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).

Emerging role of tumor suppressing microRNAs as therapeutics in managing non-small cell lung cancer.

Lung cancer (LC) is the second leading cause of death across the globe after breast cancer. There are two types of LC viz. small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all LC cases. NSCLC affects smokers and people who do not smoke and mainly arises in bronchi and peripheral lungs tissue. LC is often characterized by the alterations of key genes such as EGFR, Wnt/ß-catenin signaling, ALK, MET, K-Ras and p53 and downstream signaling pathways associated with tumor growth, differentiation, and survival. Numerous miRNAs have been discovered as a result of advances in biotechnology to treat LC. Various miRNAs those have been identified to treat LC include mir-Let7, mir-34a, mir-134, mir-16-1, mir-320a, mir-148a, mir-125a-5p, mir-497, mir-29, mir-133a, and mir-29a-3p. These miRNAs target various signaling pathways that are involved in pathogenesis of LC. However, due to rapid RNAse degradation, quick clearance, and heat instability, associated with necked miRNA leads to less effective therapeutic effect against LC. Therefore, to overcome these challenges nanocarrier loaded with miRNAs have been reported. They have been found promising because they have the capacity to target the tumor as well as they can penetrate the tumors deep due to nanometer size. Some of the clinical trials have been performed using miR-34a and let-7 for the treatment of LC. In the present manuscript we highlight the role miRNAs as well as their nanoparticle in tumor suppression.

The application of nanoparticles as advanced drug delivery systems in Attenuating COPD.

Chronic Obstructive Pulmonary Disease (COPD) is a dilapidating condition which is characterized by inflammation, an excess in free radical generation and airway obstruction. Currently, the drugs commercially available for the management of COPD pose several limitations such as systemic adverse effects, including bone density loss and an increased risk of developing pneumonia. Moreover, another limitation includes the need for regular and frequent dosing regimens; which can affect the adherence to the therapy. Furthermore, these current treatments provide symptomatic relief; however, they cannot stop the progression of COPD. Comparatively, nanoparticles (NPs) provide great therapeutic potential to treat COPD due to their high specificity, biocompatibility, and higher bioavailability. Furthermore, the NP-based drug delivery systems involve less frequent dosing requirements and in smaller doses which assist in minimizing side effects. In this review, the benefits and limitations of conventional therapies are explored, while providing an in-depth insight on advanced applications of NP-based systems in the treatment of COPD.

Zerumbone liquid crystalline nanoparticles protect against oxidative stress, inflammation and senescence induced by cigarette smoke extract in vitro.

The purpose of this study was to evaluate the potential of zerumbone-loaded liquid crystalline nanoparticles (ZER-LCNs) in the protection of broncho-epithelial cells and alveolar macrophages against oxidative stress, inflammation and senescence induced by cigarette smoke extract in vitro. The effect of the treatment of ZER-LCNs on in vitro cell models of cigarette smoke extract (CSE)-treated mouse RAW264.7 and human BCi-NS1.1 basal epithelial cell lines was evaluated for their anti-inflammatory, antioxidant and anti-senescence activities using colorimetric and fluorescence-based assays, fluorescence imaging, RT-qPCR and proteome profiler kit. The ZER-LCNs successfully reduced the expression of pro-inflammatory markers including Il-6, Il-1ß and Tnf-α, as well as the production of nitric oxide in RAW 264.7 cells. Additionally, ZER-LCNs successfully inhibited oxidative stress through reduction of reactive oxygen species (ROS) levels and regulation of genes, namely GPX2 and GCLC in BCi-NS1.1 cells. Anti-senescence activity of ZER-LCNs was also observed in BCi-NS1.1 cells, with significant reductions in the expression of SIRT1, CDKN1A and CDKN2A. This study demonstrates strong in vitro anti-inflammatory, antioxidative and anti-senescence activities of ZER-LCNs paving the path for this formulation to be translated into a promising therapeutic agent for chronic respiratory inflammatory conditions including COPD and asthma.

Clinical Subtypes of Neutrophilic Asthma: A Cluster Analysis From Australasian Severe Asthma Network.

BACKGROUND: Clinical heterogeneity may exist within asthma subtypes defined by inflammatory markers. However, the heterogeneity of neutrophilic asthma (NA) remains largely unexplored. OBJECTIVE: To explore potential clusters and the stability of NA. METHODS: Participants with NA from the Australasian Severe Asthma Network underwent a multidimensional assessment. They were then asked to participate in a 12-month longitudinal cohort study. We explored potential clusters using a hierarchical cluster analysis and validated the differential future risk of asthma exacerbations in the identified clusters. A decision tree analysis was developed to predict cluster assignments. Finally, the stability of prespecified clusters was examined within 1 month. RESULTS: Three clusters were identified in 149 patients with NA. Cluster 1 (n = 99; 66.4%) was characterized by female-predominant nonsmokers with well-controlled NA, cluster 2 (n = 16; 10.7%) by individuals with comorbid anxiety/depressive symptoms with poorly controlled NA, and cluster 3 by older male smokers with late-onset NA. Cluster 2 had a greater proportion of participants with severe exacerbations (P = .005), hospitalization (P = .010), and unscheduled visits (P = .013) and a higher number of emergency room visits (P = .039) than that of the other two clusters. The decision tree assigned 92.6% of participants correctly. Most participants (87.5%; n = 7) in cluster 2 had a stable NA phenotype, whereas participants of clusters 1 and 3 had variable phenotypes. CONCLUSIONS: We identified three clinical clusters of NA, in which cluster 2 represents an uncontrolled and stable NA subtype with an elevated risk of exacerbations. These findings have clinical implications for the management of NA.

Advances in nano-based drug delivery systems for the management of cytokine influx-mediated inflammation in lung diseases.

Asthma, lung cancer, cystic fibrosis, tuberculosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and COVID-19 are few examples of inflammatory lung conditions that cause cytokine release syndrome. It can initiate a widespread inflammatory response and may activate several inflammatory pathways that cause multiple organ failures leading to increased number of deaths and increased prevalence rates around the world. Nanotechnology-based therapeutic modalities such as nanoparticles, liposomes, nanosuspension, monoclonal antibodies, and vaccines can be used in the effective treatment of inflammatory lung diseases at both cellular and molecular levels. This would also help significantly in the reduction of patient mortality. Therefore, nanotechnology could be a potent platform for repurposing current medications in the treatment of inflammatory lung diseases. The aim and approach of this article are to highlight the clinical manifestations of cytokine storm in inflammatory lung diseases along with the advances and potential applications of nanotechnology-based therapeutics in the management of cytokine storm. Further in-depth studies are required to understand the molecular pathophysiology, and how nanotechnology-based therapeutics can help to effectively combat this problem.

Third-Hand Exposure to E-Cigarette Vapour Induces Pulmonary Effects in Mice.

In the last decade, e-cigarette usage has increased, with an estimated 82 million e-cigarette users globally. This is, in part, due to the common opinion that they are "healthier" than tobacco cigarettes or simply "water vapour". Third-hand e-vapour exposure is the chemical residue left behind from e-cigarette aerosols, which is of concern due to its invisible nature, especially among young children. However, there is limited information surrounding third-hand e-vapour exposure. This study aimed to investigate the pulmonary effects of sub-chronic third-hand e-vapour exposure in a murine model. BALB/c mice (4 weeks of age) were exposed to a towel containing nicotine free (0 mg) e-vapour, nicotine (18 mg) e-vapour, or no e-vapour (sham) and replaced daily for 4 weeks. At the endpoint, lung function was assessed, and bronchoalveolar lavage fluid and lungs were collected to measure inflammation and fibrosis. Mice exposed to third-hand e-vapour without nicotine had alveolar enlargement compared to sham exposed controls. Mice exposed to third-hand e-vapour with nicotine had reduced bronchial responsiveness to provocation, increased epithelial thickening in large airways, increased epithelial layers in small airways, alveolar enlargement, and increased small airway collagen deposition, compared to sham exposed controls. In conclusion, our study shows that third-hand e-vapour exposure, particularly in the presence of nicotine, negatively affects the lung health of mice and highlights the need for greater public awareness surrounding the dangers of third-hand exposure to e-cigarette vapour.

Effect of E-Vaping on Kidney Health in Mice Consuming a High-Fat Diet.

High-fat diet (HFD) consumption and tobacco smoking are risk factors for chronic kidney disease. E-cigarettes have gained significant popularity among younger populations worldwide, especially among overweight individuals. It is unclear whether vaping interacts with HFD consumption to impact renal health. In this study, Balb/c mice (male, 7 weeks old) were fed a pellet HFD (43% fat, 20 kJ/g) for 16 weeks when exposed to nicotine or nicotine-free e-vapour from weeks 11 to 16. While HFD alone increased collagen Ia and IV depositions, it did not cause significant oxidative stress and inflammatory responses in the kidney itself. On the other hand, e-vapour exposure alone increased oxidative stress and damaged DNA and mitochondrial oxidative phosphorylation complexes without significant impact on fibrotic markers. However, the combination of nicotine e-vapour and HFD increased inflammatory responses, oxidative stress-induced DNA injury, and pro-fibrotic markers, suggesting accelerated development of renal pathology. Nicotine-free e-vapour exposure and HFD consumption suppressed the production of mitochondrial OXPHOS complexes and extracellular matrix protein deposition, which may cause structural instability that can interrupt normal kidney function in the future. In conclusion, our study demonstrated that a HFD combined with e-cigarette vapour exposure, especially when containing nicotine, can increase susceptibility to kidney disease.

Effectiveness of Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease Therapy: Focusing on Traditional Medical Practices.

Chronic obstructive pulmonary disease (COPD) is a complex and serious disease that is characterized by dyspnea, fatigue, decreased exercise tolerance, peripheral muscle dysfunction, and mood disorders. These manifestations are successfully treated with pulmonary rehabilitation, a comprehensive intervention and holistic approach designed to improve the physical and psychological condition of people with COPD. Exercise is a big component of pulmonary rehabilitation programs, but the efficacy of non-traditional forms of exercise as used in alternative medicine is poorly understood. Here, we aim to address this gap in knowledge and summarize the clinical evidence for the use of traditional exercise regimens in the pulmonary rehabilitation of COPD patients.

Effects of e-vapour and high-fat diet on the immunohistochemical staining of nicotinic acetylcholine receptors, apoptosis, microglia and astrocytes in the adult male mouse hippocampus.

The use of e-cigarettes/e-vapour, and the consumption of a high-fat diet (HFD), are two popular lifestyle choices associated with alterations in the hippocampus. This study, using a mouse model, investigated the effects of exposure to e-vapour (± nicotine) and HFD (43% fat) consumption, on the expression of nicotinic acetylcholine receptor (nAChR) subunits α3, α4, α7 and ß2, apoptosis markers caspase-3 and TUNEL, microglial marker Iba-1, and astrocyte marker GFAP, in hippocampal subregions of dentate gyrus (DG) and cornu ammonis (CA) 1-3. The major findings included: (1) HFD alone had minimal effect with no consistent pattern or interaction between the markers, (2) E-vapour (± nicotine) predominantly affected the CA2 subregion, decreasing α7 and ß2 nAChR subunits and Iba-1, (3) Nicotine e-vapour increased TUNEL across all subregions, and (4) HFD, in the presence of nicotine-free e-vapour, decreased caspase-3 and increased TUNEL across all regions, and decreased Iba-1 in the CA subregions, while HFD and nicotine-containing e-vapour, subregion specifically affected the α3, α4 and α7 nAChR subunits, with a protective effect against change in GFAP in the DG and Iba-1 in the CA1 and CA3. These findings highlight that e-vapour itself alters nAChRs, particularly in the CA2 subregion, associated with a decrease in neuroinflammatory response (Iba-1) across the whole hippocampus, and the addition of nicotine increases cell apoptosis across the whole hippocampus. HFD alone was not detrimental in our model, but in the presence of nicotine-free e-vapour, it differentially affected apoptosis, while the addition of nicotine increased nAChR subunits.

E-Cigarette Vapour Alters High-Fat Diet-Induced Systemic Inflammatory Responses but Has No Effect on High-Fat Diet-Induced Changes in Gut Microbiota.

BACKGROUND: The gut microbiome, which can be altered by different diets or smoking, has been implicated in the pathogenesis of lung conditions. E-cigarette vaping is now recognised to have detrimental health effects, with several of these being similar to cigarette smoking. However, whether e-cigarettes can alter high-fat diet (HFD)-induced systemic effects and gut microbiota is unknown. In this study, we investigated the effects of HFD in the absence/presence of e-cigarette exposure on systemic inflammation, lipid metabolic markers, and the gut microbiome. METHODS: Mice were fed a HFD (or chow) in the absence/presence of e-vapour exposure (±nicotine) and serum inflammation, lipid levels, and microbial diversity were assessed. RESULTS: HFD increased the circulating levels of both triglycerides and non-esterified fatty acids, which were significantly reduced by e-vapour exposure in HFD-fed mice. Serum TNF-α was increased by HFD consumption or e-vapour. HFD had a significant effect on microbial diversity, but there were no additional effects of e-vapour exposure. CONCLUSIONS: This study highlights both similarities and differences in how the body responds to e-cigarette vapours, and it is therefore likely that the long-term sequelae of e-cigarette vapour exposure/vaping might not involve the significant alteration of the gut microbiome.

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.

Can biomarkers be used to diagnose attention deficit hyperactivity disorder?

Currently, the diagnosis of attention deficit hyperactivity disorder (ADHD) is solely based on behavioral tests prescribed by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). However, biomarkers can be more objective and accurate for diagnosis and evaluating treatment efficacy. Thus, this review aimed to identify potential biomarkers for ADHD. Search terms "ADHD," and "biomarker" combined with one of "protein," "blood/serum," "gene," and "neuro" were used to identify human and animal studies in PubMed, Ovid Medline, and Web of Science. Only papers in English were included. Potential biomarkers were categorized into radiographic, molecular, physiologic, or histologic markers. The radiographic analysis can identify specific activity changes in several brain regions in individuals with ADHD. Several molecular biomarkers in peripheral blood cells and some physiologic biomarkers were found in a small number of participants. There were no published histologic biomarkers for ADHD. Overall, most associations between ADHD and potential biomarkers were properly controlled. In conclusion, a series of biomarkers in the literature are promising as objective parameters to more accurately diagnose ADHD, especially in those with comorbidities that prevent the use of DSM-5. However, more research is needed to confirm the reliability of the biomarkers in larger cohort studies.

Tenascin C in Lung Diseases.

Tenascin C (TNC) is a multifunctional large extracellular matrix protein involved in numerous cellular processes in embryonic development and can be increased in disease, or under conditions of trauma or cell stress in adults. However, the role of TNC in lung diseases remains unclear. In this study, we investigated the expression of TNC during development, in offspring following maternal particulate matter (PM) exposure, asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. TNC expression is increased during lung development in biopsy cells, endothelial cells, mesenchymal cells, and epithelial cells. Maternal PM exposure increased TNC and collagen deposition, which was not affected by the removal of PM exposure after pregnancy. TNC expression was also increased in basal epithelial cells and fibroblasts in patients with asthma and AT2 and endothelial cells in patients with COPD. Furthermore, there was an increase in the expression of TNC in stage II compared to stage IA lung cancer; however, overall survival analysis showed no correlation between levels of TNC and survival. In conclusion, TNC is increased during lung development, in offspring following maternal PM exposure, and in asthma, COPD, and lung cancer tissues. Therefore, targeting TNC may provide a novel therapeutic target for lung diseases.

Mitochondrial dysfunction in a rat model and the related risk of metabolic disorders.

OBJECTIVE: To explore whether kidney deficiency (KYD) is prone to metabolic disorders may be linked to impaired mitochondrial function in thermogenesis and metabolic tissues. METHODS: A rat model of KYD was used, which was established using Sprague Dawley rat dams with warm preference subjected to herbal treatment that can improve kidney . The human relevance was confirmed by reduced serum corticosterone levels, and increased preference for warm location. RESULTS: KYD Rats were underdeveloped. Adenosine-triphosphate (ATP) production was reduced in the brown fat, but increased in the muscle. However, oxidative phosphorylated complexes to generate ATP and mitochondrial biogenesis marker were reduced in both tissues. When the second insult of high-fat diet (HFD) was introduced, KYD rats gained less weight yet developed more severe lipid and glucose metabolic disorders. This may be driven by disregulated liver gluconeogenesis marker forkhead box protein O1 and lipid metabolic regulator cholesterol 7 alpha-hydroxylase. CONCLUSION: KYD rats exhibited reduced mito-chondrial function in the brown fat, but were partially compensated by skeletal muscle, associated with the phenotype of warm preference and metabolic disorder, which was further exacerbated by additional HFD consumption. Future studies can focus on treatment targetting mitochondria function to reverse this phenotype.

Dyslipidemia Is Associated With Worse Asthma Clinical Outcomes: A Prospective Cohort Study.

BACKGROUND: Dyslipidemia has been widely documented to be associated with cardiovascular disease, and recent studies have found an association with asthma prevalence. However, longitudinal studies investigating the relationships between dyslipidemia, asthma phenotypes, and future asthma exacerbations (AEs) are lacking. OBJECTIVE: To investigate the relationships between dyslipidemia, asthma phenotypes, and AEs. METHODS: This study used an observational cohort study design with a 12-month follow-up. All subjects underwent serum lipid measurement, and they were then classified into 2 groups: the normal-lipidemia group and the dyslipidemia group. Demographic and clinical information and details regarding pulmonary function and asthma phenotypes at baseline were collected. All patients were followed up regularly to assess AEs. Associations of dyslipidemia with airway obstruction and asthma phenotypes were assessed at baseline, whereas dyslipidemia and AEs were assessed longitudinally. RESULTS: A total of 477 patients with asthma were consecutively enrolled in this study. At baseline, the dyslipidemia group (n = 218) had a higher proportion of uncontrolled asthma, defined by the 6-item Asthma Control Questionnaire score (≥1.5). Furthermore, dyslipidemia was associated with severe asthma, nonallergic asthma, asthma with fixed airflow limitation, and older adult asthma phenotypes at baseline. In addition, dyslipidemia was associated with increased frequencies of severe AEs and moderate to severe AEs during the 12-month follow-up. In sensitivity analyses, after excluding the patients who were receiving statins, results did not differ significantly from those of the main analysis. CONCLUSIONS: We identified the clinical relevance of dyslipidemia, which is associated with specific asthma phenotypes and increased AEs, independent of other components of metabolic syndrome. These findings highlight the importance of considering dyslipidemia as an "extrapulmonary trait" in asthma management.

Self-Reported Insufficient Sleep Is Associated With Clinical and Inflammatory Features of Asthma: A Prospective Cohort Study.

BACKGROUND: A few studies have explored the association between short sleep duration and worse asthma outcomes in patients with self-reported asthma; however, all of them were cross-sectional. OBJECTIVES: To investigate the association between self-reported sleep duration and asthma-related clinical and inflammatory characteristics and whether sleep duration is associated with asthma exacerbations (AEs) in the following year. METHODS: A prospective cohort study consecutively recruited participants with asthma, who were classified into short (n = 58), normal (n = 380), and long (n = 84) sleep duration groups. We investigated the clinical and inflammatory characteristics and exacerbations within a 1-year follow-up. RESULTS: Patients with short sleep duration were older and had significantly lower total IgE and FeNO levels and higher airway inflammation, characterized by increased levels of IL-6 and TNF-α in sputum than those of patients with normal sleep duration. Furthermore, they had a significantly increased risk for poorly controlled asthma (adjusted odds ratio = 2.741; 95% CI, 1.379-5.447; P = .004) and moderate to severe AEs (adjusted incidence rate ratio = 1.798; 95% CI, 1.098-2.942; P = .020). CONCLUSIONS: Short sleep duration was associated with non-type 2 inflammation and is an independent risk factor for future AEs. Therefore, as a potentially treatable trait, sleep duration may have clinical implications for asthma management.