Front Immunol. 2022 Apr 28;13:880368. doi: 10.3389/fimmu.2022.880368. eCollection 2022.

ABSTRACT

Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of outpatient visits, which result in a huge economic and healthcare burden. Most hospitalizations happen in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence on the association between early-life RSV respiratory illness and recurrent wheezing/asthma-like symptoms As such, RSV is considered a global health priority. However, despite this, the only prevention strategy currently available is palivizumab, a monoclonal antibody (mAb) indicated in a subset of preterm infants or those with comorbidities, hence leaving the majority of the infant population unprotected against this virus. Therefore, development of prevention strategies against RSV for all infants entering their first RSV season constitutes a large unmet medical need. The aim of this review is to explore different immunization approaches to protect all infants against RSV. Prevention strategies include maternal immunization, immunization of infants with vaccines, immunization of infants with licensed mAbs (palivizumab), and immunization of infants with long-acting mAbs (e.g., nirsevimab, MK-1654). Of these, palivizumab use is restricted to a small population of infants and does not offer a solution for all-infant protection, whereas vaccine development in infants has encountered various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will most likely be used in older infants (>6 months of age) and children. Consequently, maternal immunization and immunization of infants with long-acting mAbs represent the two feasible strategies for protection of all infants against RSV. Here, we present considerations regarding these two strategies covering key areas which include mechanism of action, "consistency" of protection, RSV variability, duration of protection, flexibility and optimal timing of immunization, benefit for the mother, programmatic implementation, and acceptance of each strategy by key stakeholders. We conclude that, based on current data, immunization of infants with long-acting mAbs might represent the most effective approach for protecting all infants entering their first RSV season.

PMID:35572550 | PMC:PMC9096079 | DOI:10.3389/fimmu.2022.880368

Front Immunol. 2022 Apr 27;13:885341. doi: 10.3389/fimmu.2022.885341. eCollection 2022.

ABSTRACT

The virome constitutes the viral component of the microbiome and it consists of the genomes of all the viruses that inhabit a particular region of the human body, including those that cause acute, persistent or latent infection, and retroviral elements integrated to host chromosomes. The human virome is composed by eukaryotic viruses, bacteriophages and archaeal viruses. The understanding of the virome composition and role on human health has been delayed by the absence of specific tools and techniques to accurately characterize viruses. However, more recently, advanced methods for viral diagnostics, such as deep sequencing and metagenomics, have allowed a better understanding of the diverse viral species present in the human body. Previous studies have shown that the respiratory virome modulates the host immunity and that, since childhood, the human lung is populated by viruses for whom there is no disease association. Whether these viruses are potentially pathogenic and the reason for their persistence remain elusive. Increased respiratory viral load can cause exacerbation of chronic pulmonary diseases, including COPD, cystic fibrosis, and asthma. Moreover, the presence of resident viral populations may contribute to the pathogenesis of community-acquired respiratory virus infections. In this mini review, I will discuss the recent progress on our understanding of the human lung virome and summarize the up-to-date knowledge on the relationships among community-acquired respiratory viruses, the lung virome and the immune response to better understand disease pathophysiology and the factors that may lead to viral persistence.

PMID:35572506 | PMC:PMC9091589 | DOI:10.3389/fimmu.2022.885341

Front Pharmacol. 2022 Apr 27;13:856804. doi: 10.3389/fphar.2022.856804. eCollection 2022.

ABSTRACT

Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.

PMID:35571097 | PMC:PMC9093689 | DOI:10.3389/fphar.2022.856804

Curr Drug Saf. 2022 May 13. doi: 10.2174/1574886317666220513105114. Online ahead of print.

ABSTRACT

BACKGROUND: Lumacaftor/Ivacaftor (LUM/IVA) is an approved combination therapy for cystic fibrosis (CF) patients homozygous for F508del.

OBJECTIVE: This study aimed to detect changes in liver stiffness measurement (LSM) in patients under this treatment.

METHODS: The study population consisted of CF patients homozygous for F508del, 6 to 11 years old, that had been treated for six months with LUM/IVA. Shear wave elastography (SWE) was performed in all of them, before and 6 months after the commencement of treatment.

RESULTS: Thirty-one patients were included in the study. LSM values after treatment were significantly higher than the values before treatment (medians and interquartile ranges of LSM values before and after treatment: 5.6, 5.3-6.3 kPa and, 6.4, 6.0-7.6 kPa, respectively, p<0.001).

CONCLUSION: SWE can detect early changes in LSM in some CF patients treated with LUM/IVA.

PMID:35570532 | DOI:10.2174/1574886317666220513105114

J Huntingtons Dis. 2022 May 7. doi: 10.3233/JHD-210523. Online ahead of print.

ABSTRACT

BACKGROUND: Health information-seeking is a coping strategy used globally by individuals with a personal or family history of a medical condition, including Huntington's disease (HD).

OBJECTIVE: We sought to ascertain information-seeking practices of young people who grew up at-risk for HD.

METHODS: Participants ages 18-25 were recruited from HD support organizations. An online 96-item survey assessed information-seeking motivations and timing as well as information topics accessed, sources, and needs.

RESULTS: Fifty young adults (mean age 22.2 years) who grew up at-risk for HD responded. HD had been generally kept a secret (35.4%) or talked about but difficult to bring up (43.8%) in many families. Most (78.0%) became aware of HD in their family before age 15. Few (7.1%) received information resources at the time of disclosure. Most (68.1%) first sought information independently online, half within a week of disclosure. Respondents were motivated to understand the potential impact of HD on their personal lives and family members, obtain general information about the condition, and learn about treatments and research. Most sought information on clinical features and inheritance with > 80% interested in information on symptoms and personal risk and > 70% about having children.

CONCLUSION: Limited information is provided to young people when first informed about HD in their families leading to independent, mostly online information-seeking. Information is used to build knowledge about HD to facilitate coping and life planning. Healthcare providers can direct young people to reliable resources and guide parents in talking with children to ensure that information needs are met.

PMID:35570496 | DOI:10.3233/JHD-210523

Pediatr Pulmonol. 2022 May 15. doi: 10.1002/ppul.25975. Online ahead of print.

ABSTRACT

More infants have been identified with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF) This article is protected by copyright. All rights reserved.

PMID:35570399 | DOI:10.1002/ppul.25975

Paediatr Drugs. 2022 May 16. doi: 10.1007/s40272-022-00509-y. Online ahead of print.

ABSTRACT

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

PMID:35570261 | DOI:10.1007/s40272-022-00509-y

Biochim Biophys Acta Proteins Proteom. 2022 May 12:140792. doi: 10.1016/j.bbapap.2022.140792. Online ahead of print.

ABSTRACT

As a misfolding protein, almost all of F508del-CFTR is degraded by the ubiquitin-proteasome system before its maturation, which results in no membrane expression of cystic fibrosis transmembrane conductance regulator (CFTR) and therefore, no chloride secretion across epithelial cells of cystic fibrosis (CF) patients. The conjugation of ubiquitin (Ub) chains to protein substrates is necessary for the proteasomal degradation of F508del-CFTR. Ubiquitin contains seven lysine (K) residues, all of which can be conjugated to one another, forming poly-ubiquitin chains on substrates, either by mixing together, or by only one type of lysine providing sorting signals for different pathways. Here, we report that four lysine-linked poly-Ub chains (LLPUCs) were involved in F508del-CFTR biogenesis: LLPUCs linked by K11 or K48 facilitated F508del-CFTR degradation, whereas the other two linked by K63 and K33 protected F508del-CFTR from degradation. LLPUC K11 is more potent for F508del-CFTR degradation than K48. F508del-CFTR utilizes four specific lysine-linked poly-Ub chains during its biogenesis for opposite destiny through different identification by proteasomal shuttle protein or receptors. These findings provide new insights into the CF pathogenesis and are expected to facilitate the development of therapies for this devastating disease.

PMID:35569794 | DOI:10.1016/j.bbapap.2022.140792

Indian Pediatr. 2022 May 15;59(5):365-366.

NO ABSTRACT

PMID:35567318

Can J Diabetes. 2022 Apr;46(3):294-301.e2. doi: 10.1016/j.jcjd.2021.11.004. Epub 2021 Dec 10.

ABSTRACT

OBJECTIVES: The clinical relevance of fasting and postprandial hypoglycemia in patients with cystic fibrosis (CF) is poorly characterized. Our aim in this study was to characterize the prevalence of hypoglycemia in adult patients during oral glucose tolerance test (OGTT) screening and determine its impact on the risk of developing CF-related diabetes (CFRD).

METHODS: We analyzed 2 cohorts of pancreatic insufficient patients with CF exposed to comparable treatment recommendations in France (Lyon CF cohort [DIAMUCO]) and Canada (Montréal CF cohort [MCFC]). Patients were classified into 3 groups based on hypoglycemia absence or presence as well as its severity at baseline. We defined the groups as follows: level 2 hypoglycemia (L2H; plasma glucose [PG]<3.0 mmol/L), level 1 hypoglycemia (L1H; PG 3.0 to <4.0 mmol/L) and no hypoglycemia (NH) during an OGTT.

RESULTS: A total of 153 MCFC and 114 DIAMUCO subjects were included in the study. In total, 22% of the patients experienced hypoglycemia, with 5% having it on 2 or more OGTTs. The L1H and L2H groups tended to have a lower 2-hour glucose and higher early-phase insulin secretion (insulin area under the curve at 0 to 30 minutes) compared with NH patients. In both cohorts, a greater proportion of men and patients with normal glucose tolerance had hypoglycemia. Over a 5-year period, there were no cases of CFRD in the L2H group, whereas 4 subjects in the L1H group and 36 in the NH group developed CFRD.

CONCLUSIONS: Patients with hypoglycemia were at lower risk of developing CFRD, but at higher risk of early-phase insulin secretion and unsuppressed insulin secretion. This could potentially lead to further hypoglycemia after the 2-hour OGTT, suggesting high clinical relevance.

PMID:35568431 | DOI:10.1016/j.jcjd.2021.11.004

Cell. 2022 May 10:S0092-8674(22)00471-8. doi: 10.1016/j.cell.2022.04.024. Online ahead of print.

ABSTRACT

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

PMID:35568033 | DOI:10.1016/j.cell.2022.04.024

Nutrients. 2022 Apr 25;14(9):1793. doi: 10.3390/nu14091793.

ABSTRACT

Magnesium (Mg) is an essential micronutrient that participates in various enzymatic reactions that regulate vital biological functions. The main aim was to assess the Mg status and its association with nutritional indicators in seventeen cystic fibrosis (CF) patients. The serum Mg and calcium (Ca) levels were determined using standardized methods and the dietary Mg intake by prospective 72 h dietary surveys. The mean serum Ca (2.45 mmol/L) and Mg (0.82 mmol/L) had normal levels, and the mean dietary intake of the Ca (127% DRI: Dietary Reference Intake) and Mg (125% DRI) were high. No patients had an abnormal serum Ca. A total of 47% of the subjects had hypomagnesemia and 12% insufficient Mg consumption. One patient had a serum Mg deficiency and inadequate Mg intake. A total of 47 and 82% of our series had a high serum Ca/Mg ratio of &gt;4.70 (mean 4.89) and a low Ca/Mg intake ratio of &lt;1.70 (mean 1.10), respectively. The likelihood of a high Ca/Mg ratio was 49 times higher in patients with a serum Mg deficiency than in normal serum Mg patients. Both Ca/Mg ratios were associated with the risk of developing cardiovascular disease (CVD), type 2 diabetes (T2D), metabolic syndrome (MetS), and even several cancers. Therefore, 53% of the CF patients were at high risk of a Mg deficiency and developing other chronic diseases.

PMID:35565764 | DOI:10.3390/nu14091793

Int J Environ Res Public Health. 2022 May 1;19(9):5512. doi: 10.3390/ijerph19095512.

ABSTRACT

INTRODUCTION: Spiritual care is needed in a clinical setting to improve the patients' quality of life. Deep connection with another person and delight with the beauty of nature or art and (in some cases) with God are all transcendental experiences. They may enable patients to ascribe meaning to their life with a chronic illness, find hope and well-being despite burdening symptoms. The opposite situation: lack of inner peace, inability to accept what is happening, feeling disconnected from others is called spiritual distress.

OBJECTIVES: The aim of this research is to assess spiritual distress and spiritual needs of a group of Polish chronically ill patients and find associations with independent variables in order to provide data for recommendations on spiritual care in Poland.

PATIENTS AND METHODS: 204 patients treated at the University Hospital and the Cystic Fibrosis Clinic in Poznan were surveyed in 2017 and 2018 with an original questionnaire.

RESULTS: Over half of the patients felt that their illness was life-threatening. A little more than half reported that faith was a resource to cope with suffering. Almost all patients showed signs of spiritual distress, and more than half expressed spiritual needs. The intensity of distress correlated only with the severity of the disease. The most important predictor of having spiritual needs was recognizing faith as a resource.

CONCLUSIONS: Spiritual needs are associated with personal beliefs; however, spirituality spans beyond the religious context since spiritual distress is unrelated to the level of religious devotion. Therefore, any patient with a severe chronic disease needs basic spiritual care, which includes being treated with compassion.

PMID:35564907 | DOI:10.3390/ijerph19095512

Int J Environ Res Public Health. 2022 Apr 29;19(9):5454. doi: 10.3390/ijerph19095454.

ABSTRACT

Cystic fibrosis (CF) is the most common incurable autosomal recessive disease affecting the Caucasian population. As the prognosis for life extension of CF patients improves, co-morbidities, including kidney disease, become more common. Identifying those at the highest risk of kidney injury is therefore extremely important. The aim of this study was to evaluate the biomarkers of renal function in 50 CF patients using the estimated glomerular filtration rate (eGFR) based on creatinine and cystatin C equation as well as serum creatinine (sCr), serum cystatin C (CysC), serum urea and urinary neutrophil gelatinase-associated lipocalin (uNGAL) concentrations. sCr, CysC, urea and uNGAL were estimated. eGFR was calculated according to the CKD-EPI formula. CysC was significantly increased, while eGFR was significantly lower in the CF group than in the controls (p &lt; 0.001 and p &lt; 0.01, respectively). There was no significant difference in the sCr, urea and uNGAL concentrations between patients with CF and healthy subjects. For the purpose of our analysis, in order to assess renal function in patients with CF in clinical practice, the concentration of serum CysC and eGFRCKD-EPI should be determined. Patients with CF presented with renal function impairment pictured by increased serum CysC and decreased eGFR values compared to controls. Unchanged uNGAL concentrations suggested preserved tubular function despite aminoglycoside treatment. Further prospective studies are needed to clarify whether kidney impairment observed in the course of CF progresses.

PMID:35564849 | DOI:10.3390/ijerph19095454

Int J Environ Res Public Health. 2022 Apr 23;19(9):5155. doi: 10.3390/ijerph19095155.

ABSTRACT

This study sought to investigate the association of light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time (SED), and sleep with lung function in children and adults with CF. In total, 86 children (41 females; 13.6 ± 2.8 years; FEV1%predicted: 86 ± 1%) and 43 adults (21 females; 24.6 ± 4.7 years; FEV1%predicted: 63 ± 21%) with CF participated in this study. Wrist-worn accelerometery was used to assess PA, SED and sleep. Compositional linear regression models were conducted following normalisation via isometric log-ratio transformations. Sequential binary partitioning was applied to investigate the impact of reallocating 10 to 30 min between each behaviour on FEV1%predicted. A decline in FEV1%predicted was predicted with the reallocation of 30 min from MVPA to SED or LPA or sleep to any other behaviour in children (-3.04--0.005%) and adults (-3.58--0.005%). Conversely, improvements in FEV1%predicted were predicted when 30 min was reallocated to MVPA from LPA or SED in children (0.12-1.59%) and adults (0.77-2.10%), or when 30 min was reallocated to sleep from any other behaviour in both children (0.23-2.56%) and adults (1.08-3.58%). This study supports the importance of MVPA and sleep for maintaining and promoting lung function in people with CF.

PMID:35564550 | DOI:10.3390/ijerph19095155

Foods. 2022 Apr 19;11(9):1189. doi: 10.3390/foods11091189.

ABSTRACT

The concentration of thiocyanate (SCN-) in bodily fluids is a good indicator of potential and severe health issues such as nasal bleeding, goiters, vertigo, unconsciousness, several inflammatory diseases, and cystic fibrosis. Herein, a visual SCN- sensing method has been developed using the enzyme-like nature of positively charged gold quantum dots (Au QDs) mixed with 3,3',5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide (H2O2). This research also reports a new method of synthesizing positively charged Au QDs directly from gold nanoparticles through a hydrothermal process. Microscopic imaging has showed that the Au QDs were 3-5 nm in size, and the emission wavelength was at 438 nm. Au QDs did not display any enzyme-like nature while mixed up with TMB and H2O2. However, the nanozymatic activity of Au QDs appeared when SCN- was included, leading to a very low detection limit (LOD) of 8 nM and 99-105% recovery in complex media. The steady-state kinetic reaction of Au QDs showed that Au QDs had a lower Michaelis-Menten constant (Km) toward H2O2 and TMB, which indicates that the Au QDs had a higher affinity for H2O2 and TMB than horseradish peroxidase (HRP). A mechanism study has revealed that the scavenging ability of hydroxyl (•OH) radicals by the SCN- group plays an important role in enhancing the sensitivity in this study. The proposed nanozymatic "Off-On" SCN- sensor was also successfully validated in commercial milk samples.

PMID:35563912 | DOI:10.3390/foods11091189

Cells. 2022 May 9;11(9):1587. doi: 10.3390/cells11091587.

ABSTRACT

Defective hydration of airway surface mucosa is associated with recurrent lung infection in cystic fibrosis (CF), a disease caused by CF transmembrane conductance regulator (CFTR) gene mutations. Whether the composition and/or presence of an airway surface liquid (ASL) is sufficient to prevent infection remains unclear. The susceptibility to infection of polarized wild type and CFTR knockdown (CFTR-KD) airway epithelial cells was determined in the presence or absence of a healthy ASL or physiological saline. CFTR-KD epithelia exhibited strong ASL volume reduction, enhanced susceptibility to infection, and reduced junctional integrity. Interestingly, the presence of an apical physiological saline alleviated disruption of the airway epithelial barrier by stimulating essential junctional protein expression. Thus, rehydrated CFTR-KD cells were protected from infection despite normally intense bacterial growth. This study indicates that an epithelial integrity gatekeeper is modulated by the presence of an apical liquid volume, irrespective of the liquid's composition and of expression of a functional CFTR.

PMID:35563895 | DOI:10.3390/cells11091587

Cells. 2022 Apr 27;11(9):1478. doi: 10.3390/cells11091478.

ABSTRACT

Bitter taste receptors (T2Rs) are G protein-coupled receptors (GPCRs) expressed in various cell types including ciliated airway epithelial cells and macrophages. T2Rs in these two innate immune cell types are activated by bitter products, including those secreted by Pseudomonas aeruginosa, leading to Ca2+-dependent activation of endothelial nitric oxide (NO) synthase (eNOS). NO enhances mucociliary clearance and has direct antibacterial effects in ciliated epithelial cells. NO also increases phagocytosis by macrophages. Using biochemistry and live-cell imaging, we explored the role of heat shock protein 90 (HSP90) in regulating T2R-dependent NO pathways in primary sinonasal epithelial cells, primary monocyte-derived macrophages, and a human bronchiolar cell line (H441). Immunofluorescence showed that H441 cells express eNOS and T2Rs and that the bitter agonist denatonium benzoate activates NO production in a Ca2+- and HSP90-dependent manner in cells grown either as submerged cultures or at the air-liquid interface. In primary sinonasal epithelial cells, we determined that HSP90 inhibition reduces T2R-stimulated NO production and ciliary beating, which likely limits pathogen clearance. In primary monocyte-derived macrophages, we found that HSP-90 is integral to T2R-stimulated NO production and phagocytosis of FITC-labeled Escherichia coli and pHrodo-Staphylococcus aureus. Our study demonstrates that HSP90 serves as an innate immune modulator by regulating NO production downstream of T2R signaling by augmenting eNOS activation without impairing upstream Ca2+ signaling. These findings suggest that HSP90 plays an important role in airway antibacterial innate immunity and may be an important target in airway diseases such as chronic rhinosinusitis, asthma, or cystic fibrosis.

PMID:35563784 | DOI:10.3390/cells11091478

Int J Mol Sci. 2022 May 6;23(9):5206. doi: 10.3390/ijms23095206.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl- currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl- transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease.

PMID:35563597 | DOI:10.3390/ijms23095206

Int J Mol Sci. 2022 Apr 30;23(9):5029. doi: 10.3390/ijms23095029.

ABSTRACT

Drug repurposing is an attractive strategy for developing new antibacterial molecules. Herein, we evaluated the in vitro antibacterial, antibiofilm, and antivirulence activities of eight FDA-approved "non-antibiotic" drugs, comparatively to tobramycin, against selected Pseudomonas aeruginosa strains from cystic fibrosis patients. MIC and MBC values were measured by broth microdilution method. Time-kill kinetics was studied by the macro dilution method, and synergy studies were performed by checkerboard microdilution assay. The activity against preformed biofilms was measured by crystal violet and viable cell count assays. The effects on gene expression were studied by real-time quantitative PCR, while the cytotoxic potential was evaluated against IB3-1 bronchial CF cells. Ciclopirox, 5-fluorouracil, and actinomycin D showed the best activity against P. aeruginosa planktonic cells and therefore underwent further evaluation. Time-kill assays indicated actinomycin D and ciclopirox, contrarily to 5-fluorouracil and tobramycin, have the potential for bacterial eradication, although with strain-dependent efficacy. Ciclopirox was the most effective against the viability of the preformed biofilm. A similar activity was observed for other drugs, although they stimulate extracellular polymeric substance production. Ribavirin showed a specific antibiofilm effect, not dependent on bacterial killing. Exposure to drugs and tobramycin generally caused hyperexpression of the virulence traits tested, except for actinomycin D, which downregulated the expression of alkaline protease and alginate polymerization. Ciclopirox and actinomycin D revealed high cytotoxic potential. Ciclopirox and ribavirin might provide chemical scaffolds for anti-P. aeruginosa drugs. Further studies are warranted to decrease ciclopirox cytotoxicity and evaluate the in vivo protective effects.

PMID:35563420 | DOI:10.3390/ijms23095029