Cystic Fibrosis (CF) is the most common lethal autosomal inherited disorder that affects all races and ethnicities in the United States. However, it is mostly predominant in the Caucasian populace accounting for about...Cystic Fibrosis (CF) is the most common lethal autosomal inherited disorder that affects all races and ethnicities in the United States. However, it is mostly predominant in the Caucasian populace accounting for about 80% of all CF cases. CF most severe complication can be referred to as pulmonary bronchiectasis and infections of the airways, nonetheless, the devastating effects of the disease have far-reaching consequences beyond lung damage. CF is a heterogeneous disease that is caused by mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The impairment or absence of this gene can affect multiple organs and systems and is characterized not only by chronic lung blockage, infections, and inflammation but also by exocrine gland dysfunction, intestinal obstruction, liver pathology, elevated sweat chloride concentration, and in males, infertility due to the congenital bilateral absence of the vas deferens. To this end, we briefly explore the pathological effects of CF and how CF mediates the destruction of several critical organs in the body and some of the gene therapeutical approaches such as gene editing and viral-based strategies available for the treatment of this multi-organ disease.展开更多
Low sperm motility is one of the main causes of male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR, an anion channel protein) is related to the progressive motility of sperm. CFTR disruptor CF...Low sperm motility is one of the main causes of male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR, an anion channel protein) is related to the progressive motility of sperm. CFTR disruptor CFTRinh-172 or forskolin (FSK) in this study were used to treat human sperm separately, and the rates of sperm autophagy and progressive motility, mitochondrial membrane potential (MMP) and ATP concentration, and the expression levels of related factors were detected to explore their relationship. It was showed that sperms treated with CFTRinh-172 or FSK reduced the levels of cAMP, CFTR and PKA, but increased sperm autophagy rate, expression levels of AMPK and LC3B. However, reactive oxygen species content had no significant difference. It was indicated that low level of CFTR performed with cAMP and its downstream effectors such as PKA and AMPK to regulate mitochondrial structure and function, leading to increased autophagy rate and reduced vitality of sperm.展开更多
BACKGROUND Abernethy malformation,also known as congenital extrahepatic portosystemic shunt,is an uncommon malformation resulting from aberrant development of the portal venous system.Cystic fibrosis(CF)is an autosoma...BACKGROUND Abernethy malformation,also known as congenital extrahepatic portosystemic shunt,is an uncommon malformation resulting from aberrant development of the portal venous system.Cystic fibrosis(CF)is an autosomal recessive genetic disease caused by mutations in the CFTR gene.It mainly affects the exocrine glands of the respiratory,digestive and reproductive systems.It is considered extremely rare in the Asian population.We present a clinical case involving a pediatric patient of Asian descent who was diagnosed with Abernethy malformation and CF.CASE SUMMARY A 12-year-old girl presented with a medical history of recurring respiratory infections and hemoptysis,and chest computed tomography(CT)showed bronchiectasis.Whole exome sequencing was performed for the patient,yielding findings that revealed a compound heterozygous variant of the CFTR gene:c.233_c.234insT/p.Trp79fsTer3(maternal origin);c.2909G>A/p.Gly970Asp(paternal origin).CF was diagnosed.The physician’s attention was drawn to the presence of splenomegaly during disease progression.Abdominal enhanced CT revealed splenomegaly,compression of the left kidney,and multiple tortuous dilated vascular shadows were seen at the splenic hilum,which flowed back into the left renal vein and portal vein,suggesting Abernethy malformation type II.Intraoperatively,the abnormal blood flow was seen to merge into the inferior vena cava through the left renal vein without hepatic processing,and the pathology of liver biopsy showed hypoplastic,dilated or absent portal vein branches,both of which supported the diagnosis of Abernethy malformation type II.This represents the initial documented instance of Abernethy malformation accompanied by a CFTR gene mutation in the existing body of literature.CONCLUSION Coexisting Abernethy malformation and CF are rare.Detailed medical history information,abdominal enhanced CT,venography and genetic testing contribute to diagnosis as well as differential diagnosis.展开更多
BACKGROUND Gastroesophageal reflux(GER)has been associated with poor outcomes after lung transplantation for chronic lung disease,including increased risk of chronic rejection.GER is common in cystic fibrosis(CF),but ...BACKGROUND Gastroesophageal reflux(GER)has been associated with poor outcomes after lung transplantation for chronic lung disease,including increased risk of chronic rejection.GER is common in cystic fibrosis(CF),but factors influencing the likelihood of pre-transplant pH testing,and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown.AIM To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF.METHODS This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant.Patients with pretransplant anti-reflux surgery were excluded.Baseline characteristics(age at transplantation,gender,race,body mass index),self-reported GER symptoms prior to transplantation,and pre-transplant cardiopulmonary testing results,were recorded.Reflux testing consisted of either 24-h pH-or combined multichannel intraluminal impedance and pH monitoring.Post-transplant care included a standard immunosuppressive regimen,and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients.The primary outcome of chronic lung allograft dysfunction(CLAD)was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria.Statistical analysis was performed with Fisher’s exact test to assess differences between cohorts,and time-to-event Cox proportional hazards modeling.RESULTS After applying inclusion and exclusion criteria,a total of 60 patients were included in the study.Among all CF patients,41(68.3%)completed reflux monitoring as part of pre-lung transplant evaluation.Objective evidence of pathologic reflux,defined as acid exposure time>4%,was found in 24 subjects,representing 58%of the tested group.CF patients with pre-transplant reflux testing were older(35.8 vs 30.1 years,P=0.01)and more commonly reported typical esophageal reflux symptoms(53.7%vs 26.3%,P=0.06)compared to those without reflux testing.Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing.Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses(68%vs 85%,P=0.003).There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not,after controlling for confounders(Cox Hazard Ratio 0.26;95%CI:0.08-0.92).CONCLUSION Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD.Systematic reflux testing may enhance outcomes in this patient population.展开更多
Cystic fibrosis patients often develop lung infections because of the presence of thick and sticky mucus that fills their airways. The presence of this thick mucus prevents the lungs from filtering out certain dominan...Cystic fibrosis patients often develop lung infections because of the presence of thick and sticky mucus that fills their airways. The presence of this thick mucus prevents the lungs from filtering out certain dominant bacterial types, making patients highly susceptible to infections that can range anywhere in severity from mild to life-threatening. These infections can cause great distress for patients as it becomes harder for patients to breathe and increases the chance of mortality by respiratory failure. It is important to be able to track the progression or regression of cystic fibrosis to determine the best course of treatment. Thus, this project focuses on the use of an AI model to examine the microbiology of cystic fibrosis patients and predict the condition or stage of lung function in the future, as a way to guide doctors with their treatment plan. Due to the limited amounts of publicly available patient data, we used all of the data in the training and testing of our machine learning algorithms initially and then tried a 50% training, 10% validation, and 40% testing split. Our results show that with relatively simple models (cubic polynomials), we can predict FEV1 from statistically significant bacteria sequences within 98% accuracy when training on sufficiently large samples.展开更多
BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD)seen in an estimated 15%-60%of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic st...BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD)seen in an estimated 15%-60%of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown.In the general population,hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes.Cystic fibrosis related diabetes(CFRD)impacts 40%-50%of CF adults and is characterized by both insulin insufficiency and insulin resistance.We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.AIM To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.METHODS Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study.Only pancreatic insufficient patients with CFRD or normal glucose tolerance(NGT)were included.Patients with established CFLD,end stage lung disease,or persistently elevated liver enzymes were excluded.Mean magnetic resonance imaging(MRI)proton density fat fraction(PDFF)was obtained for all participants.Clinical characteristics[age,sex,body mass index,percent predicted forced expiratory volume at 1 s(FEV1),lumacaftor/ivacaftor use]and blood chemistries were assessed for possible association with hepatic steatosis.Hepatic steatosis was defined as a mean MRI PDFF>5%.Patients were grouped by diabetes status(CFRD,NGT)and cystic fibrosis transmembrane conductance regulator(CFTR)modulator use(lumacaftor/ivacaftor,no lumacaftor/ivacaftor)to determine between group differences.Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher’s exact test.RESULTS Twenty subjects were included in the final analysis.The median age was 22.3 years(11.3-39.0)and median FEV1 was 77%(33%-105%).Twelve subjects had CFRD and 8 had NGT.Nine subjects were receiving lumacaftor/ivacaftor.The median PDFF was 3.0%(0.0%-21.0%).Six subjects(30%)had hepatic steatosis defined as PDFF>5%.Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor(median,range)(2.0%,0.0%-6.4%)than in patients not receiving lumacaftor/ivacaftor(4.1%,2.7-21.0%),P=0.002.Though patients with CFRD had lower PDFF(2.2%,0.0%-14.5%)than patients with NGT(4.9%,2.4-21.0%)this did not reach statistical significance,P=0.06.No other clinical characteristic was strongly associated with hepatic steatosis.CONCLUSION Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis.No association between CFRD and hepatic steatosis was found in this cohort.展开更多
Cystic fibrosis(CF)is a common autosomal recessive disease.Life expectancy of patients with CF continues to improve mainly driven by the evolving therapies for CF-related organ dysfunction.The prevalence of CF-related...Cystic fibrosis(CF)is a common autosomal recessive disease.Life expectancy of patients with CF continues to improve mainly driven by the evolving therapies for CF-related organ dysfunction.The prevalence of CF-related diabetes(CFRD)increases exponentially as patients’age.Clinical care guidelines for CFRD from 2010,recommend insulin as the mainstay of treatment.Many patients with CFRD may not require exogenous insulin due to the heterogeneity of this clinical entity.Maintenance of euglycemia by enhancing endogenous insulin production,secretion and degradation with novel pharmacological therapies like glucagonlike peptide-1 agonist is an option that remains to be fully explored.As such,the scope of this article will focus on our perspective of glucagon-like peptide-1 receptor agonist in the context of CFRD.Other potential options such as sodiumglucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors and their impact on this patient population is limited and further studies are required.展开更多
Cystic fibrosis(CF)is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene.CF liver disease develops in 5%-10%of patients with CF and is the third leading cause of dea...Cystic fibrosis(CF)is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene.CF liver disease develops in 5%-10%of patients with CF and is the third leading cause of death among patients with CF after pulmonary disease or lung transplant complications.We review the pathogenesis,clinical presentations,complications,diagnostic evaluation,effect of medical therapies especially CF transmembrane conductance regulator modulators and liver transplantation in CF associated liver disease.展开更多
BACKGROUND Cystic fibrosis transmembrane conductance regulator(CFTR)modulators significantly improve pulmonary function in patients with cystic fibrosis(CF)but the effect on hepatobiliary outcomes remains unknown.We h...BACKGROUND Cystic fibrosis transmembrane conductance regulator(CFTR)modulators significantly improve pulmonary function in patients with cystic fibrosis(CF)but the effect on hepatobiliary outcomes remains unknown.We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol.AIM To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF.METHODS A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF.Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use.Subjects were grouped by use of CFTR modulators,ursodiol,dual therapy,or no therapy.The primary outcome was development of cirrhosis.Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups.RESULTS A total of 7201 patients were included,of which 955(12.6%)used a CFTR modulator,529(7.0%)used ursodiol,105(1.4%)used combination therapy,and 5612(74.3%)used neither therapy.The incidence of cirrhosis was 0.1%at 1 year and 0.7%at 4 years in untreated patients,5.9%and 10.1%in the Ursodiol group,and 1.0%and 1.0%in patients who received both therapies.No patient treated with CFTR modulators alone developed cirrhosis.Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients(P=0.05),patients on Ursodiol(P<0.001),and patients on dual therapy(P=0.003).The highest incidence of cirrhosis was found among patients treated with Ursodiol alone,compared to untreated patients(P<0.001)or patients on Ursodiol and CFTR modulators(P=0.01).CONCLUSION CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.展开更多
AIM： To investigate the effect of tetramethylpyrazine （TMP）, an active compound from Ligustium Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved.METHODS： Th...AIM： To investigate the effect of tetramethylpyrazine （TMP）, an active compound from Ligustium Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved.METHODS： The short-circuit current （Isc） technique in conjunction with pharmacological agents and specific inhibitors were used in analyzing the electrolyte transport across the distal colon of rodents. The underlying cellular signaling mechanism was investigated by radioimmunoassay analysis （RIA） and a special mouse model of cystic fibrosis.RESULTS： IMP stimulated a conoentration-dependent rise in ISCl, which was dependent on both Cl^- and HCO3^-, and inhibited by apical application of diphenylamine-2,2＇-dicarboxylic acid （DPC） and glibenclamide, but resistant to 4,4＇-diisothiocyanatostilbene-2,2＇-disulfonic acid disodium salt hydrate （DIDS）. Removal of Na^＋ from basolateral solution almost completely abolished the Isc response to TMP, but it was insensitive to apical Na^＋ replacement or apical Na^＋ channel blocker, amiloride. Pretreatment of colonic mucosa with BAPTA-AM, a membrane-permeable selective Ca2＋ chelator, did not significantly alter the TMP-induced Iso No additive effect of forskolin and 3-isobutyl-l-methylxanthine （[BMX） was observed on the TMP-induced Isc, but it was significantly reduced by a protein kinase A inhibitor, H89.RIA results showed that TMP （1 mmol/L） elicited a significant increase in cellular cAMP production, which was similar to that elicited by the adenylate cyclase activator, forskolin （10μmol/L）. The TMP-elicited Isc as well as forskolin- or IBMX-induced Isc were abolished in mice with homozygous mutation of the cystic fibrosis transmembrane conductance regulator （CFTR） presenting defective CFTR functions and secretions.CONCLUSION： TMP may stimulate cAMP-dependent and CFTR-mediated Cl^- and HCO3^- secretion. This may have implications in the future development of alternative treatment for constipation.展开更多
Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs s...Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.展开更多
BACKGROUND Intestinal ischemia/reperfusion(I/R)injury is a fatal syndrome that occurs under many clinical scenarios.The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfu...BACKGROUND Intestinal ischemia/reperfusion(I/R)injury is a fatal syndrome that occurs under many clinical scenarios.The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion.However,the mechanism of I/R-induced apoptosis remains unclear.Cystic fibrosis transmembrane conductance regulator(CFTR)is a cAMP-activated chloride channel.Few researchers have paid attention to its role in intestinal I/R injury,or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation(H/R).AIM To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.METHODS An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.RESULTSThe results suggested that CFTR overexpression significantly increased the Caco2 cell viability anddecreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65,an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by theoverexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm asdetermined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in theH/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKTinhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTRoverexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment invivo or H/R treatment in vitro.CONCLUSIONThe results of the present study indicate that the overexpression of CFTR protects Caco2 cells fromH/R-induced apoptosis;furthermore, it also inhibits H/R-induced apoptosis through thePI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.展开更多
Cystic fibrosis is an autosomal recessive disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator(CFTR).Here we summarize,at the basic descriptive level,clinical and ge...Cystic fibrosis is an autosomal recessive disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator(CFTR).Here we summarize,at the basic descriptive level,clinical and genetic characteristics of cystic fibrosis gene mutations,while emphasizing differences between CF mutations found in Chinese pediatric CF patients compared to those found in Caucasian CF patients.In addition,we describe animal models used to study human cystic fibrosis disease and highlight unique features of each model that mimic specific human CF-associated signs and symptoms.At the clinical level,we summarize CF clinical manifestations and diagnostic,treatment,and prognostic methods to provide clinicians with infor-mation toward reducing CF misdiagnosis and missed diagnosis rates.展开更多
Dictamine is a furoquinoline alkaloid isolated from Dictamus dasycarpus Turcz.In the present study,we found that dictamine is able to stimulate the chloride transport activity of wild-type and ΔF508 mutant CFTR.The a...Dictamine is a furoquinoline alkaloid isolated from Dictamus dasycarpus Turcz.In the present study,we found that dictamine is able to stimulate the chloride transport activity of wild-type and ΔF508 mutant CFTR.The activity is cAMP-dependent and can be completely reversed by specific CFTR inhibitor CFTRinh-172.In addition,dictamine can further increase the chloride transport activity when CFTR is maximally activated by the combination of cAMP stimulators forskolin（FSK）and IBMX,suggesting direct interaction of dictamine with CFTR.Dictamine may be useful for probing CFTR channel gating mechanisms and used as a lead compound to develop the pharmacological therapy of CFTR-related diseases such as idiopathic chronic pancreatitis and keratoconjunctivitis sicca and cystic fibrosis.展开更多
Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis(CF). The rat is a relevant laboratory model for CF because of its zootechnical c...Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis(CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.Methods: We describe the generation of a CF rat model(F508 del) homozygous for the p.Phe508 del mutation in the transmembrane conductance regulator(Cftr) gene. This model was compared to new Cftr-/-rats(CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference(NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508 del rats.Results: Both newborn F508 del and Knock out(KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.展开更多
Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients.In this study,we established and validated a new HPLC-MS/MS method that could...Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients.In this study,we established and validated a new HPLC-MS/MS method that could simultaneously detect drug concentrations of ciprofloxacin,colistin and ivacaftor in rat plasma,human epithelial cell lysate,cell culture medium,and drug transport media.An aliquot of200 μL drug-containing rat plasma or cell culture medium was treated with 600 μL of extraction solution(acetonitrile containing 0.1% formic acid and 0.2% trifluoroacetic acid(TFA)).The addition of 0.2% TFA helped to break the drug-protein bonds.Moreover,the addition of 0.1% formic acid to the transport medium and cell lysate samples could significantly improve the response and reproducibility.After vortexing and centrifuging,the sample components were analyzed by HPLC-MS/MS.The multiple reaction monitoring mode was used to detect the following transitions:585.5-101.1(colistin A),578.5-101.1(colistin B),393.2-337.2(ivacaftor),332.2-314.2(ciprofloxacin),602.3-101.1(polymyxin B1 as internal standard(IS)) and 595.4-101.1(polymyxin B2 as IS).The running time of a single sample was only 6 min,making this a time-efficient method.Linear correlations were found for colistin A at 0.029-5.82 μg/m L,colistin B at 0.016-3.14 μg/m L,ivacaftor at 0.05-10.0 μg/m L,and ciprofloxacin at 0.043-8.58 μg/m L.Accuracy,precision,and stability of the method were within the acceptable range.This method would be highly useful for research on cytotoxicity,animal pharmacokinetics,and in vitro drug delivery.展开更多
In the present study, we identified the natural compound curcumin to be an effective G551D-CFTR activator by cell-based fluorescent assay and electrophysiological measurement. We demonstrated that curcumin can restore...In the present study, we identified the natural compound curcumin to be an effective G551D-CFTR activator by cell-based fluorescent assay and electrophysiological measurement. We demonstrated that curcumin can restore the impaired chloride conductance of G551D mutant CFTR. The activity is rapid, reversible, and cAMP-dependent. Our study identified a new natural lead compound for the pharmacological therapy of cystic fibrosis caused by G551D mutation of CFTR.展开更多
Despite the acceptance of physical activity （PA） being integral to a young person＇s health, children with disability often exhibit low levels of PA. In young people with cystic fibrosis （CF） the importance of exe...Despite the acceptance of physical activity （PA） being integral to a young person＇s health, children with disability often exhibit low levels of PA. In young people with cystic fibrosis （CF） the importance of exercise and daily PA is acknowledged by clinicians and their support teams, however, there is a lack of knowledge related to its prescription. CF is a recessive genetic disorder affecting the lung, pancreas and sweat glands. CF is the most common life shortening genetic disease in the Caucasian population for which there is no cure. In the UK, CF affects over 9000 people, with 4000 under 16 years of age. Only about half of the CF population can expect to live beyond 40 years of age. Besides drug therapies, rehabilitative exercise programmes form an important component of treatment and long term exercise programmes are considered positive treatment strategies, but all lack any detailed prescriptive information. Several reviews and editorials have highlighted the lack of evidence based research in PA and exercise training in young people with CF; but advocate a greater need for understanding the role of exercise in therapeutic interventions. The purpose of this review is to update the reader on the current recommendations and evidence in PA and exercise training for young people with CE These developments have extended our understanding of PA and exercise training in children and adolescents with CF, and its implementation in the management of this chronic disease.展开更多
The protein expression of cystic fibrosis transmembrane conductance regulator （CFTR）, a cAMP-activated Cl- channel, in ovarian stimulated premature female rat ovary during a cycle of follicle development and corpus ...The protein expression of cystic fibrosis transmembrane conductance regulator （CFTR）, a cAMP-activated Cl- channel, in ovarian stimulated premature female rat ovary during a cycle of follicle development and corpus luteum formation was investigated. Animals were injected with 10 U pregnant Mare＇s serum gonadotropin （PMSG） and subsequently 10 U hCG 48 h later. Time-dependent immunohistochemistry and Western blotting experiments were performed before and 24, 48, 72 h after hCG treatment. The immunohistochemistry revealed that administration of PMSG stimulated the CFTR expression in thecal cell layer and granulosa cell layer of mature follicles 48 h post injection, coincident with the PMSG-induced peak in follicular estradiol. However, the expression of CFTR in the granulose lutein cell layer and thecal lutein cell layer was time-dependently reduced following hCG injection, in accordance with the gradually increased progestogen level during luteum corpus formation. Western blotting analysis demonstrated that rat ovarian tissue expressed the special CFTR band at 170 kD. It is concluded that cAMP-dependent Cl- channels are involved in regulation of follicle development and luteum formation.展开更多
Gastroesophageal reflux disease(GERD) is a common gastrointestinal disorder in cystic fibrosis(CF), and based on various studies, its prevalence is elevated since childhood. There are several pathogenetic mechanisms o...Gastroesophageal reflux disease(GERD) is a common gastrointestinal disorder in cystic fibrosis(CF), and based on various studies, its prevalence is elevated since childhood. There are several pathogenetic mechanisms on the basis of association between CF and GERD. However, there are no specific guidelines for GERD in CF patients, so diagnosis is based on guidelines performed on patients not affected by CF. The aim of this review is to provide the pathophysiology, diagnostic and therapeutic options, complications, and future directions in the management of GERD patients with CF.展开更多
文摘Cystic Fibrosis (CF) is the most common lethal autosomal inherited disorder that affects all races and ethnicities in the United States. However, it is mostly predominant in the Caucasian populace accounting for about 80% of all CF cases. CF most severe complication can be referred to as pulmonary bronchiectasis and infections of the airways, nonetheless, the devastating effects of the disease have far-reaching consequences beyond lung damage. CF is a heterogeneous disease that is caused by mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The impairment or absence of this gene can affect multiple organs and systems and is characterized not only by chronic lung blockage, infections, and inflammation but also by exocrine gland dysfunction, intestinal obstruction, liver pathology, elevated sweat chloride concentration, and in males, infertility due to the congenital bilateral absence of the vas deferens. To this end, we briefly explore the pathological effects of CF and how CF mediates the destruction of several critical organs in the body and some of the gene therapeutical approaches such as gene editing and viral-based strategies available for the treatment of this multi-organ disease.
文摘Low sperm motility is one of the main causes of male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR, an anion channel protein) is related to the progressive motility of sperm. CFTR disruptor CFTRinh-172 or forskolin (FSK) in this study were used to treat human sperm separately, and the rates of sperm autophagy and progressive motility, mitochondrial membrane potential (MMP) and ATP concentration, and the expression levels of related factors were detected to explore their relationship. It was showed that sperms treated with CFTRinh-172 or FSK reduced the levels of cAMP, CFTR and PKA, but increased sperm autophagy rate, expression levels of AMPK and LC3B. However, reactive oxygen species content had no significant difference. It was indicated that low level of CFTR performed with cAMP and its downstream effectors such as PKA and AMPK to regulate mitochondrial structure and function, leading to increased autophagy rate and reduced vitality of sperm.
文摘BACKGROUND Abernethy malformation,also known as congenital extrahepatic portosystemic shunt,is an uncommon malformation resulting from aberrant development of the portal venous system.Cystic fibrosis(CF)is an autosomal recessive genetic disease caused by mutations in the CFTR gene.It mainly affects the exocrine glands of the respiratory,digestive and reproductive systems.It is considered extremely rare in the Asian population.We present a clinical case involving a pediatric patient of Asian descent who was diagnosed with Abernethy malformation and CF.CASE SUMMARY A 12-year-old girl presented with a medical history of recurring respiratory infections and hemoptysis,and chest computed tomography(CT)showed bronchiectasis.Whole exome sequencing was performed for the patient,yielding findings that revealed a compound heterozygous variant of the CFTR gene:c.233_c.234insT/p.Trp79fsTer3(maternal origin);c.2909G>A/p.Gly970Asp(paternal origin).CF was diagnosed.The physician’s attention was drawn to the presence of splenomegaly during disease progression.Abdominal enhanced CT revealed splenomegaly,compression of the left kidney,and multiple tortuous dilated vascular shadows were seen at the splenic hilum,which flowed back into the left renal vein and portal vein,suggesting Abernethy malformation type II.Intraoperatively,the abnormal blood flow was seen to merge into the inferior vena cava through the left renal vein without hepatic processing,and the pathology of liver biopsy showed hypoplastic,dilated or absent portal vein branches,both of which supported the diagnosis of Abernethy malformation type II.This represents the initial documented instance of Abernethy malformation accompanied by a CFTR gene mutation in the existing body of literature.CONCLUSION Coexisting Abernethy malformation and CF are rare.Detailed medical history information,abdominal enhanced CT,venography and genetic testing contribute to diagnosis as well as differential diagnosis.
基金The study was reviewed and approved by the Mass General Brigham Healthcare Institutional Review Board(2011P001563).
文摘BACKGROUND Gastroesophageal reflux(GER)has been associated with poor outcomes after lung transplantation for chronic lung disease,including increased risk of chronic rejection.GER is common in cystic fibrosis(CF),but factors influencing the likelihood of pre-transplant pH testing,and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown.AIM To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF.METHODS This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant.Patients with pretransplant anti-reflux surgery were excluded.Baseline characteristics(age at transplantation,gender,race,body mass index),self-reported GER symptoms prior to transplantation,and pre-transplant cardiopulmonary testing results,were recorded.Reflux testing consisted of either 24-h pH-or combined multichannel intraluminal impedance and pH monitoring.Post-transplant care included a standard immunosuppressive regimen,and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients.The primary outcome of chronic lung allograft dysfunction(CLAD)was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria.Statistical analysis was performed with Fisher’s exact test to assess differences between cohorts,and time-to-event Cox proportional hazards modeling.RESULTS After applying inclusion and exclusion criteria,a total of 60 patients were included in the study.Among all CF patients,41(68.3%)completed reflux monitoring as part of pre-lung transplant evaluation.Objective evidence of pathologic reflux,defined as acid exposure time>4%,was found in 24 subjects,representing 58%of the tested group.CF patients with pre-transplant reflux testing were older(35.8 vs 30.1 years,P=0.01)and more commonly reported typical esophageal reflux symptoms(53.7%vs 26.3%,P=0.06)compared to those without reflux testing.Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing.Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses(68%vs 85%,P=0.003).There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not,after controlling for confounders(Cox Hazard Ratio 0.26;95%CI:0.08-0.92).CONCLUSION Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD.Systematic reflux testing may enhance outcomes in this patient population.
文摘Cystic fibrosis patients often develop lung infections because of the presence of thick and sticky mucus that fills their airways. The presence of this thick mucus prevents the lungs from filtering out certain dominant bacterial types, making patients highly susceptible to infections that can range anywhere in severity from mild to life-threatening. These infections can cause great distress for patients as it becomes harder for patients to breathe and increases the chance of mortality by respiratory failure. It is important to be able to track the progression or regression of cystic fibrosis to determine the best course of treatment. Thus, this project focuses on the use of an AI model to examine the microbiology of cystic fibrosis patients and predict the condition or stage of lung function in the future, as a way to guide doctors with their treatment plan. Due to the limited amounts of publicly available patient data, we used all of the data in the training and testing of our machine learning algorithms initially and then tried a 50% training, 10% validation, and 40% testing split. Our results show that with relatively simple models (cubic polynomials), we can predict FEV1 from statistically significant bacteria sequences within 98% accuracy when training on sufficiently large samples.
基金Supported by a grant from the University Hospitals Fellowship Research Award Program(FRAP)
文摘BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD)seen in an estimated 15%-60%of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown.In the general population,hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes.Cystic fibrosis related diabetes(CFRD)impacts 40%-50%of CF adults and is characterized by both insulin insufficiency and insulin resistance.We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.AIM To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.METHODS Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study.Only pancreatic insufficient patients with CFRD or normal glucose tolerance(NGT)were included.Patients with established CFLD,end stage lung disease,or persistently elevated liver enzymes were excluded.Mean magnetic resonance imaging(MRI)proton density fat fraction(PDFF)was obtained for all participants.Clinical characteristics[age,sex,body mass index,percent predicted forced expiratory volume at 1 s(FEV1),lumacaftor/ivacaftor use]and blood chemistries were assessed for possible association with hepatic steatosis.Hepatic steatosis was defined as a mean MRI PDFF>5%.Patients were grouped by diabetes status(CFRD,NGT)and cystic fibrosis transmembrane conductance regulator(CFTR)modulator use(lumacaftor/ivacaftor,no lumacaftor/ivacaftor)to determine between group differences.Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher’s exact test.RESULTS Twenty subjects were included in the final analysis.The median age was 22.3 years(11.3-39.0)and median FEV1 was 77%(33%-105%).Twelve subjects had CFRD and 8 had NGT.Nine subjects were receiving lumacaftor/ivacaftor.The median PDFF was 3.0%(0.0%-21.0%).Six subjects(30%)had hepatic steatosis defined as PDFF>5%.Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor(median,range)(2.0%,0.0%-6.4%)than in patients not receiving lumacaftor/ivacaftor(4.1%,2.7-21.0%),P=0.002.Though patients with CFRD had lower PDFF(2.2%,0.0%-14.5%)than patients with NGT(4.9%,2.4-21.0%)this did not reach statistical significance,P=0.06.No other clinical characteristic was strongly associated with hepatic steatosis.CONCLUSION Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis.No association between CFRD and hepatic steatosis was found in this cohort.
文摘Cystic fibrosis(CF)is a common autosomal recessive disease.Life expectancy of patients with CF continues to improve mainly driven by the evolving therapies for CF-related organ dysfunction.The prevalence of CF-related diabetes(CFRD)increases exponentially as patients’age.Clinical care guidelines for CFRD from 2010,recommend insulin as the mainstay of treatment.Many patients with CFRD may not require exogenous insulin due to the heterogeneity of this clinical entity.Maintenance of euglycemia by enhancing endogenous insulin production,secretion and degradation with novel pharmacological therapies like glucagonlike peptide-1 agonist is an option that remains to be fully explored.As such,the scope of this article will focus on our perspective of glucagon-like peptide-1 receptor agonist in the context of CFRD.Other potential options such as sodiumglucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors and their impact on this patient population is limited and further studies are required.
文摘Cystic fibrosis(CF)is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene.CF liver disease develops in 5%-10%of patients with CF and is the third leading cause of death among patients with CF after pulmonary disease or lung transplant complications.We review the pathogenesis,clinical presentations,complications,diagnostic evaluation,effect of medical therapies especially CF transmembrane conductance regulator modulators and liver transplantation in CF associated liver disease.
文摘BACKGROUND Cystic fibrosis transmembrane conductance regulator(CFTR)modulators significantly improve pulmonary function in patients with cystic fibrosis(CF)but the effect on hepatobiliary outcomes remains unknown.We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol.AIM To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF.METHODS A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF.Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use.Subjects were grouped by use of CFTR modulators,ursodiol,dual therapy,or no therapy.The primary outcome was development of cirrhosis.Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups.RESULTS A total of 7201 patients were included,of which 955(12.6%)used a CFTR modulator,529(7.0%)used ursodiol,105(1.4%)used combination therapy,and 5612(74.3%)used neither therapy.The incidence of cirrhosis was 0.1%at 1 year and 0.7%at 4 years in untreated patients,5.9%and 10.1%in the Ursodiol group,and 1.0%and 1.0%in patients who received both therapies.No patient treated with CFTR modulators alone developed cirrhosis.Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients(P=0.05),patients on Ursodiol(P<0.001),and patients on dual therapy(P=0.003).The highest incidence of cirrhosis was found among patients treated with Ursodiol alone,compared to untreated patients(P<0.001)or patients on Ursodiol and CFTR modulators(P=0.01).CONCLUSION CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.
基金Supported by the Innovation and Technology Fund of Hong Kong, China
文摘AIM： To investigate the effect of tetramethylpyrazine （TMP）, an active compound from Ligustium Wollichii Franchat, on electrolyte transport across the distal colon of rodents and the mechanism involved.METHODS： The short-circuit current （Isc） technique in conjunction with pharmacological agents and specific inhibitors were used in analyzing the electrolyte transport across the distal colon of rodents. The underlying cellular signaling mechanism was investigated by radioimmunoassay analysis （RIA） and a special mouse model of cystic fibrosis.RESULTS： IMP stimulated a conoentration-dependent rise in ISCl, which was dependent on both Cl^- and HCO3^-, and inhibited by apical application of diphenylamine-2,2＇-dicarboxylic acid （DPC） and glibenclamide, but resistant to 4,4＇-diisothiocyanatostilbene-2,2＇-disulfonic acid disodium salt hydrate （DIDS）. Removal of Na^＋ from basolateral solution almost completely abolished the Isc response to TMP, but it was insensitive to apical Na^＋ replacement or apical Na^＋ channel blocker, amiloride. Pretreatment of colonic mucosa with BAPTA-AM, a membrane-permeable selective Ca2＋ chelator, did not significantly alter the TMP-induced Iso No additive effect of forskolin and 3-isobutyl-l-methylxanthine （[BMX） was observed on the TMP-induced Isc, but it was significantly reduced by a protein kinase A inhibitor, H89.RIA results showed that TMP （1 mmol/L） elicited a significant increase in cellular cAMP production, which was similar to that elicited by the adenylate cyclase activator, forskolin （10μmol/L）. The TMP-elicited Isc as well as forskolin- or IBMX-induced Isc were abolished in mice with homozygous mutation of the cystic fibrosis transmembrane conductance regulator （CFTR） presenting defective CFTR functions and secretions.CONCLUSION： TMP may stimulate cAMP-dependent and CFTR-mediated Cl^- and HCO3^- secretion. This may have implications in the future development of alternative treatment for constipation.
基金Supported by American Cancer Society Institutional Research to Li C,No.11-053-01-IRGNational Institutes of Health grant HL128647
文摘Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.
基金Supported by National Natural Science Foundation of China, No.81800473"Young Eagle Project"of Air Force Medical University, No.KT2021DX007
文摘BACKGROUND Intestinal ischemia/reperfusion(I/R)injury is a fatal syndrome that occurs under many clinical scenarios.The apoptosis of intestinal cells caused by ischemia can cause cell damage and provoke systemic dysfunction during reperfusion.However,the mechanism of I/R-induced apoptosis remains unclear.Cystic fibrosis transmembrane conductance regulator(CFTR)is a cAMP-activated chloride channel.Few researchers have paid attention to its role in intestinal I/R injury,or the relationship between CFTR and intestinal apoptosis induced by hypoxia/reoxygenation(H/R).AIM To investigate the effects of CFTR on I/R-induced intestinal apoptosis and its underlying molecular mechanisms.METHODS An intestinal I/R injury model was established in mice with superior mesenteric artery occlusion, and Caco2 cells were subjected to H/R for the simulation of I/R in vivo.RESULTSThe results suggested that CFTR overexpression significantly increased the Caco2 cell viability anddecreased cell apoptosis induced by the H/R. Interestingly, we found that the translocation of p65,an NF-κB member, from the cytoplasm to the nucleus after H/R treatment can be reversed by theoverexpression of CFTR, the NF-κB P65 would return from the nucleus to the cytoplasm asdetermined by immunostaining. We also discovered that CFTR inhibited cell apoptosis in theH/R-treated cells, and this effect was significantly curbed by the NF-κB activator BA, AKTinhibitor GSK690693 and the PI3K inhibitor LY294002. Moreover, we demonstrated that CFTRoverexpression could reverse the decreased PI3K/AKT expression induced by the I/R treatment invivo or H/R treatment in vitro.CONCLUSIONThe results of the present study indicate that the overexpression of CFTR protects Caco2 cells fromH/R-induced apoptosis;furthermore, it also inhibits H/R-induced apoptosis through thePI3K/AKT/NF-κB signaling pathway in H/R-treated Caco2 cells and intestinal tissues.
基金This work was supported by the National Natural Science Foundation of China(81600002)Science and Technology Project of Quanzhou,Fujian Province(2020N050s).
文摘Cystic fibrosis is an autosomal recessive disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator(CFTR).Here we summarize,at the basic descriptive level,clinical and genetic characteristics of cystic fibrosis gene mutations,while emphasizing differences between CF mutations found in Chinese pediatric CF patients compared to those found in Caucasian CF patients.In addition,we describe animal models used to study human cystic fibrosis disease and highlight unique features of each model that mimic specific human CF-associated signs and symptoms.At the clinical level,we summarize CF clinical manifestations and diagnostic,treatment,and prognostic methods to provide clinicians with infor-mation toward reducing CF misdiagnosis and missed diagnosis rates.
基金Supported by the National Natural Science Foundation of China(Nos.30470405and30570864).
文摘Dictamine is a furoquinoline alkaloid isolated from Dictamus dasycarpus Turcz.In the present study,we found that dictamine is able to stimulate the chloride transport activity of wild-type and ΔF508 mutant CFTR.The activity is cAMP-dependent and can be completely reversed by specific CFTR inhibitor CFTRinh-172.In addition,dictamine can further increase the chloride transport activity when CFTR is maximally activated by the combination of cAMP stimulators forskolin（FSK）and IBMX,suggesting direct interaction of dictamine with CFTR.Dictamine may be useful for probing CFTR channel gating mechanisms and used as a lead compound to develop the pharmacological therapy of CFTR-related diseases such as idiopathic chronic pancreatitis and keratoconjunctivitis sicca and cystic fibrosis.
基金TEFOR,Grant/Award Number:RIIINSB-0014France Life Imaging,Grant/Award Number:ANR-11-INBS-0006+6 种基金Swiss Cystic Fibrosis Foundation CFCHFondation Maladies RaresInfrastructures Biologie-SantéIHU-CESTI,Grant/Award Number:ANR-10-IBHU-005IRSR Pays de la LoireVaincre la MucoviscidoseSwiss National Foundation,Grant/Award Number:310030_172909
文摘Background: Genetically engineered animals are essential for gaining a proper understanding of the disease mechanisms of cystic fibrosis(CF). The rat is a relevant laboratory model for CF because of its zootechnical capacity, size, and airway characteristics, including the presence of submucosal glands.Methods: We describe the generation of a CF rat model(F508 del) homozygous for the p.Phe508 del mutation in the transmembrane conductance regulator(Cftr) gene. This model was compared to new Cftr-/-rats(CFTR KO). Target organs in CF were examined by histological staining of tissue sections and tooth enamel was quantified by micro-computed tomography. The activity of CFTR was evaluated by nasal potential difference(NPD) and short-circuit current measurements. The effect of VX-809 and VX-770 was analyzed on nasal epithelial primary cell cultures from F508 del rats.Results: Both newborn F508 del and Knock out(KO) animals developed intestinal obstruction that could be partly compensated by special diet combined with an osmotic laxative. The two rat models exhibited CF phenotypic anomalies such as vas deferens agenesis and tooth enamel defects. Histology of the intestine, pancreas, liver, and lungs was normal. Absence of CFTR function in KO rats was confirmed ex vivo by short-circuit current measurements on colon mucosae and in vivo by NPD, whereas residual CFTR activity was observed in F508 del rats. Exposure of F508 del CFTR nasal primary cultures to a combination of VX-809 and VX-770 improved CFTR-mediated Cl-transport.Conclusions: The F508 del rats reproduce the phenotypes observed in CFTR KO animals and represent a novel resource to advance the development of CF therapeutics.
基金supported by the National Institute of Health’s National Institute of Allergy and Infectious Diseases under Award Nos. R01AI146160 and R01AI132681。
文摘Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients.In this study,we established and validated a new HPLC-MS/MS method that could simultaneously detect drug concentrations of ciprofloxacin,colistin and ivacaftor in rat plasma,human epithelial cell lysate,cell culture medium,and drug transport media.An aliquot of200 μL drug-containing rat plasma or cell culture medium was treated with 600 μL of extraction solution(acetonitrile containing 0.1% formic acid and 0.2% trifluoroacetic acid(TFA)).The addition of 0.2% TFA helped to break the drug-protein bonds.Moreover,the addition of 0.1% formic acid to the transport medium and cell lysate samples could significantly improve the response and reproducibility.After vortexing and centrifuging,the sample components were analyzed by HPLC-MS/MS.The multiple reaction monitoring mode was used to detect the following transitions:585.5-101.1(colistin A),578.5-101.1(colistin B),393.2-337.2(ivacaftor),332.2-314.2(ciprofloxacin),602.3-101.1(polymyxin B1 as internal standard(IS)) and 595.4-101.1(polymyxin B2 as IS).The running time of a single sample was only 6 min,making this a time-efficient method.Linear correlations were found for colistin A at 0.029-5.82 μg/m L,colistin B at 0.016-3.14 μg/m L,ivacaftor at 0.05-10.0 μg/m L,and ciprofloxacin at 0.043-8.58 μg/m L.Accuracy,precision,and stability of the method were within the acceptable range.This method would be highly useful for research on cytotoxicity,animal pharmacokinetics,and in vitro drug delivery.
基金National Natural Science Fund for Distinguished Young Scholars(No.30325011)National Natural Science Foundation of China(Nos.30470405, 30570864, 30670477)+1 种基金Distinguished Young Scholars Fund of Jilin Province (No.20030112) Excellent Young Teachers Program of Ministry of Education, China
文摘In the present study, we identified the natural compound curcumin to be an effective G551D-CFTR activator by cell-based fluorescent assay and electrophysiological measurement. We demonstrated that curcumin can restore the impaired chloride conductance of G551D mutant CFTR. The activity is rapid, reversible, and cAMP-dependent. Our study identified a new natural lead compound for the pharmacological therapy of cystic fibrosis caused by G551D mutation of CFTR.
文摘Despite the acceptance of physical activity （PA） being integral to a young person＇s health, children with disability often exhibit low levels of PA. In young people with cystic fibrosis （CF） the importance of exercise and daily PA is acknowledged by clinicians and their support teams, however, there is a lack of knowledge related to its prescription. CF is a recessive genetic disorder affecting the lung, pancreas and sweat glands. CF is the most common life shortening genetic disease in the Caucasian population for which there is no cure. In the UK, CF affects over 9000 people, with 4000 under 16 years of age. Only about half of the CF population can expect to live beyond 40 years of age. Besides drug therapies, rehabilitative exercise programmes form an important component of treatment and long term exercise programmes are considered positive treatment strategies, but all lack any detailed prescriptive information. Several reviews and editorials have highlighted the lack of evidence based research in PA and exercise training in young people with CF; but advocate a greater need for understanding the role of exercise in therapeutic interventions. The purpose of this review is to update the reader on the current recommendations and evidence in PA and exercise training for young people with CE These developments have extended our understanding of PA and exercise training in children and adolescents with CF, and its implementation in the management of this chronic disease.
文摘The protein expression of cystic fibrosis transmembrane conductance regulator （CFTR）, a cAMP-activated Cl- channel, in ovarian stimulated premature female rat ovary during a cycle of follicle development and corpus luteum formation was investigated. Animals were injected with 10 U pregnant Mare＇s serum gonadotropin （PMSG） and subsequently 10 U hCG 48 h later. Time-dependent immunohistochemistry and Western blotting experiments were performed before and 24, 48, 72 h after hCG treatment. The immunohistochemistry revealed that administration of PMSG stimulated the CFTR expression in thecal cell layer and granulosa cell layer of mature follicles 48 h post injection, coincident with the PMSG-induced peak in follicular estradiol. However, the expression of CFTR in the granulose lutein cell layer and thecal lutein cell layer was time-dependently reduced following hCG injection, in accordance with the gradually increased progestogen level during luteum corpus formation. Western blotting analysis demonstrated that rat ovarian tissue expressed the special CFTR band at 170 kD. It is concluded that cAMP-dependent Cl- channels are involved in regulation of follicle development and luteum formation.
文摘Gastroesophageal reflux disease(GERD) is a common gastrointestinal disorder in cystic fibrosis(CF), and based on various studies, its prevalence is elevated since childhood. There are several pathogenetic mechanisms on the basis of association between CF and GERD. However, there are no specific guidelines for GERD in CF patients, so diagnosis is based on guidelines performed on patients not affected by CF. The aim of this review is to provide the pathophysiology, diagnostic and therapeutic options, complications, and future directions in the management of GERD patients with CF.
