J Nutr Metab. 2021 Jun 9;2021:9949453. doi: 10.1155/2021/9949453. eCollection 2021.

ABSTRACT

OBJECTIVE: To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention. Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. This study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented. Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. These conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn's disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles. There are also a number of other conditions that may show benefit; however, the evidence is not as robust.

CONCLUSION: The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.

PMID:34221501 | PMC:PMC8211525 | DOI:10.1155/2021/9949453

Front Genet. 2021 Jun 16;12:678374. doi: 10.3389/fgene.2021.678374. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF) is a common monogenic disease caused by pathogenic variants in the CFTR gene. The distribution and frequency of CFTR variants vary in different countries and ethnic groups. The spectrum of pathogenic variants of the CFTR gene was previously studied in more than 1,500 CF patients from different regions of the European and North Caucasian region of Russia and the spectrum of the most frequent pathogenic variants of the CFTR gene and ethnic features of their distribution were determined. To assess the population frequency of CFTR gene mutations some of the common variants were analyzed in the samples of healthy unrelated individuals from the populations of the European part of the Russian Federation: 1,324 Russians from four European regions (Pskov, Tver, Rostov, and Kirov regions), representatives of five indigenous ethnic groups of the Volga-Ural region [Mari (n = 505), Udmurts (n = 613), Chuvash (n = 780), Tatars (n = 704), Bashkirs (n = 517)], and six ethnic groups of the North Caucasus [Karachay (n = 324), Nogais (n = 118), Circassians (n = 102), Abazins (n = 128), Ossetians (n = 310), and Chechens (n = 100)]. The frequency of common CFTR mutations was established in studied ethnic groups. The frequency of F508del mutation in Russians was found to be 0.0056 on average, varying between four regions, from 0.0027 in the Pskov region to 0.0069 in the Rostov region. Three variants W1282X, 1677delTA, and F508del were identified in the samples from the North Caucasian populations: in Karachay, the frequency of W1282X mutation was 0.0092, 1677delTA mutation - 0.0032; W1282X mutation in the Nogais sample - 0.0127, the frequency of F508del mutations was 0.0098 and 1677delTA - 0.0098 in Circassians; in Abazins F508del (0.0039), W1282X (0.0039) and 1677delTA (0.0117) mutations were found. In the indigenous peoples of the Volga-Ural region, the maximum frequency of the F508del mutation was detected in the Tatar population (0.099), while this mutation was never detected in the Mari and Bashkir populations. The E92K variant was found in Chuvash and Tatar populations. Thus, interethnic differences in the spectra of CFTR gene variants were shown both in CF patients and in healthy population of the European and North Caucasian part of Russia.

PMID:34220950 | PMC:PMC8242336 | DOI:10.3389/fgene.2021.678374

Front Microbiol. 2021 Jun 17;12:639362. doi: 10.3389/fmicb.2021.639362. eCollection 2021.

ABSTRACT

The life-threatening pandemic concerning multi-drug resistant (MDR) bacteria is an evolving problem involving increased hospitalizations, billions of dollars in medical costs and a remarkably high number of deaths. Bacterial pathogens have demonstrated the capacity for spontaneous or acquired antibiotic resistance and there is virtually no pool of organisms that have not evolved such potentially clinically catastrophic properties. Although many diseases are linked to such organisms, three include cystic fibrosis (CF), burn/blast wounds and urinary tract infections (UTIs), respectively. Thus, there is a critical need to develop novel, effective antimicrobials for the prevention and treatment of such problematic infections. One of the most formidable, naturally MDR bacterial pathogens is Pseudomonas aeruginosa (PA) that is particularly susceptible to nitric oxide (NO), a component of our innate immune response. This susceptibility sets the translational stage for the use of NO-based therapeutics during the aforementioned human infections. First, we discuss how such NO therapeutics may be able to target problematic infections in each of the aforementioned infectious scenarios. Second, we describe a recent discovery based on years of foundational information, a novel drug known as AB569. AB569 is capable of forming a "time release" of NO from S-nitrosothiols (RSNO). AB569, a bactericidal tandem consisting of acidified NaNO2 (A-NO2 -) and Na2-EDTA, is capable of killing all pathogens that are associated with the aforementioned disorders. Third, we described each disease state in brief, the known or predicted effects of AB569 on the viability of PA, its potential toxicity and highly remote possibility for resistance to develop. Finally, we conclude that AB569 can be a viable alternative or addition to conventional antibiotic regimens to treat such highly problematic MDR bacterial infections for civilian and military populations, as well as the economical burden that such organisms pose.

PMID:34220733 | PMC:PMC8245851 | DOI:10.3389/fmicb.2021.639362

Indian J Clin Biochem. 2021 Jul;36(3):255-256. doi: 10.1007/s12291-021-00988-9. Epub 2021 Jun 15.

NO ABSTRACT

PMID:34220000 | PMC:PMC8215001 | DOI:10.1007/s12291-021-00988-9

Pediatr Pulmonol. 2021 Jul 5. doi: 10.1002/ppul.25559. Online ahead of print.

ABSTRACT

RATIONALE: Methicillin resistant Staphylococcus aureus (MRSA) is prevalent and consequential in cystic fibrosis (CF). Whole genome sequencing (WGS) could reveal genomic differences in MRSA associated with poorer outcomes or detect MRSA transmission.

OBJECTIVES: To identify MRSA genes associated with low lung function and potential MRSA transmission in CF.

METHODS: We collected 97 MRSA isolates from 74 individuals with CF from 2017 and performed short-read WGS. We determined sequence type (ST) and the phylogenetic relationship between isolates. We aligned accessory genes from 25 reference genomes to genome assemblies, classified isolates by accessory gene content, and correlated the accessory genome to clinical outcomes.

RESULTS: The most prevalent ST were ST5 (N=55), ST8 (N=15), and ST105 (N=14). Closely related MRSA strains were shared by family members with CF, but rarely between unrelated individuals. Three clusters of MRSA were identified by accessory genome content. Cluster A, including ST5 and ST105, was highly prevalent at all ages. Cluster B, including ST8, was more limited to younger patients. Cluster C included 6 distantly related strains. Patients 20 years old and younger infected with Cluster A had lower FEV1 and higher sputum biomass compared to similar-aged patients with Cluster B.

CONCLUSIONS: In this CF cohort, we identified MRSA subtypes that predominate at different ages and differ by accessory gene content. The most prevalent cluster of MRSA, including ST5 and ST105, was associated with lower FEV1 . ST8 MRSA was more common in younger patients and thus has the potential to rise in prevalence as these patients age. This article is protected by copyright. All rights reserved.

PMID:34219414 | DOI:10.1002/ppul.25559

J Expo Sci Environ Epidemiol. 2021 Jul 3. doi: 10.1038/s41370-021-00360-2. Online ahead of print.

ABSTRACT

RATIONALE: Nontuberculous mycobacteria (NTM) are ubiquitous environmental bacteria that may cause chronic lung disease and are one of the most difficult-to-treat infections among persons with cystic fibrosis (pwCF). Environmental factors likely contribute to increased NTM densities, with higher potential for exposure and infection.

OBJECTIVE: To identify water-quality constituents that influence odds of NTM infection among pwCF in Colorado.

METHODS: We conducted a population-based nested case-control study using patient data from the Colorado CF Center NTM database. We associated data from pwCF and water-quality data extracted from the Water Quality Portal to estimate odds of NTM infection. Using Bayesian generalized linear models with binomial-distributed discrete responses, we modeled three separate outcomes; any NTM infection, infections due to Mycobacterium avium complex species, and infections due to M. abscessus group species.

RESULTS: We observed a consistent association with molybdenum in the source water and M. abscessus group species infection among pwCF in all models. For every 1-unit increase in the log concentration of molybdenum in surface water, the odds of infection for those with M. abscessus group species compared to those who were NTM culture-negative increased by 79%. The odds of M. abscessus group infection varied by county; the counties with the highest probability of infection are located along the major rivers.

CONCLUSIONS: We have identified molybdenum in the source water as the most predictive factor of M. abscessus group infection among pwCF in Colorado. This finding will help inform patients at risk for NTM of their relative risks in residing within specific regions.

PMID:34218259 | DOI:10.1038/s41370-021-00360-2

Nutrition. 2021 May 24;89:111348. doi: 10.1016/j.nut.2021.111348. Online ahead of print.

ABSTRACT

In cystic fibrosis (CF), 85% to 90% of patients develop exocrine pancreatic insufficiency. Despite enzyme substitution, low pancreatic phospholipase A2 (sPLaseA2-IB) activity causes fecal loss of bile phosphatidylcholine and choline deficiency. We report on a female patient who has CF and progressive hepatosteatosis from 4.5 y onward. At 22.3 y, the liver comprised 27% fat (2385 mL volume) and transaminases were strongly increased. Plasma choline was 1.9 µmol/L (normal: 8-12 mol/L). Supplementation with 3 × 1g/d choline chloride decreased liver fat and volume (3 mo: 8.2%; 1912 mL) and normalized transaminases. Plasma choline increased to only 5.6 µmol/L upon supplementation, with high trimethylamine oxide levels (12-35 µmol/L; normal: 3 ± 1 mol/L) proving intestinal microbial choline degradation. The patient was homozygous for rs12325817, a frequent single-nucleotide polymorphism in the PEMT gene, associated with severe hepatosteatosis in response to choline deficiency. Resolution of steatosis required 2 y (4.5% fat). Discontinuation/resumption of choline supplementation resulted in rapid relapse/resolution of steatosis, increased transaminases, and abdominal pain.

PMID:34217074 | DOI:10.1016/j.nut.2021.111348

Med Ultrason. 2021 Jun 23. doi: 10.11152/mu-3323. Online ahead of print.

ABSTRACT

Ultrasound (US) is an ideal diagnostic tool for paediatric patients owning to its high spatial and temporal resolution, realtime imaging, and lack of ionizing radiation and bedside availability. The lack of superficial adipose tissue and favourable acoustic windows in children makes US the first line of investigation for evaluation of pleural and chest wall abnormalities.In the first part of the topic the technical requirements were explained and the use of ultrasound in the lung and pleura in paediatric patients were discussed. In the second part lung parenchymal diseases with their subpleural consolidations are reflected. In the third part, the use of ultrasound for chest wall, mediastinum, diaphragmatic diseases, trachea, interventions and artifacts in paediatric patients are summarized.

PMID:34216456 | DOI:10.11152/mu-3323

Paediatr Respir Rev. 2021 May 19:S1526-0542(21)00054-3. doi: 10.1016/j.prrv.2021.05.002. Online ahead of print.

ABSTRACT

There has been growing interest in telemedicine for cystic fibrosis over recent years based largely on convenience for patients and/or increasing the frequency of surveillance and early detection which, it is assumed, could improve treatment outcomes. During 2020, the covid-19 pandemic catalysed the pace of development of this field, as CF patients were presumed to be at high risk of infection. Most clinics adapted to digital platforms with provision of lung function monitoring and sample collection systems. Here, we present the views of multidisciplinary team members at a large paediatric CF centre on what has worked well and what requires further optimisation in the future. In response to the question posed, 'Do we still need face to face clinics?' our answer is 'Yes, but not every time, and not for everyone'.

PMID:34215541 | DOI:10.1016/j.prrv.2021.05.002

Viruses. 2021 Jun 21;13(6):1182. doi: 10.3390/v13061182.

ABSTRACT

Successful joint replacement is a life-enhancing procedure with significant growth in the past decade. Prosthetic joint infection occurs rarely; it is a biofilm-based infection that is poorly responsive to antibiotic alone. Recent interest in bacteriophage therapy has made it possible to treat some biofilm-based infections, as well as those caused by multidrug-resistant pathogens, successfully when conventional antibiotic therapy has failed. Here, we describe the case of a 61-year-old woman who was successfully treated after a second cycle of bacteriophage therapy administered at the time of a two-stage exchange procedure for a persistent methicillin-sensitive Staphylococcus aureus (MSSA) prosthetic knee-joint infection. We highlight the safety and efficacy of both intravenous and intra-articular infusions of bacteriophage therapy, a successful outcome with a single lytic phage, and the development of serum neutralization with prolonged treatment.

PMID:34205687 | PMC:PMC8233819 | DOI:10.3390/v13061182

Pediatr Pulmonol. 2021 Jul 2. doi: 10.1002/ppul.25552. Online ahead of print.

ABSTRACT

We are writing this letter to provide an update of published information on antibiotics for cystic fibrosis (CF) pulmonary exacerbations to the State of the Art articles by Zobell et al. Information on meropenem-vaborbactam and cefiderocol were not available when the original articles were published. These new antibiotics, approved in 2017 and 2019, possess antipseudomonal properties like the other carbapenems and cephalosporins in the original articles however, existing literature refers to their use for other less common bacteria. As patients with CF age, the microorganisms in their bacterial cultures change and some can colonize multiple or uncommon bacterial species including, Burkholderia, Achromobacter, and Stenotrophomonas spp. In 2019, these nonlactose fermenting bacterial species made up for approximately 15% of respiratory microorganisms cultured in pediatric patients. Though infrequent, compared to Staphylococcus aureus or Pseudomonas aeruginosa, these bacteria are opportunistic pathogens and patients at the highest risk for these infections include those with CF. Like other Gram negative bacteria, Burkholderia, Achromobacter, and Stenotrophomonas spp., are frequently drug resistant and can make treatment extremely challenging, thus it is crucial that data for treatment of these less common pathogens be evaluated.

PMID:34215020 | DOI:10.1002/ppul.25552

Eur J Pediatr. 2021 Jul 2. doi: 10.1007/s00431-021-04168-y. Online ahead of print.

ABSTRACT

Cystic fibrosis is the most prevalent inherited disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impaired electrolyte homeostasis caused by the mutated or absent protein leads to symptoms in multiple organ systems. However, the pulmonary manifestation with chronic infections and eventually respiratory failure remains the most important threat. Until one decade ago, only symptomatic treatment was available. However, since 2012, different combinations of CFTR modulators are available for people with cystic fibrosis (pwCF) that carry different mutations. The advent of these drugs has impressively changed life expectancy and quality of life in people with cystic fibrosis and raised new challenges regarding long-term complications and tapering of conventional therapies.Conclusion: In this review, we provide an update on the latest developments around diagnostics, treatment, and prognosis of pwCF. What is Known: • Cystic fibrosis is an incurable and life-shortening disease asking for life-long symptomatic treatment. • Three combination CFTR modulating drugs has gained marked approval over the last 10 years. What is New: • The emerge of new (modulating) therapies contribute to the increasing life expectancy. • A high unmet need to develop new therapies for people with CF who cannot access or benefit from these drugs remains. This review gives an update on the current status.

PMID:34213646 | DOI:10.1007/s00431-021-04168-y

Biomed Chromatogr. 2021 Jul 1:e5208. doi: 10.1002/bmc.5208. Online ahead of print.

ABSTRACT

In the management of cystic fibrosis, treatments against Staphylococcus aureus and Haemophilus influenzae such as amoxicillin or cotrimoxazole have to be prescribed and the antibiotherapy efficacy may be linked to the concentration that reaches the infected site. As cystic fibrosis patients present disturbed pharmacokinetics parameters, a drug monitoring would be relevant to assess lungs distribution of antibiotics and to optimize dosing regimens. In this context, the aim of the study was to develop and validate HPLC-based methods for the determination of both antibiotics in bronchial sputum from cystic fibrosis patients, in order to assess drugs distribution into lungs. Plasma proteins were precipitated by acetonitrile, amoxicillin concentrations in sputum were determined by HPLC coupled with tandem-mass spectrometry. Following a liquid extraction with ethyl acetate, cotrimoxazole was quantified by HPLC using ultraviolet detection. Both methods were found rapid, specific, accurate and reproducible. The method was applied to patient's samples. In three treated patients, concentration of amoxicillin in sputum were closed and below the lower limit of quantification (0.1 μg/g) and in six patients, sputum concentrations up to 11.1 μg/g and 6.4 μg/g were measured for sulfamethoxazole and trimethoprim respectively.

PMID:34212399 | DOI:10.1002/bmc.5208

Front Physiol. 2021 Jun 11;12:690247. doi: 10.3389/fphys.2021.690247. eCollection 2021.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed on the apical membrane of epithelial cells, where it plays a pivotal role in chloride transport and overall tissue homeostasis. CFTR constitutes a unique member of the ATP-binding cassette transporter superfamily, due to its distinctive cytosolic regulatory (R) domain carrying multiple phosphorylation sites that allow the tight regulation of channel activity and gating. Mutations in the CFTR gene cause cystic fibrosis, the most common lethal autosomal genetic disease in the Caucasian population. In recent years, major efforts have led to the development of CFTR modulators, small molecules targeting the underlying genetic defect of CF and ultimately rescuing the function of the mutant channel. Recent evidence has highlighted that this class of drugs could also impact on the phosphorylation of the R domain of the channel by protein kinase A (PKA), a key regulatory mechanism that is altered in various CFTR mutants. Therefore, the aim of this review is to summarize the current knowledge on the regulation of the CFTR by PKA-mediated phosphorylation and to provide insights into the different factors that modulate this essential CFTR modification. Finally, the discussion will focus on the impact of CF mutations on PKA-mediated CFTR regulation, as well as on how small molecule CFTR regulators and PKA interact to rescue dysfunctional channels.

PMID:34211404 | PMC:PMC8240754 | DOI:10.3389/fphys.2021.690247

Eur J Intern Med. 2021 Jun 24:S0953-6205(21)00230-2. doi: 10.1016/j.ejim.2021.06.019. Online ahead of print.

ABSTRACT

BACKGROUND: In the emergency department (ED) definitive diagnosis of SARS-COV-2 pneumonia is challenging as nasopharyngeal swab (NPS) can give false negative results. Strategies to reduce false negative rate of NPS have limitations. Serial NPSs (24-48 h from one another) are time-consuming, sputum can not be collected in the majority of patients, and bronchoalveolar lavage (BAL), the most sensitive test, requires specific expertise. Laryngotracheal aspiration (LTA) is easy to perform and showed a similar accuracy to BAL for diagnosis of other pulmonary diseases, however it was not studied to diagnose SARS-COV-2 pneumonia.

OBJECTIVE: An observational cross-sectional study was performed to evaluate the negative predictive value of LTA in patients with suspected SARS-COV-2 pneumonia despite a negative NPS.

METHODS: In the EDs of two university hospitals, consecutive patients with suspected SARS-COV-2 pneumonia despite a negative NPS underwent LTA performed with a nasotracheal tube connected to a vacuum system. Final diagnosis based on all respiratory specimen tests (NPS, LTA and BAL) and hospital data was established by two reviewers and in case of discordance by a third reviewer.

RESULTS: 117 patients were enrolled. LTA was feasible in all patients and no patients experienced adverse events. Fifteen (12.7%) patients were diagnosed with community-acquired SARS-COV-2 pneumonia: 13 LTA positive and only 2 (1.7%) LTA negative. The negative predictive value of NPS and LTA was 87.3% (79.9% - 92.7%) and 98.1% (93.3%99.8%) respectively.

CONCLUSIONS: LTA resulted feasible, safe and reduced false negative rate in patients with suspected SARS-COV-2 pneumonia despite a negative NPS.

PMID:34210553 | DOI:10.1016/j.ejim.2021.06.019

Microorganisms. 2021 Jun 11;9(6):1275. doi: 10.3390/microorganisms9061275.

ABSTRACT

The importance and abundance of strict anaerobic bacteria in the respiratory microbiota of people with cystic fibrosis (PWCF) is now established through studies based on high-throughput sequencing or extended-culture methods. In CF respiratory niche, one of the most prevalent anaerobic genera is Prevotella, and particularly the species Prevotella melaninogenica. The objective of this study was to evaluate the antibiotic susceptibility of this anaerobic species. Fifty isolates of P. melaninogenica cultured from sputum of 50 PWCF have been included. Antibiotic susceptibility testing was performed using the agar diffusion method. All isolates were susceptible to the following antibiotics: amoxicillin/clavulanic acid, piperacillin/tazobactam, imipenem and metronidazole. A total of 96% of the isolates (48/50) were resistant to amoxicillin (indicating beta-lactamase production), 34% to clindamycin (17/50) and 24% to moxifloxacin (12/50). Moreover, 10% (5/50) were multidrug-resistant. A significant and positive correlation was found between clindamycin resistance and chronic azithromycin administration. This preliminary study on a predominant species of the lung "anaerobiome" shows high percentages of resistance, potentially exacerbated by the initiation of long-term antibiotic therapy in PWCF. The anaerobic resistome characterization, focusing on species rather than genera, is needed in the future to better prevent the emergence of resistance within lung microbiota.

PMID:34208093 | DOI:10.3390/microorganisms9061275

Genes (Basel). 2021 Jun 9;12(6):892. doi: 10.3390/genes12060892.

ABSTRACT

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, triggering dysfunction of the anion channel in several organs including the lung and gut. The main cause of morbidity and mortality is chronic infection. The microbiota is now included among the additional factors that could contribute to the exacerbation of patient symptoms, to treatment outcome, and more generally to the phenotypic variability observed in CF patients. In recent years, various omics tools have started to shed new light on microbial communities associated with CF and host-microbiota interactions. In this context, proteomics targets the key effectors of the responses from organisms, and thus their phenotypes. Recent advances are promising in terms of gaining insights into the CF microbiota and its relation with the host. This review provides an overview of the contributions made by proteomics and metaproteomics to our knowledge of the complex host-microbiota partnership in CF. Considering the strengths and weaknesses of proteomics-based approaches in profiling the microbiota in the context of other diseases, we illustrate their potential and discuss possible strategies to overcome their limitations in monitoring both the respiratory and intestinal microbiota in sample from patients with CF.

PMID:34207804 | DOI:10.3390/genes12060892

Vaccines (Basel). 2021 Jun 18;9(6):670. doi: 10.3390/vaccines9060670.

ABSTRACT

Human infections caused by the opportunist pathogens Burkholderia cepacia complex and Pseudomonas aeruginosa are of particular concern due to their severity, their multiple antibiotic resistance, and the limited eradication efficiency of the current available treatments. New therapeutic options have been pursued, being vaccination strategies to prevent or limit these infections as a rational approach to tackle these infections. In this review, immunization and immunotherapy approaches currently available and under study against these bacterial pathogens is reviewed. Ongoing active and passive immunization clinical trials against P. aeruginosa infections is also reviewed. Novel identified bacterial targets and their possible exploitation for the development of immunization and immunotherapy strategies against P. aeruginosa and B. cepacia complex and infections are also presented and discussed.

PMID:34207253 | DOI:10.3390/vaccines9060670

Int J Mol Sci. 2021 Jun 18;22(12):6531. doi: 10.3390/ijms22126531.

ABSTRACT

Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.

PMID:34207085 | DOI:10.3390/ijms22126531

Int J Environ Res Public Health. 2021 Jun 22;18(13):6690. doi: 10.3390/ijerph18136690.

ABSTRACT

The consequences of air pollution pose one of the most serious threats to human health, and especially impact children from large agglomerations. The measurement of nitric oxide concentration in exhaled air (FeNO) is a valuable biomarker in detecting and monitoring airway inflammation. However, only a few studies have assessed the relationship between FeNO and the level of air pollution. The study aims to estimate the concentration of FeNO in the population of children aged 8-9 attending the third grade of public primary schools in Krakow, as well as to determine the relationship between FeNO concentration and dust and gaseous air pollutants. The research included 4580 children aged 8-9 years who had two FeNO measurements in the winter-autumn and spring-summer periods. The degree of air pollution was obtained from the Regional Inspectorate of Environmental Protection in Krakow. The concentration of pollutants was obtained from three measurement stations located in different parts of the city. The FeNO results were related to air pollution parameters. The study showed weak but significant relationships between FeNO and air pollution parameters. The most significant positive correlations were found for CO8h (r = 0.1491, p < 0.001), C6H6 (r = 0.1420, p < 0.001), PM10 (r = 0.1054, p < 0.001) and PM2.5 (r = 0.1112, p < 0.001). We suggest that particulate and gaseous air pollutants impact FeNO concentration in children aged 8-9 years. More research is needed to assess the impact of air pollution on FeNO concentration in children. The results of such studies could help to explain the increase in the number of allergic and respiratory diseases seen in children in recent decades.

PMID:34206247 | DOI:10.3390/ijerph18136690