Biol Reprod. 2025 May 9:ioaf103. doi: 10.1093/biolre/ioaf103. Online ahead of print.

ABSTRACT

Cervical mucus changes throughout the menstrual cycle in response to hormonal fluctuations, regulating access of sperm and pathogens to the reproductive tract. CFTR is an anion channel that plays a critical role in mediating epithelial mucus secretions. Primary endocervical cells obtained from rhesus macaques Macaca mulatta were cultured using conditional reprogramming and treated with vehicle controls or CFTR inhibitors. In order to measure changes in hydration and viscosity of secreted mucus, we adapted two airway mucus assays, airway surface liquid and particle-tracking microrheology, for our endocervical culture system. Endocervical cells treated with CFTR inhibitors demonstrated dehydrated, thicker mucus secretions compared to controls in both assay outputs. Our studies suggest that CFTR may be an important mediator of fertility changes and provide experimental evidence for the infertility phenotype seen in women with cystic fibrosis. Additionally, assays developed in these studies provide new endpoints for assessing cervical mucus changes in vitro.

PMID:40342009 | DOI:10.1093/biolre/ioaf103

J Am Chem Soc. 2025 May 9. doi: 10.1021/jacs.5c00955. Online ahead of print.

ABSTRACT

Cholera is a severe infectious disease caused by the Gram-negative bacterium Vibrio cholerae after colonization in the intestinal tract. Cholera toxin (CT), a key exotoxin protein, primarily causes acute secretory diarrhea and life-threatening complications in infected patients. Traditional approaches remain insufficient for effectively treating cholera, underscoring the need for innovative countermeasures to eliminate CT-caused symptoms. Here, we report a glycan-modified cellular nanosponge for the enhanced treatment of CT-induced secretory diarrhea. Specifically, intestinal epithelial cell membrane-camouflaged nanosponges are functionalized with a glycan receptor to promote their capability for CT neutralization, thereby competitively inhibiting CT entry into host cells. Moreover, an inhibitor is encapsulated into the cellular nanosponge to synergistically improve the therapeutic effect of diarrhea by blocking the excessive chloride ion efflux from the cystic fibrosis transmembrane conductance regulator (a crucial anion channel) on the membrane of CT-intoxicated epithelial cells. Upon oral administration, the biomimetic nanomedicine effectively eliminates CT-induced secretory diarrhea and intestinal injuries in mice. Overall, this study highlights the potential of glycan-modified cellular nanosponges as promising and broad-spectrum therapeutic agents against secretory diarrhea caused by bacterial exotoxins.

PMID:40340322 | DOI:10.1021/jacs.5c00955

J Cyst Fibros. 2025 May 7:S1569-1993(25)00768-4. doi: 10.1016/j.jcf.2025.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary hypertension (PH) is an important, life-limiting co-morbidity in cystic fibrosis (CF), where multiple mechanisms such as hypoxia, inflammation and primary CF-transmembrane regulator (CFTR) dysfunction may affect vascular integrity. We aimed to characterize the structural impact of vascular wall changes in the pulmonary microcirculation, to uncover the potential need for therapeutic strategies targeting vascular disease.

METHODS: End-stage inflated CF (n=6), and control (n=4) lungs were processed to lung cores (2.8cm³) and scanned with micro-computed tomography (resolution: 8.5µm). The diameter and number of distal pulmonary arteries (dPA), distal airways (DA) and open terminal bronchioles (TB) were measured on 3D models (n= 2 cores/lobe) and compared per generation and within pairs. Morphometric assessment was paired with histological analysis (n= 1/lobe) to assess tissue morphology, collagen and connective tissue components.

RESULTS: dPA in CF were narrowed and disappeared in the last generations of dichotomous branching, resulting in a decreased total diameter per generation. While narrowing was already present where TB remained open, dPA disappearance was only present where no TB were left. dPA narrowing increased when DA collapsed. Histologically, fibrotic dPA changes were present in areas without distal airway disease.

CONCLUSION: We showed for the first time the presence of dPA lumen narrowing and disappearance with fibrotic vascular wall changes in end-stage CF. Narrowing was present diffusely and fibrosis was also present in areas without airway disease. These findings suggest that vascular dysfunction in CF may not solely be secondary to hypoxic vasoconstriction and inflammation but may represent a distinct pathophysiological process related to CFTR dysfunction in the endothelium, warranting further study.

PMID:40340199 | DOI:10.1016/j.jcf.2025.04.002

Respir Med. 2025 May 6:108136. doi: 10.1016/j.rmed.2025.108136. Online ahead of print.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis (NCFB) is often complicated by chronic Pseudomonas aeruginosa infection. Inhaled antibiotics, such as tobramycin, have been explored for their efficacy in managing these infections, but their efficacy and safety in NCFB remains uncertain.

METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of inhaled tobramycin in NCFB patients. PubMed, EMBASE, Cochrane Library, and ISI Web of Science databases were searched up to June 2024 using predefined keywords. Studies comparing inhaled tobramycin versus placebo were included if they reported outcomes related to P. aeruginosa eradication, sputum density, exacerbations, hospital admissions, and adverse events.

RESULTS: Nine RCTs involving 772 patients met the inclusion criteria. Inhaled tobramycin significantly increased P. aeruginosa eradication rates compared to placebo (I2=22.0%, P=0.255; RR 2.422, 95% CI 1.570 to 3.738, P<0.001). There was a marked reduction in hospital admissions (I2=27.9%, P=0.250; WMD -0.523, 95% CI -0.879 to -0.167, P=0.004) but no significant difference in exacerbation rates (I2=31.9%, P=0.196; RR 0.837, 95% CI 0.519 to 1.349, P=0.464). Adverse events leading to trial discontinuation were higher in the tobramycin group (I2=0.0%, P=0.634; RR 1.968, 95% CI 1.197 to 3.236, P=0.008).

CONCLUSIONS: Inhaled tobramycin therapy demonstrated efficacy in eradicating P. aeruginosa and reducing hospital admissions in patients with NCFB. However, no significant impact on exacerbation rates was observed, and the higher incidence of adverse events necessitates careful consideration in clinical practice.

PMID:40339664 | DOI:10.1016/j.rmed.2025.108136

mSphere. 2025 May 8:e0108124. doi: 10.1128/msphere.01081-24. Online ahead of print.

ABSTRACT

Biofilms are an important colonization mechanism employed by several microbial species to better establish themselves and monopolize the acquisition of resources across different environs. Some bacteria have evolved specialized metabolites that, when secreted, disrupt the formation and stability of biofilms generated by competing heterospecies, providing the producing organism with an ecological advantage. Soil-derived species are probable candidates for the identification of such compounds, given the intense level of competition that occurs within the terrestrial ecosystem. The MS14 strain of Burkholderia contaminans isolated from soil in Mississippi has previously been shown to produce antimicrobial compounds like occidiofungin and ornibactin. In this report, we demonstrate that this strain also produces 4-hydroxy-3-methyl-2-alkenylquinoline (HMAQ-7), an alkaloid-based metabolite structurally similar to others produced by Burkholderia. HMAQ-7 was isolated and purified in sufficient quantities to enable the elucidation of its covalent structure and the evaluation of its biological effects. The compound was found to possess a unique ability to inhibit biofilm biosynthesis in several species, including opportunistic pathogens like Staphylococcus haemolyticus and within saliva-derived multispecies biofilms. HMAQ-7 also demonstrated an ability to modulate additional cellular behaviors in Bacillus subtilis, including motility and sporulation, suggesting that this molecule is important to the interspecies dynamics present across many diverse microenvironments.IMPORTANCEThe present study furthers our understanding of the structural complexity and the biological functions of the 2-alkyl-4(1H)-quinolone metabolites produced by Burkholderia spp. Low micromolar concentrations of HMAQ-7' induced observable bacterial growth morphology differences. The antibiofilm properties of the HMAQ-7' characterized in this study will promote future investigations into possible biological and applied roles. The ability to alter biofilm formation using HMAQ-7' may facilitate Burkholderia spp. colonization in a multitude of environments, that is, aquatic, soil, and possibly during infection. HMAQ may subvert competition by potential competitor species in natural environments of Burkholderia spp. and possibly lung infections of cystic fibrosis patients.

PMID:40338090 | DOI:10.1128/msphere.01081-24

ERJ Open Res. 2025 May 6;11(3):00623-2024. doi: 10.1183/23120541.00623-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: Lung transplantation is a highly dynamic segment of solid organ transplantation in which gender plays a central role. Our objective was to investigate the causes of outcome differences between women and men all along the lung transplantation pathway.

METHODS: We used data from the French COhort in Lung Transplantation (COLT) study (12 participating lung transplantation centres). Analyses were performed in three phases: baseline clinical characteristics, peri-transplantation period and post-transplantation follow-up.

RESULTS: Overall, 1710 participants (802 women and 908 men) were included in this study. Women were less likely than men to undergo transplantation (91.6% versus 95.6%; p=0.001) and waited longer before transplantation (115 versus 73 days; p<0.001). Female gender and pre-transplantation class I anti-human leukocyte antigen antibodies were identified as independent factors associated with longer waiting time duration. Female transplant recipients commonly received lungs from height- and sex-matched donors, despite higher female waiting list mortality and a higher proportion of male donors. Importantly, women with oversized lung transplantation (defined by predicted total lung capacity (pTLC) ratio and weight mismatch) did not have worse survival. The overall post-transplantation survival of female recipients was significantly higher than that of male recipients (65.6% versus 57.3%; p<0.001), although the prevalence of specific major lung transplantation outcomes did not differ according to gender.

CONCLUSION: Women waited longer and were less likely to undergo transplantation. Women transplanted with an oversized lung did not have worse survival after transplantation, suggesting that size matching criteria based on pTLC ratio and weight mismatch may be less stringent in this context.

PMID:40337341 | PMC:PMC12053738 | DOI:10.1183/23120541.00623-2024

Thorac Res Pract. 2025 May 8. doi: 10.4274/ThoracResPract.2025.2025-1-1. Online ahead of print.

ABSTRACT

The objective of the study was to assess and compare the efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) treatment with TEZ/IVA treatment in individuals diagnosed with cystic fibrosis (CF) and carrying the F508del allele. An extensive search of relevant literature was conducted using online resources, namely, PubMed, ScienceDirect, and Google Scholar. The initial search identified 248 articles, and after a careful examination of the full text of 18 articles, 7 met the inclusion and exclusion criteria. These selected reports were then thoroughly examined to perform a comparative analysis of the effectiveness of TEZ/IVA versus ELX/TEZ/IVA in CF patients with the F508del allele. The quality of the selected reports was evaluated using the Cochrane risk-of-bias tool for randomized studies, known as RoB 2. ELX/TEZ/IVA has shown significant improvements in key indicators of CF treatment. It has demonstrated a significant increase in forced expiratory volume in one second levels, indicating improved respiratory capacity and airflow. Additionally, ELX/TEZ/IVA successfully reduced sweat chloride levels and positively impacted Cystic Fibrosis Questionnaire-Revised Respiratory Domain scores, reflecting enhanced respiratory function and improved quality of life for patients. Overall, the study concluded that ELX/TEZ/IVA provided a clinically robust benefit compared to TEZ/IVA alone while maintaining a favourable safety profile.

PMID:40336353 | DOI:10.4274/ThoracResPract.2025.2025-1-1

Nat Commun. 2025 May 7;16(1):4235. doi: 10.1038/s41467-025-56910-x.

ABSTRACT

Chronic care manages long-term, progressive conditions, while acute care addresses short-term conditions. Chronic conditions increasingly strain health systems, which are often unprepared for these demands. This study examines the burden of conditions requiring acute versus chronic care, including sequelae. Conditions and sequelae from the Global Burden of Diseases Study 2019 were classified into acute or chronic care categories. Data were analysed by age, sex, and socio-demographic index, presenting total numbers and contributions to burden metrics such as Disability-Adjusted Life Years (DALYs), Years Lived with Disability (YLD), and Years of Life Lost (YLL). Approximately 68% of DALYs were attributed to chronic care, while 27% were due to acute care. Chronic care needs increased with age, representing 86% of YLDs and 71% of YLLs, and accounting for 93% of YLDs from sequelae. These findings highlight that chronic care needs far exceed acute care needs globally, necessitating health systems to adapt accordingly.

PMID:40335470 | DOI:10.1038/s41467-025-56910-x

Talanta. 2025 May 5;294:128278. doi: 10.1016/j.talanta.2025.128278. Online ahead of print.

ABSTRACT

The early diagnosis of diseases largely relies on the monitoring and accurate detection of biomarkers within biological systems. The quantification of chloride ions (Cl-) and glutathione (GSH) can effectively assess the progression of diseases such as cystic fibrosis and cancer, as well as the alterations in the body's internal environment. However, developing reliable sensing platforms with high sensitivity and selectivity poses significant challenges. Based on the dual-functional silver-based metal-organic frameworks (Ag MOF), an electrochemical/electrochemiluminescent (EC/ECL) dual-channel nanoplatform was developed for the detection of Cl- and GSH, aided by graphitic carbon nitride (g-C3N4). In the EC mode, the interaction between Ag MOF and Cl- leads to the formation of silver chloride (AgCl), which is characterized by an increased peak current of AgCl solid-state electrochemistry as Cl- concentration rises. The further introduction of GSH generates a non-electroactive complex through competition with Cl-, resulting in a decrease in the peak current of AgCl. In the ECL mode, the quenching of ECL signals from g-C3N4 by Ag MOF is alleviated by Cl-, due to the etching of the Ag-MOF. The ECL recovery effect is further enhanced with the addition of GSH. For Cl-, both EC and ECL responses exhibit good linear relationships with concentrations ranging from 0.5 to 10 mM, with detection limit (LOD) of 0.4 mM and 0.1 mM, respectively. For GSH, EC and ECL also show good linear relationships in range of 0.01-100 μM, with LOD of 9.8 nM and 1.02 nM. The unique properties of Ag MOF, acting both as an electrochemical sensing component that generates sensitive current outputs for Cl- and GSH, and as a quencher for the ECL of g-C3N4, facilitate the sequential detection of Cl- and GSH, providing mutual validation that significantly enhances accuracy and reliability. The specific interactions of Ag MOF with these analytes offer the innovative platform good selectivity, demonstrating significant potential for advancements in biological analysis and disease diagnosis.

PMID:40334507 | DOI:10.1016/j.talanta.2025.128278

PLoS One. 2025 May 7;20(5):e0311711. doi: 10.1371/journal.pone.0311711. eCollection 2025.

ABSTRACT

Arsenic is associated with lung disease and experimental models suggest that arsenic-induced degradation of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) is a mechanism of arsenic toxicity. We examined associations between arsenic exposure, sweat chloride concentration (measure of CFTR function), and pulmonary function among 269 adults in Bangladesh. Participants with sweat chloride ≥ 60 mmol/L had higher arsenic exposures than those with sweat chloride < 60 mmol/L (water: median 77.5 µg/L versus 34.0 µg/L, p = 0.025; toenails: median 4.8 µg/g versus 3.7 µg/g, p = 0.024). In linear regression models, a one-unit µg/g increment in toenail arsenic was associated with a 0.59 mmol/L higher sweat chloride concentration, p < 0.001. Among the entire study population, after adjusting for covariates including age, sex, smoking, education, and height, toenail arsenic concentration was associated with increased odds of airway obstruction (OR: 1.97, 95%: 1.06, 3.67, p = 0.03); however, sweat chloride concentration did not mediate this association. Our findings suggest that sweat chloride concentration may serve as novel biomarker for arsenic exposure, warranting further investigation in diverse populations, and that arsenic likely acts on the lung through mechanisms other than inducing CFTR dysfunction. Alternative mechanisms by which environmental arsenic exposure may lead to obstructive lung disease, such as arsenic-induced direct lung injury and/or increase lung proteinase activity, require additional exploration in future work.

PMID:40333927 | DOI:10.1371/journal.pone.0311711

Pathogens. 2025 Apr 15;14(4):387. doi: 10.3390/pathogens14040387.

ABSTRACT

This study analyzed eleven isolates of colistin-resistant Pseudomonas aeruginosa, originating from Portugal and Taiwan, which are associated with various pathologies. The results revealed significant genetic diversity among the isolates, with each exhibiting a distinct genetic profile. A prevalence of sequence type ST235 was observed, characterizing it as a high-risk clone, and serotyping indicated a predominance of type O11, associated with chronic respiratory infections in cystic fibrosis (CF) patients. The phylogenetic analysis demonstrated genetic diversity among the isolates, with distinct clades and complex evolutionary relationships. Additionally, transposable elements such as Tn3 and IS6 were identified in all isolates, highlighting their importance in the mobility of antibiotic resistance genes. An analysis of antimicrobial resistance profiles revealed pan-drug resistance in all isolates, with a high prevalence of genes conferring resistance to β-lactams and aminoglycosides. Furthermore, additional analyses revealed mutations in regulatory networks and specific loci previously implicated in colistin resistance, such as pmrA, cprS, phoO, and others, suggesting a possible contribution to the observed resistant phenotype. This study has a strong impact because it not only reveals the genetic diversity and resistance mechanisms in P. aeruginosa but also identifies mutations in regulatory genes associated with colistin resistance.

PMID:40333140 | DOI:10.3390/pathogens14040387

Int J Mol Sci. 2025 Apr 17;26(8):3788. doi: 10.3390/ijms26083788.

ABSTRACT

Genome organization is essential for precise spatial and temporal gene expression and relies on interactions between promoters and distal cis-regulatory elements (CREs), which constitute ~8% of the human genome. For the cystic fibrosis transmembrane conductance regulator (CFTR) gene, tissue-specific expression, especially in the pancreas, remains poorly understood. Unraveling its regulation could clarify the clinical heterogeneity observed in cystic fibrosis and CFTR-related disorders. To understand the role of 3D chromatin architecture in establishing tissue-specific expression of the CFTR gene, we mapped chromatin interactions and epigenomic regulation in Capan-1 pancreatic cells. Candidate CREs are validated by luciferase reporter assay and CRISPR knock-out. We identified active CREs not only around the CFTR gene but also outside the topologically associating domain (TAD). We demonstrate the involvement of multiple CREs upstream and downstream of the CFTR gene and reveal a cooperative effect of the -44 kb, -35 kb, +15.6 kb, and +37.7 kb regions, which share common predicted transcription factor (TF) motifs. We also extend our analysis to compare 3D chromatin conformation in intestinal and pancreatic cells, providing valuable insights into the tissue specificity of CREs in regulating CFTR gene expression.

PMID:40332394 | DOI:10.3390/ijms26083788

Int J Mol Sci. 2025 Apr 16;26(8):3750. doi: 10.3390/ijms26083750.

ABSTRACT

Mammalian spermatozoa undergo a series of physiological and biochemical changes in the oviduct that lead them to acquire the ability to fertilize eggs. During their transit in the oviduct, spermatozoa face a series of environmental changes that can affect sperm viability. A series of ion channels and transporters, as well as the sperm cytoskeleton, allow spermatozoa to remain viable and functional. Cl- channels such as TMEM16A (calcium-activated chloride channel), CFTR (cystic fibrosis transmembrane conductance regulator), and ClC3 (chloride voltage-gated channel 3) are some of the ion transporters involved in maintaining cellular homeostasis. They are expressed in mammalian spermatozoa and are associated with capacitation, acrosomal reaction, and motility. However, little is known about their role in maintaining sperm volume. Therefore, this study aimed to determine the mechanism through which TMEM16A maintains sperm volume during capacitation. The effects of TMEM16A were compared to those of CFTR and ClC3. Spermatozoa were capacitated in the presence of specific TMEM16A, CFTR, and ClC3 inhibitors, and the results showed that only TMEM16A inhibition increased acrosomal volume, leading to changes within the acrosome. Similarly, only TMEM16A inhibition prevented actin polymerization during capacitation. Further analysis showed that TMEM16A inhibition also prevented ERK1/2 and RhoA activation. On the other hand, TMEM16A and CFTR inhibition affected both capacitation and spontaneous acrosomal reaction, whereas ClC3 inhibition only affected the spontaneous acrosomal reaction. In conclusion, during capacitation, TMEM16A activity regulates acrosomal structure through actin polymerization and by regulating ERK1/2 and RhoA activities.

PMID:40332387 | DOI:10.3390/ijms26083750

Arq Gastroenterol. 2025 May 2;62:e24110. doi: 10.1590/S0004-2803.24612024-110. eCollection 2025.

ABSTRACT

BACKGROUND: In patients with cystic fibrosis (pwCF) acid suppression therapy, gastrointestinal dysmotility, and post-operative bowel status, may predispose to the development of small intestinal bacterial overgrowth (SIBO). SIBO may continue to be present in the progression of the disease even on modulators. Breath testing is the most simple, non-invasive and available method for diagnosing SIBO. There are some divergencies over the operational procedures used to carry out and interpret breath tests in pwCF.

OBJECTIVE: We performed a systematic review of SIBO in pwCF to assess the methods used in breath tests and the existence of causal relationship between SIBO and following CF co-morbidities: liver disease, fat absorption, and eating disorders.

METHODS: We searched the PubMed, Cochrane Library, Embase, LILACS, MEDLINE, OpenGray, medRxiv, Google Scholar, and CAPES databases up to March 20, 2024. We selected clinical cohort and case-control studies to assess SIBO in cwCF. We selected studies that met the following criteria: (1) participants - children and adolescents diagnosed with CF; (2) intervention - assessment of SIBO using H2 and CH4 breath tests; (3) control - patients without SIBO; and (4) outcome - assessment of breath tests for SIBO diagnosis and the causal relationship between SIBO and CF co-morbidities. The PRISMA statement was used to report the search. QUADAS 2 tool was used for assessing the quality of each study methodology. The protocol for this review was registered in the Prospective Registration of Systematic Review Database (CRD42024503593).

RESULTS: The search strategy identified 279 studies. After screening titles and abstracts, 36 studies were selected for full-text review and 27 were excluded; nine studies involving 206 pwCFs were reviewed. All nine studies used H2 breath tests as a diagnostic method for SIBO, and five of them used a combined H2/CH4 test. There was no consistency in the timing of cessation of antibiotic therapy prior to testing. All patients performed the test after an overnight fast. A basal sample was collected prior to substrate (glucose or lactulose) ingestion, which ranged from 7 to 20 ppm. There was great variability between respiratory sample collection times, being times 0, 15, 30, 45, 60, 90, and 120 minutes the most used protocol. The methods for performing breath tests varied widely, making it difficult to reach conclusions on the role of SIBO as a co-morbidity in pwCF. There was no association between increased serum AST, ALT, and GGT levels and positive breath tests. There was no agreement regarding the role of SIBO and nutritional deficiency, but a reduction in fat absorption and the presence of hyporexia have been described under this condition.

CONCLUSION: Data on assessment of SIBO in pwCF is limited by the small number of studies available, the lack of appropriate controls in some studies, and the varying test methodology and diagnostic cut-offs applied. Protocols to investigate and diagnosing SIBO in pwCF need to be developed.

PMID:40332310 | DOI:10.1590/S0004-2803.24612024-110

Int J Mol Sci. 2025 Apr 11;26(8):3623. doi: 10.3390/ijms26083623.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most frequent mutation (p.Phe508del) results in a misfolded protein (p.Phe508del-CFTR) with an altered transport to the membrane of the cells via the conventional protein secretion (CPS) pathway. Nevertheless, it can use unconventional protein secretion (UPS). Indeed, p.Phe508del-CFTR forms a complex with GRASP55 to assist its direct trafficking from the endoplasmic reticulum to the plasma membrane. While GRASP55 is a key player of UPS, it is also a key player of stress-induced autophagy. In parallel, the unfolded protein response (UPR), which is activated in the presence of misfolded proteins, is tightly linked to UPS and autophagy through the key effectors IRE1, PERK, and ATF6. A better understanding of how UPS, UPR, and stress-induced autophagy interact to manage protein trafficking in CF and other conditions could lead to novel therapeutic strategies. By enhancing or modulating these pathways, it may be possible to increase p.Phe508del-CFTR surface expression. In summary, this review highlights the critical roles of UPS- and UPR-induced autophagy in managing protein transport, offering new perspectives for therapeutic approaches.

PMID:40332143 | DOI:10.3390/ijms26083623

Am J Physiol Lung Cell Mol Physiol. 2025 May 7. doi: 10.1152/ajplung.00287.2024. Online ahead of print.

ABSTRACT

Lumacaftor, the corrector of Orkambi, enhances the processing of F508del cystic fibrosis transmembrane conductance regulator (CFTR) but its impact on the channel activity of rescued F508del CFTR (rF508del) is unclear. Using an electrode-based, real-time iodide efflux assay performed at room temperature, acute exposure to lumacaftor was shown to increase the processing of F508del CFTR without a proportional increase in channel activity in a CFBE41o- cell line stably expressing F508del CFTR (CFBE-DF). A similar effect was not observed on wild-type CFTR in a HEK293 cell line. At 37°C, rF508del channel activity is significantly inhibited in CFBE-DF cells by acute exposure to 5mM lumacaftor, but not to 5mM tezacaftor or 1mM elexacaftor, the two correctors of Trikafta. Lumacaftor's inhibitory effect was characterized by a major left-shift of the peak channel activity relative to the peak CFTR processing in the dose response chart, which is absent for tezacaftor or elexacaftor. Ussing chamber analysis on polarized CFBE-DF cells reveals an inhibitory effect for lumacaftor on the forskolin- and ivacaftor-induced change in short circuit current. Single channel patch clamp on HEK-DF cells shows that acute application of cytosolic lumacaftor significantly decreases rF508del channel open probability. Taken together, despite its strong corrector activity, lumacaftor inhibits rF508del channel activity, compromising the degree of functional rescue. This effect may contribute to the limited clinical efficacy of Orkambi.

PMID:40331529 | DOI:10.1152/ajplung.00287.2024

Expert Opin Pharmacother. 2025 May 7. doi: 10.1080/14656566.2025.2491515. Online ahead of print.

ABSTRACT

INTRODUCTION: Ensifentrine, recently approved by the FDA for chronic obstructive pulmonary disease (COPD) maintenance treatment, is a novel inhaled therapy with a dual mechanism of action targeting phosphodiesterase (PDE)3 and PDE4. While long-acting bronchodilators and inhaled corticosteroids remain initial guideline-based COPD treatments, persistent symptoms and disease exacerbations highlight an existing unmet need. Ensifentrine offers both bronchodilator and anti-inflammatory benefits, offering the potential to address this treatment gap.

AREAS COVERED: This article reviews the mechanism of action of ensifentrine, details supporting preclinical evidence, and summarizes key clinical studies. It further explores ensifentrine's potential impact on the COPD treatment landscape and its potential applicability in other pulmonary diseases.

EXPERT OPINION: Ensifentrine's dual bronchodilator and anti-inflammatory action offer a promising adjunct to standard COPD treatments, particularly for patients with persistent symptoms despite conventional therapy. It improves lung function, meaningfully reduces exacerbation frequency, reduces symptoms, and enhances quality of life. Its inhaled delivery minimizes systemic exposure and side effects commonly observed with oral PDE inhibitors. Furthermore, its anti-inflammatory properties suggest potential applications in other chronic respiratory diseases, such as asthma and non-cystic fibrosis bronchiectasis.

PMID:40331465 | DOI:10.1080/14656566.2025.2491515

Front Immunol. 2025 Apr 22;16:1576141. doi: 10.3389/fimmu.2025.1576141. eCollection 2025.

ABSTRACT

In recent years, the study of the interaction between gut microbiota and distant organs such as the heart, lungs, brain, and liver has become a hot topic in the field of gut microbiology. With a deeper understanding of its immune regulation and mechanisms of action, these findings have increasingly highlighted their guiding value in clinical practice. The gut is not only the largest digestive organ in the human body but also the habitat for most microorganisms. Imbalances in gut microbial communities have been associated with various lung diseases, such as allergic asthma and cystic fibrosis. Furthermore, gut microbial communities have significant impacts on metabolic function and immune responses. Their metabolites not only regulate gastrointestinal immune systems but may also affect distant organs such as the lungs and brain. As one of the most common types of respiratory system diseases worldwide, pulmonary infections have high morbidity and mortality rates. Pulmonary infections caused by immune dysfunction can lead to gastrointestinal problems like diarrhea, further resulting in imbalances within complex interactions that are associated with abnormal manifestations under disequilibrium conditions. Meanwhile, clinical interventions can significantly modulate the composition of gut microbiota, and alteration in gut microbiota may subsequently indicate susceptibility to pulmonary infections and even contribute to the prevention or regulation of their progression. This review delves into the interaction between gut microbiota and pulmonary infections, elucidating the latest advancements in gut-lung axis research and providing a fresh perspective for the treatment and prevention of pneumonia.

PMID:40330490 | PMC:PMC12052896 | DOI:10.3389/fimmu.2025.1576141

Int J Cardiol Congenit Heart Dis. 2025 Apr 15;20:100584. doi: 10.1016/j.ijcchd.2025.100584. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: High-throughput proteomics platforms using aptamers (SomaScan) or proximity extension assay (Olink) provide novel opportunities for improving diagnostic and risk stratification tools in cardiovascular diseases, including understudied congenital heart diseases. The correlation between these proteomics approaches has not yet been studied among individuals with a Fontan circulation.

OBJECTIVE: The correlation of plasma protein measurements between SomaScan and Olink platforms was evaluated in adults with a Fontan circulation.

METHODS: We measured 491 proteins in plasma of 71 adults with a Fontan circulation using Olink and SomaScan. Missing Olink measurements (0.13%, 47/34,861) were imputed using non-parametric imputation. Spearman's rank correlation coefficient for absolute values of protein expression between platforms was calculated. Protein correlation frequencies were compared to 3 cohorts reported in the literature using Pearson's Chi-squared test of independence.

RESULTS: Overall, protein correlations between Olink and SomaScan measurements were moderately strong for most proteins, (rho > 0.4 for 57.2%), but with substantial variability (median correlation = 0.457, IQR = 0.538). The distribution of protein correlations was qualitatively similar to published literature in non-Fontan cohorts. Both Olink and SomaScan identified proteins with sex-based differences; both identified differences in myostatin and leptin, but each identified additional nonoverlapping sexually dimorphic proteins (n = 14 Olink, n = 5 SomaScan).

CONCLUSIONS: In adults with a Fontan circulation, correlations between plasma proteins measured by Olink and SomaScan varied widely, approximately in line with prior reports in other populations. While these tools may be uniquely useful to generate hypotheses, specifically regarding potential molecular mechanisms, more definitive inference requires independent validation.

PMID:40330320 | PMC:PMC12053979 | DOI:10.1016/j.ijcchd.2025.100584

JAMA Netw Open. 2025 May 1;8(5):e256908. doi: 10.1001/jamanetworkopen.2025.6908.

ABSTRACT

IMPORTANCE: Current therapeutic approaches are inaccessible to many people with chronic pain and frequently fail to address emotion dysregulation as a key factor in psychological comorbidity and pain intensity. An effective and accessible emotion regulation-focused intervention is needed.

OBJECTIVES: To compare the efficacy of online dialectical behavioral therapy for chronic pain plus treatment as usual (iDBT-Pain) with only treatment as usual on emotion dysregulation in people with chronic pain.

DESIGN, SETTING, AND PARTICIPANTS: This 2-arm randomized clinical trial was conducted from March 2023 to September 2024 in Australia. Participants were adults with chronic pain (lasting ≥3 months) and weekly pain intensity of 3 or higher out of 10 (10 indicating worst pain), without psychotic or personality disorders, and without dementia. Eligible participants were randomly assigned (1:1 ratio) to receive either iDBT-Pain for 9 weeks or treatment as usual only. Intention-to-treat data analyses were performed between August and September 2024.

INTERVENTIONS: The iDBT-Pain group received 8 group-based 90-minute therapist-guided online sessions as well as an app and a handbook for self-learning. Content focused on DBT skills training, including pain science education. Participants in the treatment-as-usual group continued usual care, which consisted of treatment options that can be accessed in the community.

MAIN OUTCOMES AND MEASURES: The primary outcome was emotion dysregulation at 9 weeks after randomization. The Difficulties in Emotion Regulation Scale (score range: 18-90, with higher scores indicating higher emotion dysregulation) was used in assessment.

RESULTS: Among 89 participants (mean [SD] age, 51.5 [14.2] years; 74 females [83%]), 44 (49%) were randomly assigned to the treatment-as-usual group and 45 (51%) were randomly assigned to the iDBT-Pain group. Overall, 79 participants (89%) completed the 9-week assessment. Between-group difference in emotion dysregulation over time favored iDBT-Pain over treatment as usual at 9 weeks (-4.88; 95% CI, -9.20 to -0.55; P = .03; Cohen d = -0.46 [95% CI, -0.87 to -0.08]).

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the iDBT-Pain intervention, delivered through a self-learning and therapist-guided hybrid approach, resulted in sustained improvements in emotion dysregulation in people with chronic pain.

TRIAL REGISTRATION: Anzctr.org.au Identifier: ACTRN12622000113752.

PMID:40327344 | PMC:PMC12056567 | DOI:10.1001/jamanetworkopen.2025.6908