Clin Appl Thromb Hemost. 2025 Jan-Dec;31:10760296251327593. doi: 10.1177/10760296251327593. Epub 2025 Mar 13.

ABSTRACT

IntroductionPlasma-derived von Willebrand factor containing FVIII concentrates (pdVWF/FVIII-C) are indicated as replacement therapy for patients with von Willebrand disease (VWD). This study assessed safety and efficacy associated with long-term real-world experience of the pdVWF/FVIII-C, Fanhdi®, in patients with VWD.MethodsThis observational, prospective, post-authorization cohort study was conducted at five centers in Spain. Patients with VWD were treated with the pdVWF/FVIII-C to achieve satisfactory hemostasis for on-demand (bleeding episodes and surgical/invasive procedures) and prophylaxis treatment. Clinical efficacy was evaluated as the response to treatment in both settings. Safety parameters were assessed.ResultsFifteen VWD patients received at least one dose of the pdVWF/FVIII-C and were followed for 12 months. Forty-six bleeding episodes were reported for 9 (60.0%) patients, and 6 surgical/invasive procedures for 5 (33.3%) patients. Most frequently reported bleedings were gastrointestinal (3 [33.0%] patients) and gynecological (3 [33.0%] patients). No complications nor bleeding episodes related to surgical/invasive procedures were reported. Overall clinical efficacy of treatment (including on-demand and prophylaxis) achieved 100% excellent and/or good (n = 15 patients), being excellent for 7 (46.7%) patients. There were 27 treatment-emergent adverse events in 8 (53.3%) patients, 11 serious adverse events in 3 (20.0%) patients, but none of them were drug-related. No clinical signs and symptoms of immunogenicity or thromboembolic events were reported.ConclusionsThis real-world evidence study confirmed the efficacy of the pdVWF/FVIII-C as on-demand and/or prophylaxis treatment in patients with bleeding episodes or surgical procedures in VWD. Fanhdi® was well tolerated without any safety concerns.

PMID:40079811 | DOI:10.1177/10760296251327593

Int J Mol Sci. 2025 Feb 28;26(5):2195. doi: 10.3390/ijms26052195.

ABSTRACT

Sphingolipidoses, a subgroup of lysosomal storage diseases (LSDs), are rare and debilitating disorders caused by defects in sphingolipid metabolism. Despite advancements in treatment, therapeutic options remain limited. Miglustat, a glucosylceramide synthase EC 2.4.1.80 (GCS) inhibitor, is one of the few available pharmacological treatments; however, it is associated with significant adverse effects that impact patients' quality of life. Drug repurposing offers a promising strategy to identify new therapeutic agents from approved drugs, expanding treatment options for rare diseases with limited therapeutic alternatives. This study aims to identify potential alternative inhibitors of GCS through a drug-repurposing approach, using computational and experimental methods to assess their therapeutic potential for sphingolipidoses. A library of approved drugs was screened using advanced computational techniques, including molecular docking, molecular dynamics simulations, and metadynamics, to identify potential GCS inhibitors. Promising candidates were selected for further in vitro validation to evaluate their inhibitory activity and potential as therapeutic alternatives to Miglustat. Computational screening identified several potential GCS inhibitors, with Dapagliflozin emerging as the most promising candidate. Experimental validation confirmed its efficacy, revealing a complementary mechanism of action to Miglustat while potentially offering a more favorable side effect profile. This study underscores the utility of computational and experimental methodologies in drug repurposing for rare diseases. The identification of Dapagliflozin as a potential GCS inhibitor provides a foundation for further preclinical and clinical evaluation, supporting its potential application in the treatment of sphingolipidoses.

PMID:40076817 | DOI:10.3390/ijms26052195

Int J Mol Sci. 2025 Feb 23;26(5):1910. doi: 10.3390/ijms26051910.

ABSTRACT

Reductive stress (RS), characterized by excessive accumulation of reducing equivalents such as NADH and NADPH, is emerging as a key factor in metabolic disorders and cancer. While oxidative stress (OS) has been widely studied, RS and its complex interplay with endocrine regulation remain less understood. This review explores molecular circuits of bidirectional crosstalk between metabolic hormones and RS, focusing on their role in diabetes, obesity, cardiovascular diseases, and cancer. RS disrupts insulin secretion and signaling, exacerbates metabolic inflammation, and contributes to adipose tissue dysfunction, ultimately promoting insulin resistance. In cardiovascular diseases, RS alters vascular smooth muscle cell function and myocardial metabolism, influencing ischemia-reperfusion injury outcomes. In cancer, RS plays a dual role: it enhances tumor survival by buffering OS and promoting metabolic reprogramming, yet excessive RS can trigger proteotoxicity and mitochondrial dysfunction, leading to apoptosis. Recent studies have identified RS-targeting strategies, including redox-modulating therapies, nanomedicine, and drug repurposing, offering potential for novel treatments. However, challenges remain, particularly in distinguishing physiological RS from pathological conditions and in overcoming therapy-induced resistance. Future research should focus on developing selective RS biomarkers, optimizing therapeutic interventions, and exploring the role of RS in immune and endocrine regulation.

PMID:40076537 | DOI:10.3390/ijms26051910

Molecules. 2025 Feb 24;30(5):1031. doi: 10.3390/molecules30051031.

ABSTRACT

Our research group aimed for the optimization of pharmacologic ascorbate (Ph-Asc)-induced cancer cell death. To reduce the required time and resources needed for development, an in silico system biological approach, an already approved medication, and a mild bioactive compound were used in our previous studies. It was revealed that both Ph-Asc and resveratrol (RES) caused DSBs in the DNA, and chloroquine (CQ) treatment amplified the cytotoxic effect of both Ph-Asc and RES in an autophagy independent way. In the present study, we aimed at the further clarification of the cytotoxic mechanism of Ph-Asc, CQ, and RES by comparing their DNA damaging abilities, effects on the cells' bioenergetic status, ROS, and lipid ROS generation abilities with those of the three currently investigated compounds (menadione, RSL3, H2O2). It could be assessed that the induction of DSBs is certainly a common point of their mechanism of action; furthermore, the observed cancer cell death due to the investigated treatments are independent of the bioenergetic status. Contrary to other investigated compounds, the DNA damaging effect of CQ seemed to be ROS independent. Surprisingly, the well-known ferroptosis inducer RSL3 was unable to induce lipid peroxidation in the pancreas ductal adenocarcinoma (PDAC) Mia PaCa-2 cell line. At the same time, it induced DSBs in the DNA, and the RSL3-induced cell death could not be suspended by the well-known ferroptosis inhibitors. All these observations suggest the ferroptosis resistance of this cell line. The observed DNA damaging effect of RSL3 definitely creates a new perspective in anticancer research.

PMID:40076255 | DOI:10.3390/molecules30051031

Cancers (Basel). 2025 Mar 6;17(5):903. doi: 10.3390/cancers17050903.

ABSTRACT

Background/Objectives: The molecular heterogeneity and metabolic flexibility of Hepatocellular Carcinoma (HCC) pose significant challenges to the efficacy of systemic therapy for advanced cases. Early screening difficulties often delay diagnosis, leading to more advanced stages at presentation. Combined with the inconsistent responses to current systemic therapies, HCC continues to have one of the highest mortality rates among cancers. Thus, this paper seeks to contribute to the development of systemic therapy options through the consideration of HCC's metabolic vulnerabilities and lay the groundwork for future in vitro studies. Methods: Transcriptomic data were used to calculate single and double knockout options for HCC using genetic Minimal Cut Sets. Furthermore, using QSAR modeling, drug repositioning opportunities were assessed to inhibit the selected genes. Results: Two single knockout options that were also annotated as essential pairs were found within the pyrimidine metabolism pathway of HCC, wherein the knockout of either DHODH or TYMS is potentially disruptive to proliferation. The result of the flux balance analysis and gene knockout simulation indicated a significant decrease in biomass production. Three machine learning algorithms were assessed for their performance in predicting the pIC50 of a given compound for the selected genes. SVM-rbf performed the best on unseen data achieving an R2 of 0.82 for DHODH and 0.81 for TYMS. For DHODH, the drugs Oteseconazole, Tipranavir, and Lusutrombopag were identified as potential inhibitors. For TYMS, the drugs Tadalafil, Dabigatran, Baloxavir Marboxil, and Candesartan Cilexetil showed promise as inhibitors. Conclusions: Overall, this study suggests in vitro testing of the identified drugs to assess their capabilities in inducing pyrimidine starvation on HCC.

PMID:40075750 | DOI:10.3390/cancers17050903

Purinergic Signal. 2025 Mar 13. doi: 10.1007/s11302-025-10078-7. Online ahead of print.

ABSTRACT

Neuroblastoma is a pediatric tumor accounting for approximately 8% of childhood cancers and is associated with high mortality rates among children aged 1 to 5 years. Standard treatments often fall short, leading to recurrence and metastasis due to the development of chemoresistance. A promising approach to address this challenge involves targeting purinergic signaling pathways and drug repurposing. The combination of flubendazole in nanoformulation and vincristine exhibited synergistic effects in ACN cells, enhancing treatment efficacy. Vincristine combined with the P2X7 receptor antagonist Brilliant Blue-G showed antagonistic effects, and interactions between nanoFBZ and Brilliant Blue-G were dose-dependent. Furthermore, ACN cells exposed to 213 nM of vincristine weekly for three weeks resulted in vincristine-resistant cells with significantly higher resistance (IC50 approximately 300 times greater) compared to parental cells. P2Y2 receptor expression was augmented in vincristine-resistant cells, particularly after treatment with nanoFBZ and Brilliant Blue-G, while adenosine A1, A2B, and P2Y6 receptor expression levels decreased. P2X7 receptor expression was also reduced in vincristine-resistant cells treated with nanoFBZ. P2X7 receptor agonism and P2Y2 receptor blockade slightly elevated resistance. In conclusion, this study suggests that combining nanoFBZ with vincristine chemotherapy may offer a promising strategy for improving the treatment efficacy of neuroblastoma. The synergy between nanoFBZ and vincristine enhanced therapeutic outcomes, and P2X7 receptor antagonism further reduced neuroblastoma cell viability.

PMID:40075009 | DOI:10.1007/s11302-025-10078-7

Sci Rep. 2025 Mar 12;15(1):8518. doi: 10.1038/s41598-024-83633-8.

ABSTRACT

Although the SARS-CoV-2 epidemic worldwide has gradually decreased, in some areas, the situation has not yet been stamped and has become a global health emergency. It is quite possible that we could again be threatened by a new coronavirus. Therefore, new nucleotide analog drugs and vaccines or using drug repositioning for SARS-CoV-2 still has been developed, yet their safety and efficacy against COVID-19 remains underexplored. Malabaricone C is 2,6-dihydroxyphenyl acylphenol found in edible plants such as the mace spice of nutmeg derived from the seeds of Myristica fragrans. In this study, we identified malabaricone C as the first inhibitor of SARS-CoV-2 from natural food with a safe alternative for drugs. Malabaricone C and its chemical derivatives showed EC50 values of 1-1.5 μM against SARS-CoV-2 (WK-521, ancestral strain) and its variant strains in mammalian cells (HEK293T and Vero E6). In addition, we have successfully established novel evaluation system for the inhibition of SARS virus cell fusion by visualization for providing a versatile tool for study SARS-CoV-2 mediated fusion. Furthermore, our experiments suggested that malabaricone C could affect the distribution of sphingomyelin on the plasma membrane, which involves in viral infections. Thus, in light of the beneficial effect of malabaricone C on viral infection, the nontoxic malabaricone C is a suitable candidate as a drug that can be employed in the treatment and prevention of COVID-19. Moreover, it may potentially be used to treat acute infections of other enveloped viruses.

PMID:40074774 | DOI:10.1038/s41598-024-83633-8

Front Public Health. 2025 Feb 26;13:1510818. doi: 10.3389/fpubh.2025.1510818. eCollection 2025.

ABSTRACT

BACKGROUND: Undiagnosed rare diseases (URDs) are a complex and multifaceted challenge, especially in low-and medium-income countries. They affect individuals with unique clinical features and lack a clear diagnostic label. Although the Undiagnosed Diseases Network International (UDNI) definition of URDs is not universally accepted, it is widely recognized.

METHODS: We surveyed UDNI members and participants from other countries to explore the challenges posed by URDs and identify possible solutions. Participation in the survey was completely voluntary.

RESULTS: The survey revealed a need for more consensus on a universally accepted definition for URDs. Still, the UDNI definition gained widespread recognition and serves as a valuable framework for understanding and addressing the challenges of URDs. In addition to national or international networks, fostering a more substantial engagement and resource-sharing ethos among member countries is critical. Despite advances in genomics and diagnostic tools, the diagnostic journey for people living with URDs (PLURDs) remains arduous and often inconclusive. The availability of specialized centers and the utilization of whole exome sequencing (WES) and whole genome sequencing (WGS) vary across countries, with disparities due to healthcare systems, economic status, and government policies. Advocacy groups play a crucial role in supporting PLURDs.

CONCLUSION: A unified commitment to prioritizing URDs on the global health agenda, paired with targeted funding, stipulated national strategies, and aligned international cooperation, is imperative to leveling the playing field for the diagnosis and management of URDs and capitalizing on the potential of Advocacy Groups as allies in this endeavor.

PMID:40078755 | PMC:PMC11897027 | DOI:10.3389/fpubh.2025.1510818

Clin Transl Sci. 2025 Mar;18(3):e70194. doi: 10.1111/cts.70194.

ABSTRACT

Pharmacogenomics research has predominantly focused on populations of European ancestry, limiting the application to diverse populations such as American Indian and Alaska Native (AIAN) communities. Our community-centric study aims to understand perspectives on utilizing pharmacogenomics to guide tobacco cessation in an AIAN community using a survey with qualitative and quantitative components. We assessed participant (n = 273) tobacco usage and cessation history, pharmacogenomics knowledge, and perceptions of utilizing pharmacogenomics in the context of tobacco cessation. We found that the majority of participants (92%) were aware of the risks associated with tobacco usage and believed it to be a problem within their community (76%). Our results showed that 29% of participants had some level of knowledge regarding pharmacogenomics and only 6% had previously participated in pharmacogenomics research, demonstrating the need for further education and awareness. Community involvement was a priority for participants, with 64% preferring Tribal inclusion in all research stages and 63% favoring partnerships with local health centers. We also found support for future research, with 68% viewing pharmacogenomics as a beneficial tool. Concerns were raised regarding the handling of genetic material and result dissemination, emphasizing the importance of ethical research practices, transparent communication, and community partnership. Our findings serve as a foundation for shaping future research efforts and developing a framework for implementing tobacco cessation interventions. Our community-centered approach addresses the specific needs of this AIAN community and offers insights applicable to research practices within other underserved and marginalized populations, particularly those with a historical distrust of research.

PMID:40078094 | DOI:10.1111/cts.70194

Int J Mol Sci. 2025 Feb 24;26(5):1960. doi: 10.3390/ijms26051960.

ABSTRACT

Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.

PMID:40076585 | DOI:10.3390/ijms26051960

Pharmacogenomics J. 2025 Mar 12;25(1-2):7. doi: 10.1038/s41397-025-00366-1.

ABSTRACT

In view of the limited data related to preemptive pharmacogenomics (PGx) testing in the primary care setting, we designed a study to assess the feasibility of implementing preemptive PGx services at outpatient clinics, with the aim to assess the practicality and challenges of implementing preemptive PGx testing within primary care, and its impact on clinical workflows and patient care. This prospective study was conducted between October 2022 and August 2023 at five outpatient clinics located in Singapore. Patients aged 21 to 65 with a reported history or risk of developing any of the target chronic conditions or any patients receiving one of the 29 PGx-associated medications were recruited. Patients' buccal samples were processed using a multi-gene qPCR-based panel of 21 allele variants of five pharmacogenes. Surveys were administered to study participants and clinicians to assess their perceptions and outcomes related to PGx testing. Among the 222 patients, 95% had at least one clinically actionable variant. Of these patients, 113 reported taking at least one of the 29 studied drugs, with 21.2% of them receiving at least one clinically actionable recommendation based on their PGx results. A total of 150 patients (67.6%) participated in the post-test follow-up survey. Among them, 70% expressed feeling relieved and happy upon receiving their test reports and reported increased confidence in taking their prescribed medication. Furthermore, clinicians identified the necessity for clearer legal regulations regarding PGx testing and insurance coverage to enhance future adoption of PGx testing. Given a high prevalence of clinically actionable variants in almost all tested patients, this study underscores the feasibility and clinical benefits of preemptive PGx testing in primary care clinics in Singapore.Clinical Trial Registration: This study is registered with ClinicalTrials.gov, identifier NCT05504135, with the registration date of August 17, 2022.

PMID:40074758 | DOI:10.1038/s41397-025-00366-1

Can J Respir Ther. 2025 Mar 3;61:20-32. doi: 10.29390/001c.129988. eCollection 2025.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This condition disrupts chloride channels and leads to the production of thick, sticky mucus, affecting the respiratory and gastrointestinal systems. CF's prevalence is particularly high in Saudi Arabia, where the incidence has increased from 1 in 2,000 to 1 in 1,000 births. Effective management of CF is essential for improving patient outcomes, yet there is a notable lack of understanding regarding respiratory therapists' (RTs) adherence to established CF management protocols.

METHODS: This descriptive quantitative study aimed to assess RTs' adherence to the Cystic Fibrosis Foundation's guidelines. Using a convenience sampling technique, a self-report survey was distributed to 750 members of the Saudi Society for Respiratory Care (SSRC), resulting in 351 responses, of which 166 were fully completed and met the inclusion criteria. The survey focused on RTs' knowledge and management practices related to CF. Data analysis was conducted using SPSS version 25, with descriptive statistics (mean, standard deviation, frequency, percentage, and mode) and non-parametric tests. The Kruskal-Wallis Test was employed to evaluate differences in adherence scores across demographic groups (e.g., education level, years of experience). Chi-square analysis was applied to examine relationships between categorical demographic variables (e.g., region of practice) and adherence to guidelines.

RESULTS: The analysis revealed significant gaps in RTs' adherence to CF guidelines, with only 42.8% accurately identifying the sweat chloride threshold for CF diagnosis and a limited 36.1% recognizing Pseudomonas aeruginosa as a common CF pathogen. Additionally, just 56.6% correctly identified the gold-standard airway clearance therapy. The Wilcoxon signed-ranks test further highlighted a statistically significant disparity (p = 0.00) between RTs' theoretical knowledge and practical application of CF management techniques, emphasizing the need for improved training.

DISCUSSION: The findings suggest a need for enhanced training and resources to bridge the gap between theoretical knowledge and practical management of CF. The lack of adherence to clinical guidelines could impact patient outcomes and survival rates.

CONCLUSION: Improving RTs' adherence to CF management guidelines through ongoing education and updated clinical standards is essential. Addressing these gaps could elevate the standard of care and contribute to better patient outcomes and survival rates in Saudi Arabia.

PMID:40078596 | PMC:PMC11901341 | DOI:10.29390/001c.129988

Front Med (Lausanne). 2025 Feb 26;12:1479638. doi: 10.3389/fmed.2025.1479638. eCollection 2025.

ABSTRACT

BACKGROUND: Little information is available regarding whether active physical activity lowers mortality risk in individuals with bronchiectasis.

METHODS: We used the Korean National Health Insurance Service database from 2010 to 2016 to evaluate the association between changes in physical activity and mortality risk in individuals with bronchiectasis. Of 552,510 individuals with newly diagnosed bronchiectasis, we enrolled 165,842 individuals who had two consecutive health examinations before and after bronchiectasis diagnosis, within two years, as the study aimed to measure changes in exercise habits between the two time points. Active physical activity was defined as engaging in moderate- or vigorous-intensity physical activity at least once a week, either before or after bronchiectasis diagnosis. The outcome measure was all-cause mortality.

RESULTS: During a mean follow-up of 6.2 ± 2.1 years, 10,535 (6.4%) individuals with bronchiectasis died. Individuals with bronchiectasis who were physically active exhibited a lower mortality rate than those who were physically inactive. Mortality reduction was particularly evident in the exercise maintainers group (aHR [adjusted hazard ratio] = 0.69, 95% confidence interval [CI] = 0.64-0.74) and individuals with physical activity ≥1,000 metabolic equivalent of task-min per week (aHR = 0.73, 95% CI = 0.70-0.77) compared to those who were physically inactive.

CONCLUSION: Engaging in active physical activity is associated with a decreased risk of mortality in individuals with bronchiectasis.

PMID:40078390 | PMC:PMC11896819 | DOI:10.3389/fmed.2025.1479638

Nutrients. 2025 Feb 28;17(5):868. doi: 10.3390/nu17050868.

ABSTRACT

BACKGROUND: Exocrine pancreatic insufficiency in cystic fibrosis (CF) increases fecal choline losses, but the postnatal course of plasma choline and its metabolites in these patients is unknown. While choline homeostasis is crucial for cellular, bile, and lipoprotein metabolism, via phosphatidylcholine (PC) and via betaine as a methyl donor, choline deficiency is associated with impaired lung and liver function, including hepatic steatosis.

OBJECTIVE: The goal of our study was to evaluate the plasma levels of choline, betaine, trimethylamine oxide (TMAO), PC, and PC subclasses in CF patients from infancy to adulthood and compare those with exocrine pancreatic insufficiency (EPI) to those with pancreatic sufficiency (EPS).

METHODS: Retrospective analysis of target parameters in plasma samples (July 2015-November 2023) of CF patients (0.64-24.6 years) with tandem mass spectrometry.

RESULTS: A total of 477 samples from 162 CF patients were analyzed. In CF patients with EPI (N = 148), plasma choline and betaine concentrations were lower and decreased with age compared to EPS patients showing normal values. TMAO concentrations, indicating intestinal choline degradation by bacterial colonization, were frequently elevated in EPI from infancy onwards, and inversely related to plasma choline and betaine levels. PC-containing linoleic acid levels were lower in EPI, but arachidonic and docosahexaenoic acid content was similar in both patient groups.

CONCLUSION: CF patients with EPI are at risk of choline and betaine deficiency compared to exocrine pancreas-sufficient CF patients. Elevated TMAO concentrations in EPI patients indicate increased bacterial colonization leading to choline degradation before absorption. These findings indicate that laboratory testing of choline, betaine, and TMAO as well as clinical trials on choline supplementation are warranted in CF patients.

PMID:40077735 | DOI:10.3390/nu17050868

Int J Mol Sci. 2025 Mar 6;26(5):2336. doi: 10.3390/ijms26052336.

ABSTRACT

Atherosclerosis (AS) is a disease characterised by the accumulation of atherosclerotic plaques on the inner walls of blood vessels, resulting in their narrowing. In its early stages, atherosclerosis remains asymptomatic and undetectable by conventional pathological methods. However, as the disease progresses, it can lead to a series of cardiovascular diseases, which are a leading cause of mortality among middle-aged and elderly populations worldwide. Neutrophil extracellular traps (NETs) are composed of chromatin and granular proteins released by neutrophils. Upon activation by external stimuli, neutrophils undergo a series of reactions, resulting in the release of NETs and subsequent cell death, a process termed NETosis. Research has demonstrated that NETosis is a means by which neutrophils contribute to immune responses. However, studies on neutrophil extracellular traps have identified NETs as the primary cause of various inflammation-induced diseases, including cystic fibrosis, systemic lupus erythematosus, and rheumatoid arthritis. Consequently, the present review will concentrate on the impact of neutrophil extracellular traps on atherosclerosis formation, analysing it from a molecular biology perspective. This will involve a systematic dissection of their proteomic components and signal pathways.

PMID:40076955 | DOI:10.3390/ijms26052336

Int J Mol Sci. 2025 Feb 27;26(5):2066. doi: 10.3390/ijms26052066.

ABSTRACT

The introduction of CFTR modulators in the clinics has improved body mass index in cystic fibrosis (CF) individuals. Leptin is a major regulator of appetite and energy expenditure but is also involved in bone metabolism. Whether circulating leptin levels are associated with low bone mineral density (BMD) and fracture risk in CF remains unknown. Therefore, the present study aims to analyze and integrate the current evidence linking leptin and bone loss in CF. As no scientific evidence was found, we focused on secondary dysregulations of bone loss in CF that may be linked to pathologies that are similar to the various dysregulations and multisystemic manifestations in CF. Studies published from 2001 to 2022 were identified through the PubMed, Scopus, and Web of Science databases, and screening was performed following the PRISMA guidelines. The included studies were assessed using a quality checklist. From the 774 records identified, 28 studies met the inclusion criteria. Although no evidence has been found directly related to bone loss in CF individuals, some studies revealed a positive association between leptin levels and BMD, while others found an inverse association. Current evidence suggests that for circulating leptin levels to be a predictive biomarker of bone health, further research will be needed to reveal the direct and indirect mechanisms behind leptin and bone loss and to understand whether changes in leptin levels correlate with changes in BMD. Of note, studies with CF people would be of high importance to understand the role of leptin in CF-related bone disease.

PMID:40076690 | DOI:10.3390/ijms26052066

Int J Mol Sci. 2025 Feb 25;26(5):2012. doi: 10.3390/ijms26052012.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen with a multidrug-resistant profile that has become a critical threat to global public health. It is one of the main causes of severe nosocomial infections, including ventilator-associated pneumonia, chronic infections in patients with cystic fibrosis, and bloodstream infections in immunosuppressed individuals. Development of vaccines against P. aeruginosa is a major challenge owing to the high capacity of this bacterium to form biofilms, its wide arsenal of virulence factors (including secretion systems, lipopolysaccharides, and outer membrane proteins), and its ability to evade the host immune system. This review provides a comprehensive historical overview of vaccine development efforts targeting this pathogen, ranging from early attempts in the 1970s to recent advancements, including vaccines based on novel proteins and emerging technologies such as nanoparticles and synthetic conjugates. Despite numerous promising preclinical developments, very few candidates have progressed to clinical trials, and none have achieved final approval. This panorama highlights the significant scientific efforts undertaken and the inherent complexity of successfully developing an effective vaccine against P. aeruginosa.

PMID:40076637 | DOI:10.3390/ijms26052012

Int J Mol Sci. 2025 Feb 21;26(5):1871. doi: 10.3390/ijms26051871.

ABSTRACT

Cystic fibrosis (CF) is characterized by chronic respiratory infections and excessive inflammation, driven by both host- and pathogen-derived proteases. The dysregulated activity of proteolytic enzymes such as neutrophil elastase (NE), cathepsin G, and matrix metalloproteases (MMPs) degrades lung tissue, exacerbates airway remodeling, and perpetuates inflammatory cycles. Concurrently, bacterial proteases from pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus contribute to immune evasion and tissue destruction, compounding disease severity. Despite advances in antimicrobial and anti-inflammatory therapies, protease-driven lung damage remains a critical challenge. This review examines the dual role of host and bacterial proteases in CF pathophysiology, highlighting emerging protease-targeted therapies aimed at mitigating lung damage and inflammation. Strategies explored include the inhibition of NE, MMPs, and bacterial proteases, with a focus on innovative therapeutic approaches such as dual-function inhibitors, biologics, and advanced drug delivery systems. By restoring the protease-antiprotease balance, these interventions offer the potential to improve clinical outcomes and quality of life for CF patients.

PMID:40076497 | DOI:10.3390/ijms26051871

Hum Genomics. 2025 Mar 12;19(1):25. doi: 10.1186/s40246-025-00736-7.

ABSTRACT

BACKGROUND: Global fertility decline has led to increased use of assisted reproductive technology (ART), raising concerns about genetic risks to offspring. This study aimed to investigate cystic fibrosis transmembrane conductance regulator (CFTR) variants in Chinese families and assess their association with pregnancy complications and neonatal outcomes.

METHODS: This prospective cohort study included 446 Chinese families (148 natural conceptions, 298 ART conceptions) who underwent whole genome sequencing. We analyzed the frequency of pathogenic/likely pathogenic CFTR variants and their association with preterm birth (PTB), pregnancy complications, and neonatal outcomes.

RESULTS: Twelve pathogenic/likely pathogenic CFTR variants were identified, with K464N (c.1392G > T) being the most prevalent (2.9% of cohort). PTB incidence was significantly higher in pregnancies with fetal CFTR variants (43.1%, 22/51) compared to those without (17.5%, 69/395; p < 0.001). Fetuses carrying the CFTR K464N variant exhibited a 3.39-fold increased risk of PTB (95% confidence interval (CI): 1.39-8.23, p = 0.007) after adjusting for confounders. Neither fetal nor maternal CFTR variants were significantly associated with other neonatal outcomes, including neonatal weight, Apgar scores, respiratory distress, or hyperbilirubinemia (p > 0.050).

CONCLUSION: These findings suggest a potential association between fetal CFTR K464N variant and increased risk of preterm birth in Chinese families, highlighting the importance of considering CFTR genotyping in prenatal care.

PMID:40075526 | DOI:10.1186/s40246-025-00736-7

Cell Mol Life Sci. 2025 Mar 13;82(1):109. doi: 10.1007/s00018-025-05627-7.

ABSTRACT

Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) protein that regulates ion and fluid transport in epithelial tissue. Female CF patients face considerable fertility challenges, with higher prevalence of deficient fertility compared to healthy women. Not much is known about the underlying causes. In particular, the pathobiology of the endometrium, the uterus' inner lining essential for pregnancy and expressing fluctuating CFTR levels during the menstrual cycle, is unexplored in CF. To address this gap, we developed organoid models from CF patient endometrium. The organoids recapitulated CF characteristics and revealed molecular and pathway differences in cycle-recapitulating hormone responses compared to healthy endometrial organoids. Furthermore, specific functional aberrations were restored by CFTR modulator treatment. To further complement human organoid models for unraveling endometrial pathobiology in CF, we also developed organoids from a genetic CF mouse model that were also found to recapitulate CF characteristics. Moreover, single-cell RNA-sequencing analysis of the CF mouse uterus revealed molecular traits in the endometrium similar to the human CF endometrium (as evidenced by its organoid model). Our study provides new endometrium models to advance our understanding of CF-associated endometrial pathobiology, particularly regarding menstrual cycle aberrations that impact fertility. This research is timely since improved CF therapeutics result in increased life expectancy, allowing more CF patients to consider starting a family.

PMID:40074868 | DOI:10.1007/s00018-025-05627-7