared outcomes in those diagnosed by NBS to those diagnosed following symptomatic presentation will be presented. Compiling the evidence base used to evaluate the impact of NBS on pulmonary outcomes has been complicated by improvements in clinical management, infection control practices, as well as public health interventions (such as tobacco smoking bans in public places) that have evolved substantially over recent decades. Forced expiratory volumes have been used as the main outcome but it is important not to draw conclusions for 'early lung function' from tests such as spirometry alone, which lack sensitivity in early lung disease. There is, at present, insufficient evidence to draw firm conclusions about the effect of NBS on early lung function. In an era of highly effective treatments targeting the underlying molecular defect responsible for CF, future opportunities for early initiation of treatment may mean that the impact of NBS on early lung function may yet to be realised.

PMID: 32952050 [PubMed - as supplied by publisher]

Exploring the Functional Consequences of Protein Backbone Alteration in Ubiquitin through Native Chemical Ligation.

Chembiochem. 2019 09 16;20(18):2346-2350

Authors: Werner HM, Estabrooks SK, Preston GM, Brodsky JL, Horne WS

Abstract
Ubiquitin (Ub) plays critical roles in myriad protein degradation and signaling networks in the cell. We report herein Ub mimetics based on backbones that blend natural and artificial amino acid units. The variants were prepared by a modular route based on native chemical ligation. Biological assays show that some are enzymatically polymerized onto protein substrates, and that the resulting Ub tags are recognized for downstream pathways. These results advance the size and complexity of folded proteins mimicked by artificial backbones and expand the functional scope of such agents.

PMID: 31059184 [PubMed - indexed for MEDLINE]

Low rates of macrolide-resistant Mycobacterium avium complex in cystic fibrosis despite chronic azithromycin therapy.

J Cyst Fibros. 2020 Sep 16;:

Authors: Richter WJ, Nguyen JA, Wu AE, Jennings MT, Lechtzin N, Parrish NM, Psoter KJ, Cohen KA

PMID: 32950412 [PubMed - as supplied by publisher]

Trends in nontuberculous mycobacteria infection in children and young people with cystic fibrosis.

J Cyst Fibros. 2020 Sep 16;:

Authors: Abidin NZ, Gardner AI, Robinson HL, Haq IJ, Thomas MF, Brodlie M

Abstract
Nontuberculous mycobacteria (NTM) infection is of growing concern in cystic fibrosis (CF). UK CF Registry data were analyzed from 2016 to 2018. Prevalence of infection stabilized in the pediatric age-group during this period but remained substantially higher than in 2010. Allergic bronchopulmonary aspergillosis and Pseudomonas aeruginosa infection were associated with NTM infection.

PMID: 32950411 [PubMed - as supplied by publisher]

Physical Function Measured Prior to Lung Transplantation Is Associated With Posttransplant Patient Outcomes.

Transplant Proc. 2020 Sep 16;:

Authors: Mayer KP, Henning AN, Gaines KM, Cassity EP, Morris PE, Villasante Tezanos AG, Johnson CA, Lee JT, Baz M, Dupont-Versteegden EE

Abstract
INTRODUCTION: The primary objective of this study was to determine whether pretransplant physical function is correlated with posttransplantation outcomes.
METHODS: We performed a retrospective study of patients that participated in pretransplantation screening and subsequently underwent lung transplantation. Pretransplant variables of interest included demographics, muscle mass, body composition, physical function, and physical frailty. Correlation tests were performed to assess relationships with significance set at 0.05.
RESULTS: Twenty-five patients with a mean age of 57 ± 13 years (68% male) with pretransplant lung allocation score of 45 ± 14 were included. This cohort had a 3-year mortality rate of 32% (n = 8). Pretransplant 4-m gait speed was significantly related to performance on the Short Physical Performance Battery (r = 0.74, P = .02) and distance ambulated on the 6-minute walk test (r = 0.62, P = .07) at hospital discharge. Older age was associated with slower gait speed and worse performance on sit-to-stand testing at hospital discharge (r = -0.76, P = .01 and r = -0.75, P = .01, respectively). Statistically, only diagnosis of cystic fibrosis was associated with 3-year mortality.
DISCUSSION: Our study demonstrates that demographic, clinical, and physical function assessed prior to lung transplantation may be indicators of functional recovery.

PMID: 32950260 [PubMed - as supplied by publisher]

Tissue Doppler and speckle tracking echocardiography assessment of left ventricular function in children with cystic fibrosis.

Echocardiography. 2020 Sep 19;:

Authors: Kizilca O, Demircan T, Isik S, Yılmaz N, Kir M, Uzuner N, Unal N

Abstract
BACKGROUND: Cystic fibrosis may lead to left ventricular (LV) dysfunction. This dysfunction can be documented by methods such as tissue Doppler echocardiographic (TDI) imaging and two-dimensional speckle tracking echocardiography (STE) in early stage.
STUDY DESIGN: This was prospective cohort study.
METHODS: A total of 34 patients diagnosed with cystic fibrosis (mean age and SD 9.9 ± 4.9 years) and 37 healthy control subjects with a comparable gender and age distribution (mean age 9.8 ± 4.3) were studied. The results for the two groups were compared along with the results of published reports.
RESULTS: No significant relationship was found between the groups in terms of systolic and diastolic measurements of the interventricular septum and posterior left ventricular wall, and ejection fraction (P > .05). Myocardial performance indexes of left ventricular free wall and interventricular septum increased in the patient group compared with the controls (P < .05). As measured by STE, seven segments in the LV myocardial longitudinal strain and three segments in the LV myocardial circumferential strain showed significant reductions in patients with cystic fibrosis compared with controls (P < .05). The longitudinal global, circumferential global, and total global strain values had no significant difference between the groups (P > .05). Longitudinal strain rates and circumferential strain rates were both lower in five segments in the patient group (P < .05).
CONCLUSIONS: Tissue Doppler echocardiographic imaging and STE may help identifying subclinical LV dysfunction in cystic fibrosis patients with unremarkable conventional echocardiography. They may be considered for the routine follow-up of cystic fibrosis patients.

PMID: 32949427 [PubMed - as supplied by publisher]

Effect of Endoscope Sinus Surgery on Pulmonary Function in Cystic Fibrosis Patients: A Meta-Analysis.

Laryngoscope. 2020 Sep 19;:

Authors: Yin M, Gao X, Di L, Yang P, Liu J, Li X, Yan X, Wang W, Cui H

Abstract
OBJECTIVE: The objective of this study was to quantify the effect of endoscopic sinus surgery on pulmonary function in patients with cystic fibrosis and chronic rhinosinusitis.
METHODS: The PubMed, MEDLINE, Cochrane Library, and Embase databases were searched for studies published in English, without any language and time restrictions from their inception to March 1, 2020. Studies examining pulmonary function outcomes in patients with cystic fibrosis and chronic rhinosinusitis following endoscopic sinus surgery were included. Primary outcomes were pulmonary function tests, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF), and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75 ).
RESULTS: A total of 12 studies with 570 patients were included for data extraction and meta-analysis. For FEV1 (%), the summarized mean difference (MD) was -6.92 (95% confidence interval [CI] = -19.67 to 5.83, P = .29) and 0.70 (95% CI = -3.81 to 5.21, P = .76) for the postoperative results after 6 months and 12 months, respectively. The pooled MDs for FVC (%) and FEV1/FVC ratio (%) for the postoperative results after 6 months were 0.60 (95% CI = -4.12 to 5.31, P = .80) and -1.29 (95% CI = -6.14 to 3.55, P = .60).
CONCLUSION: Endoscopic sinus surgery in chronic rhinosinusitis patients with cystic fibrosis did not improve the pulmonary function in chronic rhinosinusitis patients with cystic fibrosis. More prospective studies and meta-analyses addressing the same topic are needed in the future. Laryngoscope, 2020.

PMID: 32949423 [PubMed - as supplied by publisher]

Multi-dimensional clinical phenotyping of a national cohort of adult cystic fibrosis patients.

J Cyst Fibros. 2020 Sep 15;:

Authors: Conrad DJ, Billings J, Teneback C, Koff J, Rosenbluth D, Bailey BA, Jain R

Abstract
BACKGROUND: Cystic Fibrosis (CF) is a multi-systemic disorder resulting from genetic variation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which can result in bronchiectasis, chronic sinusitis, pancreatic malabsorption, cholestatic liver disease and distal intestinal obstructive syndrome. This study generates multi-dimensional clinical phenotypes that capture the complexity and spectrum of the disease manifestations seen in adult CF patients using statistically robust techniques.
METHODS: Pre-transplant clinical data from adult (age ≥18 years) CF patients (n = 992) seen in six regionally distinct US CF centers between 1/1/2014 and 6/30/2015 were included. Demographic, spirometry, nutritional, microbiological and therapy data were used to generate clusters using the Random Forests statistical-learning and Partitioning around Medoids (PAM) clustering algorithms. Five commonly measured demographic, physiological and nutritional parameters were needed to create the final phenotypes that are highly similar to a regionally matched group of patients from the CF Foundation Patient Registry RESULTS: This approach identified high-risk phenotypes with expected characteristics including high rates of pancreatic insufficiency, diabetes and Pseudomonas aeruginosa colonization. It also identified unexpected populations including a) a male-dominated, well-nourished group with good lung function with a high prevalence of severe genotypes (i.e. 60% subjects had two minimal function CFTR variations), b) and an older, "survivor" phenotype that had high rates of chronic P. aeruginosa infection.
CONCLUSIONS: This study identified recognizable phenotypes that capture the clinical complexity in a statistically robust manner and which may aide in the identification of specific genetic and environmental factors responsible for these disease manifestation patterns.

PMID: 32948498 [PubMed - as supplied by publisher]

LncRNA and transcriptomic analysis of fetal membrane reveal potential targets involved in oligohydramnios.

BMC Med Genomics. 2020 Sep 18;13(1):137

Authors: Ou YH, Liu YK, Zhu LQ, Chen MQ, Yi XC, Chen H, Zhang JP

Abstract
BACKGROUND: The multiple causes of oligohydramnios make it challenging to study. Long noncoding RNAs (lncRNAs) are sets of RNAs that have been proven to function in multiple biological processes. The purpose of this study is to study expression level and possible role of lncRNAs in oligohydramnios.
METHODS: In this study, total RNA was isolated from fetal membranes resected from oligohydramnios pregnant women (OP) and normal amount of amniotic fluid pregnant women (Normal). LncRNA microarray was used to analyze the differentially expressed lncRNAs and mRNAs. Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to analyze the main enrichment pathways of differentially expressed mRNAs. Real-time quantitative PCR (qPCR) was used to validate the lncRNA expression level.
RESULTS: LncRNA microarray analysis revealed that a total of 801 lncRNAs and 367 mRNAs were differentially expressed in OP; in these results, 638 lncRNAs and 189 mRNAs were upregulated, and 163 lncRNAs and 178 mRNAs were downregulated. Of the lncRNAs, 566 were intergenic lncRNAs, 351 were intronic antisense lncRNAs, and 300 were natural antisense lncRNAs. The differentially expressed lncRNAs were primarily located in chromosomes 2, 1, and 11. KEGG enrichment pathways revealed that the differentially expressed mRNAs were enriched in focal adhesion as well as in the signaling pathways of Ras, tumor necrosis factor (TNF), estrogen, and chemokine. The qPCR results confirmed that LINC00515 and RP11-388P9.2 were upregulated in OP. Furthermore, the constructed lncRNA-miRNA-mRNA regulatory network revealed tenascin R (TNR), cystic fibrosis transmembrane conductance regulator (CFTR), ATP-binding cassette sub-family A member 12 (ABCA12), and collagen 9A2 (COL9A2) as the candidate targets of LINC00515 and RP11-388P9.2.
CONCLUSIONS: In summary, we revealed the profiles of lncRNA and mRNA in OP. These results might offer potential targets for biological prevention for pregnant women with oligohydramnios detected before delivery and provided a reliable basis for clinical biological treatment in OP.

PMID: 32948205 [PubMed - as supplied by publisher]

Protease inhibitors elicit anti-inflammatory effects in CF mice with Pseudomonas aeruginosa acute lung infection.

Clin Exp Immunol. 2020 Sep 18;:

Authors: Sandri A, Lleo MM, Signoretto C, Boaretti M, Boschi F

Abstract
INTRODUCTION: Pseudomonas aeruginosa is the major respiratory pathogen in patients with cystic fibrosis (CF). P. aeruginosa secreted proteases, in addition to host proteases, degrade lung tissue and interfere with immune processes. In this study, we aimed at evaluating the possible anti-inflammatory effects of protease inhibitors Marimastat and Ilomastat in the treatment of P. aeruginosa infection.
METHODS: Lung infection with P. aeruginosa PAO1 strain was established in wild-type and CFTR-knockout C57BL/6 mice expressing a luciferase gene under control of bovine IL-8 promoter. After intratracheal instillation with 150µM Marimastat and Ilomastat, lung inflammation was monitored by in vivo bioluminescence imaging and bacterial load in the lungs was assessed. In vitro, effects of protease inhibitors on PAO1 growth and viability were evaluated.
RESULTS: Acute lung infection was established in both wild-type and CFTR-knockout mice. After 24 hours, the infection induced IL-8-dependent bioluminescence emission indicating lung inflammation. In infected mice with ongoing inflammation, intratracheal treatment with 150µM Marimastat and Ilomastat reduced the bioluminescence signal in comparison to untreated, infected animals. Bacterial load in the lungs was not affected by the treatment and in vitro the same dose of Marimastat and Ilomastat did not affect PAO1 growth and viability, confirming that these molecules have no additional anti-bacterial activity.
CONCLUSIONS: Our results show that inhibition of protease activity elicits anti-inflammatory effects in CF mice with acute P. aeruginosa lung infection. Thus, Marimastat and Ilomastat represent candidate molecules for the treatment of CF patients, encouraging further studies on protease inhibitors and their application in inflammatory diseases.

PMID: 32946591 [PubMed - as supplied by publisher]

Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus.

PLoS One. 2020;15(9):e0238178

Authors: Madani A, Mallick I, Guy A, Crauste C, Durand T, Fourquet P, Audebert S, Camoin L, Canaan S, Cavalier JF

Abstract
Mycobacterium abscessus (M. abscessus), a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of M. abscessus pulmonary infections are poorly effective due to the intrinsic resistance of this bacteria against a broad range of antibiotics including anti-tuberculosis agents. Consequently, the number of drugs that are efficient against M. abscessus remains limited. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of M. abscessus. Several OXs impair extracellular M. abscessus growth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibiting M. abscessus growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of M. abscessus growth, i.e., compound iBpPPOX, via activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in M. abscessus lipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target of iBpPPOX. This study clearly emphasizes the potential of the OX derivatives to inhibit the extracellular and/or intracellular growth of M. abscessus by targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.

PMID: 32946441 [PubMed - as supplied by publisher]

Epidemiology of Burkholderia Infections in People with Cystic Fibrosis in Canada between 2000 - 2017.

Ann Am Thorac Soc. 2020 Sep 18;:

Authors: Zlosnik JEA, Henry DA, Hird TJ, Hickman R, Campbell M, Cabrera A, Laino Chiavegatti G, Chilvers MA, Sadarangani M

Abstract
RATIONALE: Infections by Burkholderia species bacteria in CF maybe transmissible, necessitating infection control measures, and remain a serious cause of morbidity and mortality. The last major study of Burkholderia epidemiology in Canada included cases up until July 2000 and was marked by the dominance of a limited number of epidemic clones of B. cenocepacia.
OBJECTIVES: Describe the nationwide epidemiology of Burkholderia species infections in people with cystic fibrosis in Canada over the 17-year period, since 2000.
METHODS: Isolates were collected from across Canada between August 2000 and July 2017 and identified to the species and, for isolates between 2015 and 2017, strain level.
RESULTS: We analyzed 1,362 Burkholderia isolates from at least 396 people with CF. 49% (n = 666) of all isolates and 47% (n = 179) of new incident infections were identified as B. multivorans. The incidence of Burkholderia infection in the Canadian CF population did not change between 2000 and 2017 at 6 cases per 1,000 annually. Multi-locus sequence typing analysis suggested minimal sharing of clones in Canada.
CONCLUSIONS: The epidemiology of Burkholderia in CF in Canada has shifted from limited numbers of epidemic strains of B. cenocepacia to largely non-clonal isolates of B. multivorans, B. cenocepacia and other species. Despite widespread infection control, however, Burkholderia species bacteria continue to be acquired by people with CF at an unchanged rate posing a continued hazard.

PMID: 32946281 [PubMed - as supplied by publisher]

FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms.

Am J Respir Cell Mol Biol. 2020 Sep 18;:

Authors: Miyashita N, Horie M, Suzuki HI, Saito M, Mikami Y, Okuda K, Boucher RC, Suzukawa M, Hebisawa A, Saito A, Nagase T

Abstract
Fibroblasts provide a structural framework for multiple organs, and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of forkhead box L1 (FOXL1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcript levels associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, in contrast to fibroblasts derived from other organs. RNA in situ hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ/YAP signature genes and PDGF receptor-α. FOXL1 silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased FOXL1 mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis (IPF) lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor, and is involved in IPF pathogenesis.

PMID: 32946266 [PubMed - as supplied by publisher]