Integrating massive RNA-seq data to elucidate transcriptome dynamics in Drosophila melanogaster.

The volume of ribonucleic acid (RNA)-seq data has increased exponentially, providing numerous new insights into various biological processes. However, due to significant practical challenges, such as data heterogeneity, it is still difficult to ensure the quality of these data when integrated. Although some quality control methods have been developed, sample consistency is rarely considered and these methods are susceptible to artificial factors. Here, we developed MassiveQC, an unsupervised machine learning-based approach, to automatically download and filter large-scale high-throughput data. In addition to the read quality used in other tools, MassiveQC also uses the alignment and expression quality as model features. Meanwhile, it is user-friendly since the cutoff is generated from self-reporting and is applicable to multimodal data. To explore its value, we applied MassiveQC to Drosophila RNA-seq data and generated a comprehensive transcriptome atlas across 28 tissues from embryogenesis to adulthood. We systematically characterized fly gene expression dynamics and found that genes with high expression dynamics were likely to be evolutionarily young and expressed at late developmental stages, exhibiting high nonsynonymous substitution rates and low phenotypic severity, and they were involved in simple regulatory programs. We also discovered that human and Drosophila had strong positive correlations in gene expression in orthologous organs, revealing the great potential of the Drosophila system for studying human development and disease.

Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma.

BACKGROUND: Non-neuronal cholinergic system (NNCS) contributes to various inflammatory airway diseases. However, the role of NNCS in severe asthma (SA) remains largely unexplored. OBJECTIVE: To explore airway NNCS in SA. METHODS: In this prospective cohort study based on the Australasian Severe Asthma Network in a real-world setting, patients with SA (n = 52) and non-SA (n = 104) underwent clinical assessment and sputum induction. The messenger RNA (mRNA) levels of NNCS components and proinflammatory cytokines in the sputum were detected using real-time quantitative polymerase chain reaction, and the concentrations of acetylcholine (Ach)-related metabolites were evaluated using liquid chromatography coupled with tandem mass spectrometry. Asthma exacerbations were prospectively investigated during the next 12 months. The association between NNCS and future asthma exacerbations was also analyzed. RESULTS: Patients with SA were less controlled and had worse airway obstruction, a lower bronchodilator response, higher doses of inhaled corticosteroids, and more add-on treatments. The sputum mRNA levels of NNCS components, such as muscarinic receptors M1R-M5R, OCT3, VACHT, and ACHE; proinflammatory cytokines; and Ach concentration in the SA group were significantly higher than those in the non-SA group. Furthermore, most NNCS components positively correlated with non-type (T) 2 inflammatory profiles, such as sputum neutrophils, IL8, and IL1B. In addition, the mRNA levels of sputum M2R, M3R, M4R, M5R, and VACHT were independently associated with an increased risk of moderate-to-severe asthma exacerbations. CONCLUSION: This study indicated that the NNCS was significantly activated in SA, leading to elevated Ach and was associated with clinical features, non-T2 inflammation, and future exacerbations of asthma, highlighting the potential role of the NNCS in the pathogenesis of SA. CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-16009529 (http://www.chictr.org.cn).

Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques.

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.

Nutraceuticals: unlocking newer paradigms in the mitigation of inflammatory lung diseases.

Persistent respiratory tract inflammation contributes to the pathogenesis of various chronic respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. These inflammatory respiratory diseases have been a major public health concern as they are the leading causes of worldwide mortality and morbidity, resulting in heavy burden on socioeconomic growth throughout these years. Although various therapeutic agents are currently available, the clinical applications of these agents are found to be futile due to their adverse effects, and most patients remained poorly controlled with a low quality of life. These drawbacks have necessitated the development of novel, alternative therapeutic agents that can effectively improve therapeutic outcomes. Recently, nutraceuticals such as probiotics, vitamins, and phytochemicals have gained increasing attention due to their nutritional properties and therapeutic potential in modulating the pathological mechanisms underlying inflammatory respiratory diseases, which could ultimately result in improved disease control and overall health outcomes. As such, nutraceuticals have been held in high regard as the possible alternatives to address the limitations of conventional therapeutics, where intensive research are being performed to identify novel nutraceuticals that can positively impact various inflammatory respiratory diseases. This review provides an insight into the utilization of nutraceuticals with respect to their molecular mechanisms targeting multiple signaling pathways involved in the pathogenesis of inflammatory respiratory diseases.

Smoking induces shifts in cellular composition and transcriptome within the bronchial mucus barrier.

BACKGROUND AND OBJECTIVE: Smoking disturbs the bronchial-mucus-barrier. This study assesses the cellular composition and gene expression shifts of the bronchial-mucus-barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single-cell-RNA-sequencing (scRNA-seq) based cellular deconvolution (CD) can predict cell-type composition in RNA-seq data. METHODS: RNA-seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers; 18 ex-smokers), 77 participants without COPD (40 never-smokers; 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non-COPD-smokers). Differential gene expression was used to investigate gene expression shifts. The CD-derived goblet cell ratios were validated by correlating with staining-derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (false discovery rate p-value < 0.05). RESULTS: Both CD methods indicate a shift in bronchial-mucus-barrier cell composition towards goblet cells in COPD and non-COPD-smokers compared to ex- and never-smokers. It shows that the effect was reversible within a year of smoking cessation. A reduction of ciliated and basal cells was observed with current smoking, which resolved following smoking cessation. The expression of mucin and sodium channel (ENaC) genes, but not chloride channel genes, were altered in COPD and current smokers compared to never smokers or ex-smokers. The goblet cell-derived staining scores correlate with CD-derived goblet cell ratios. CONCLUSION: Smoking alters bronchial-mucus-barrier cell composition, transcriptome and increases mucus production. This effect is partly reversible within a year of smoking cessation. CD methodology can predict goblet-cell percentages from RNA-seq.

E-Cigarette Aerosol Condensate Leads to Impaired Coronary Endothelial Cell Health and Restricted Angiogenesis.

Cardiovascular disease (CVD) is a leading cause of mortality worldwide, with cigarette smoking being a major preventable risk factor. Smoking cessation can be difficult due to the addictive nature of nicotine and the withdrawal symptoms following cessation. Electronic cigarettes (e-Cigs) have emerged as an alternative smoking cessation device, which has been increasingly used by non-smokers; however, the cardiovascular effects surrounding the use of e-Cigs remains unclear. This study aimed to investigate the effects of e-Cig aerosol condensate (EAC) (0 mg and 18 mg nicotine) in vitro on human coronary artery endothelial cells (HCAEC) and in vivo on the cardiovascular system using a mouse model of 'e-vaping'. In vitro results show a decrease in cell viability of HCAEC when exposed to EAC either directly or after exposure to conditioned lung cell media (p < 0.05 vs. control). Reactive oxygen species were increased in HCAEC when exposed to EAC directly or after exposure to conditioned lung cell media (p < 0.0001 vs. control). ICAM-1 protein expression levels were increased after exposure to conditioned lung cell media (18 mg vs. control, p < 0.01). Ex vivo results show an increase in the mRNA levels of anti-angiogenic marker, FKBPL (p < 0.05 vs. sham), and endothelial cell adhesion molecule involved in barrier function, ICAM-1 (p < 0.05 vs. sham) in murine hearts following exposure to electronic cigarette aerosol treatment containing a higher amount of nicotine. Immunohistochemistry also revealed an upregulation of FKBPL and ICAM-1 protein expression levels. This study showed that despite e-Cigs being widely used for tobacco smoking cessation, these can negatively impact endothelial cell health with a potential to lead to the development of cardiovascular disease.

Aim2 suppresses cigarette smoke-induced neutrophil recruitment, neutrophil caspase-1 activation and anti-Ly6G-mediated neutrophil depletion.

Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) and absent in melanoma-2 (AIM2) inflammasomes in cigarette smoke-induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2-/- mice in cigarette smoke-induced experimental COPD. MCC950 treatment had minimal effects on disease development and/or progression. Aim2-/- mice had increased airway neutrophils with decreased caspase-1 levels, independent of changes in lung neutrophil chemokines. Suppressing neutrophils with anti-Ly6G in experimental COPD in wild-type mice reduced neutrophils in bone marrow, blood and lung. By contrast, anti-Ly6G treatment in Aim2-/- mice with experimental COPD had no effect on neutrophils in bone marrow, partially reduced neutrophils in the blood and had no effect on neutrophils or neutrophil caspase-1 levels in the lungs. These findings identify that following cigarette smoke exposure, Aim2 is important for anti-Ly6G-mediated depletion of neutrophils, suppression of neutrophil recruitment and mediates activation of caspase-1 in neutrophils.

Adverse roles of mast cell chymase-1 in COPD.

BACKGROUND: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown. METHODS: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5-deficient (-/-) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms. RESULTS: The levels of hCMA1 mRNA and CMA1+ mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 -/- mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 -/- mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD. CONCLUSION: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.

Treatment of chronic airway diseases using nutraceuticals: Mechanistic insight.

Respiratory diseases, both acute and chronic, are reported to be the leading cause of morbidity and mortality, affecting millions of people globally, leading to high socio-economic burden for the society in the recent decades. Chronic inflammation and decline in lung function are the common symptoms of respiratory diseases. The current treatment strategies revolve around using appropriate anti-inflammatory agents and bronchodilators. A range of anti-inflammatory agents and bronchodilators are currently available in the market; however, the usage of such medications is limited due to the potential for various adverse effects. To cope with this issue, researchers have been exploring various novel, alternative therapeutic strategies that are safe and effective to treat respiratory diseases. Several studies have been reported on the possible links between food and food-derived products in combating various chronic inflammatory diseases. Nutraceuticals are examples of such food-derived products which are gaining much interest in terms of its usage for the well-being and better human health. As a consequence, intensive research is currently aimed at identifying novel nutraceuticals, and there is an emerging notion that nutraceuticals can have a positive impact in various respiratory diseases. In this review, we discuss the efficacy of nutraceuticals in altering the various cellular and molecular mechanisms involved in mitigating the symptoms of respiratory diseases.

Effects of air pollution on human health - Mechanistic evidence suggested by in vitro and in vivo modelling.

Airborne particulate matter (PM) comprises both solid and liquid particles, including carbon, sulphates, nitrate, and toxic heavy metals, which can induce oxidative stress and inflammation after inhalation. These changes occur both in the lung and systemically, due to the ability of the small-sized PM (i.e. diameters ≤2.5 µm, PM2.5) to enter and circulate in the bloodstream. As such, in 2016, airborne PM caused ∼4.2 million premature deaths worldwide. Acute exposure to high levels of airborne PM (eg. during wildfires) can exacerbate pre-existing illnesses leading to hospitalisation, such as in those with asthma and coronary heart disease. Prolonged exposure to PM can increase the risk of non-communicable chronic diseases affecting the brain, lung, heart, liver, and kidney, although the latter is less well studied. Given the breadth of potential disease, it is critical to understand the mechanisms underlying airborne PM exposure-induced disorders. Establishing aetiology in humans is difficult, therefore, in-vitro and in-vivo studies can provide mechanistic insights. We describe acute health effects (e.g. exacerbations of asthma) and long term health effects such as the induction of chronic inflammatory lung disease, and effects outside the lung (e.g. liver and renal change). We will focus on oxidative stress and inflammation as this is the common mechanism of PM-induced disease, which may be used to develop effective treatments to mitigate the adverse health effect of PM exposure.

Endogenous Adenosine 5'-Monophosphate, But Not Acetylcholine or Histamine, is Associated with Asthma Control, Quality of Life, and Exacerbations.

OBJECTIVE: Endogenous adenosine 5'-monophosphate (AMP), acetylcholine (ACh), and histamine (HA) are known to be important in bronchial contraction, but their clinical relevance to asthma is poorly understood. We aimed to quantify endogenous AMP, ACh, and HA in induced sputum samples and explore their relationships with asthma control and exacerbations. METHODS: 20 healthy subjects and 112 asthmatics underwent clinical assessment, sputum induction, and blood sampling. The level of asthma control was determined by the asthma control test (ACT) questionnaire. Asthma exacerbation was evaluated according to the criteria of the American Thoracic Society/European Respiratory Society. Levels of AMP, ACh, and HA in sputum were measured by liquid chromatography coupled to tandem mass spectrometry. IL-ß, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17A, TNF-α, IFN-γ, and macrophage-derived chemokine (MDC) were also measured. RESULTS: Compared to healthy controls, asthmatics had higher levels of HA, lower levels of ACh, and similar levels of AMP in induced sputum samples. Compared to controlled asthma (n = 54), uncontrolled asthma (n = 58) showed higher AMP levels (P = 0.002), but similar HA and ACh levels. AMP was negatively correlated with ACT scores (r = - 0.348) and asthma quality of life questionnaire scores (r = - 0.188) and positively correlated with blood monocytes percentage (r = 0.195), sputum MDC (r = 0.214), and IL-6 levels (r = 0.196). Furthermore, AMP was associated with an increased risk of exacerbations in the preceding year. CONCLUSION: Endogenous AMP, but not ACh or HA, was associated with asthma control, quality of life, and exacerbations in the previous year, which indicates that AMP could be a clinically useful biomarker of asthma.

Effective-component compatibility of Bufei Yishen formula III ameliorated COPD by improving airway epithelial cell senescence by promoting mitophagy via the NRF2/PINK1 pathway.

BACKGROUND: Effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) demonstrates positive effects on stable chronic obstructive pulmonary disease (COPD). PURPOSE: To investigate the mechanisms of ECC-BYF III on COPD rats from the aspect of airway epithelial cell senescence. METHODS: COPD model rats (Sprague-Dawley rat) were treated with ECC-BYF III for 8 weeks, and the efficacy was evaluated. Cigarette smoke extract (CSE)-induced senescence model of airway epithelial cells was treated with ECC-BYF III, and related enzymes and proteins involved in oxidative stress and mitophagy were detected. RESULTS: ECC-BYF III markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including the reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9 levels, increase of the level in total superoxide dismutase (T-SOD), and decease in the p21 level in the airways. Furthermore, ECC-BYF III suppressed p16 and p21 expressions and senescence-associated ß-galactosidase (SA-ß-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF III upregulated mitophagy-related proteins, including the co-localizations of TOM20 and LC3B, PINK1 and PARK2, and improved mitochondrial function by upregulating mitochondrial mitofusin (MFN)2 and reducing dynamin-related protein 1 (DRP1) expression. ECC-BYF III enhanced the activities of T-SOD and GSH-PX by up-regulating NRF2, thus inhibiting oxidative stress. After intervention with NRF2 inhibitor, the regulation effects of ECC-BYF III on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed. CONCLUSIONS: ECC-BYF III exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through the activation of NRF2 signaling.

In-utero exposure to air pollution and early-life neural development and cognition.

Air pollution remains one of the major health threats around the world. Compared to adults, foetuses and infants are more vulnerable to the effects of environmental toxins. Maternal exposure to air pollution causes several adverse birth outcomes and may lead to life-long health consequences. Given that a healthy intrauterine environment is a critical factor for supporting normal foetal brain development, there is a need to understand how prenatal exposure to air pollution affects brain health and results in neurological dysfunction. This review summarised the current knowledge on the adverse effects of prenatal air pollution exposure on early life neurodevelopment and subsequent impairment of cognition and behaviour in childhood, as well as the potential of early-onset neurodegeneration. While inflammation, oxidative stress, and endoplasmic reticulum are closely involved in the physiological response, sex differences also occur. In general, males are more susceptible than females to the adverse effect of in-utero air pollution exposure. Considering the evidence provided in this review and the rising concerns of global air pollution, any efforts to reduce pollutant emission or exposure will be protective for the next generation.

A comparison of attitudes toward remote learning during the COVID-19 pandemic between students attending a Chinese and an Australian campus.

The COVID-19 pandemic has been a strong driver for moving more teaching and learning activities online. Border restrictions have had a severe impact on international students either hoping to enroll in courses offered in Australia or continue with such courses if they are already enrolled. The online learning experience is likely different between students onshore and offshore. This study took a unique opportunity to investigate any such differences in students' attitudes toward remote learning, necessitated by the pandemic, by comparing two cohorts of students, Australia versus China based. An anonymous survey using the Likert Scale and open-ended questions was available for student feedback on subject delivery. The students based in Australia expressed a preference for remote learning due to the convenience of attendance and availability of the video recordings. However, students in China had a strong preference for face-to-face sessions, with the lack of prior experience in an English-speaking learning environment and hesitance to speak with the lecturers and engage in the learning activities possible reasons for this. In quizzes, students in Australia performed better than those in China regardless of local or international student status. This difference may be due to the Australian-based students' prior experience of English-speaking environments and open-book quizzes. In conclusion, remote learning in a familiar language and learning environment is accepted by students, whereas if the teaching is delivered in a second language using unfamiliar teaching methods, remote learning will require additional scaffolding to enhance their learning experience.

Targeting intercellular adhesion molecule-1 (ICAM-1) to reduce rhinovirus-induced acute exacerbations in chronic respiratory diseases.

The chronic respiratory non-communicable diseases, asthma and chronic obstructive pulmonary disease (COPD) are among the leading causes of global mortality and morbidity. Individuals suffering from these diseases are particularly susceptible to respiratory infections caused by bacterial and/or viral pathogens, which frequently result in exacerbation of symptoms, lung function decline, frequent hospital emergency visits and increased socioeconomic burden. Human rhinoviruses (HRV) remain the major viral pathogen group implicated in exacerbations of both asthma and COPD. The rhinoviral entry into the host lung epithelium is facilitated primarily by the adhesion site ("receptor") intercellular adhesion molecule-1 (ICAM-1), coincidentally expressed on the respiratory epithelium in these conditions. Multiple observations of increased airway ICAM-1 protein in asthmatics, smokers and smoking-related COPD have been recorded in the literature. However, the lack of robust therapies for COPD in particular has triggered a renewed interest in assessing receptor antagonism-based anti-viral strategies for treatment of intercurrent viral infections in those with pre-existing chronic lung diseases. Given the crucial role ICAM-1 plays in facilitating HRV adhesion and, thus, transmissibility to the host respiratory system, as well as the up-regulation of ICAM-1 by smoking, we summarize the role of HRV in smoking-induced COPD and especially highlight the role of ICAM-1 in epithelial viral adhesion and chronic lung disease progression. Further, the review also sheds light specifically on evolving precision therapeutic strategies in blocking ICAM-1 for preventing viral adhesion and exacerbations of COPD.

Rediscovering the Therapeutic Potential of Agarwood in the Management of Chronic Inflammatory Diseases.

The inflammatory response is a central aspect of the human immune system that acts as a defense mechanism to protect the body against infections and injuries. A dysregulated inflammatory response is a major health concern, as it can disrupt homeostasis and lead to a plethora of chronic inflammatory conditions. These chronic inflammatory diseases are one of the major causes of morbidity and mortality worldwide and the need for them to be managed in the long term has become a crucial task to alleviate symptoms and improve patients' overall quality of life. Although various synthetic anti-inflammatory agents have been developed to date, these medications are associated with several adverse effects that have led to poor therapeutic outcomes. The hunt for novel alternatives to modulate underlying chronic inflammatory processes has unveiled nature to be a plentiful source. One such example is agarwood, which is a valuable resinous wood from the trees of Aquilaria spp. Agarwood has been widely utilized for medicinal purposes since ancient times due to its ability to relieve pain, asthmatic symptoms, and arrest vomiting. In terms of inflammation, the major constituent of agarwood, agarwood oil, has been shown to possess multiple bioactive compounds that can regulate molecular mechanisms of chronic inflammation, thereby producing a multitude of pharmacological functions for treating various inflammatory disorders. As such, agarwood oil presents great potential to be developed as a novel anti-inflammatory therapeutic to overcome the drawbacks of existing therapies and improve treatment outcomes. In this review, we have summarized the current literature on agarwood and its bioactive components and have highlighted the potential roles of agarwood oil in treating various chronic inflammatory diseases.

Advances and applications of monoolein as a novel nanomaterial in mitigating chronic lung diseases.

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease, lung cancer, and the recently emerged COVID-19, are a huge threat to human health, and among the leading causes of global morbidity and mortality every year. Despite availability of various conventional therapeutics, many patients remain poorly controlled and have a poor quality of life. Furthermore, the treatment and diagnosis of these diseases are becoming increasingly challenging. In the recent years, the application of nanomedicine has become increasingly popular as a novel strategy for diagnosis, treatment, prevention, as well as follow-up of chronic lung diseases. This is attributed to the ability of nanoscale drug carriers to achieve targeted delivery of therapeutic moieties with specificity to diseased site within the lung, thereby enhancing therapeutic outcomes of conventional therapies whilst minimizing the risks of adverse reactions. For this instance, monoolein is a polar lipid nanomaterial best known for its versatility, thermodynamic stability, biocompatibility, and biodegradability. As such, it is commonly employed in liquid crystalline systems for various drug delivery applications. In this review, we present the applications of monoolein as a novel nanomaterial-based strategy for targeted drug delivery with the potential to revolutionize therapeutic approaches in chronic lung diseases.

Current Smoking Alters Gene Expression and DNA Methylation in the Nasal Epithelium of Patients with Asthma.

Current smoking contributes to worsened asthma prognosis and more severe symptoms and limits the beneficial effects of corticosteroids. As the nasal epithelium can reflect smoking-induced changes in the lower airways, it is a relevant source to investigate changes in gene expression and DNA methylation. This study explores gene expression and DNA methylation changes in current and ex-smokers with asthma. Matched gene expression and epigenome-wide DNA methylation samples collected from nasal brushings of 55 patients enrolled in a clinical trial investigation of current and ex-smoker patients with asthma were analyzed. Differential gene expression and DNA methylation analyses were conducted comparing current smokers with ex-smokers. Expression quantitative trait methylation (eQTM) analysis was completed to explore smoking-relevant genes by CpG sites that differ between current and ex-smokers. To investigate the relevance of the smoking-associated DNA methylation changes for the lower airways, significant CpG sites were explored in bronchial biopsies from patients who had stopped smoking. A total of 809 genes and 18,814 CpG sites were differentially associated with current smoking in the nose. The cis-eQTM analysis uncovered 171 CpG sites with a methylation status associated with smoking-related gene expression, including AHRR, ALDH3A1, CYP1A1, and CYP1B1. The methylation status of CpG sites altered by current smoking reversed with 1 year of smoking cessation. We confirm that current smoking alters epigenetic patterns and affects gene expression in the nasal epithelium of patients with asthma, which is partially reversible in bronchial biopsies after smoking cessation. We demonstrate the ability to discern molecular changes in the nasal epithelium, presenting this as a tool in future investigations into disease-relevant effects of tobacco smoke.

Sex-specific effects of in utero and adult tobacco smoke exposure.

Tobacco smoke has harmful effects on a multiorgan level. Exposure to smoke, whether in utero or environmental, significantly increases susceptibility. This susceptibility has been identified to be divergent between males and females. However, there remains a distinct lack of thorough research into the relationship between sex and exposure to tobacco. Females tend to generate a more significant response than males during adulthood exposure. The intrauterine environment is meticulously controlled, and exposure to tobacco presents a significant factor that contributes to poor health outcomes and susceptibility later in life. Analysis of these effects in relation to the sex of the offspring is yet to be holistically reviewed and summarized. In this review, we will delineate the time-dependent relationship between tobacco smoke exposure and sex-specific disease susceptibility. We further outline possible biological mechanisms that may contribute to the identified pattern.

LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.