Microplastics and Nanoplastics in Atheromas and Cardiovascular Events.

BACKGROUND: Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking. METHODS: We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis-gas chromatography-mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs. RESULTS: A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 µg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 µg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001). CONCLUSIONS: In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947.).

5α-dihydrotestosterone abrogates sex bias in asthma like features in the mouse.

Androgen levels inversely correlate with the incidence, susceptibility and severity of asthma. However, whether male sex hormones such as 5α-dihydrotestosterone (DHT) have beneficial effects on asthma symptoms and/or could affect asthma susceptibility have not been investigated. DHT administration to female mice, during the sensitization phase, abrogates the sex bias in bronchial hyperreactivity. This effect correlates with inhibition of leukotriene biosynthesis in the lung. DHT significantly inhibits also other asthma-like features such as airway hyperplasia and mucus production in sensitized female mice. Conversely, DHT does not affect plasma IgE levels as well as CD3+CD4+ IL-4+ cell and IgE+c-Kit+ cell infiltration within the lung but prevents pulmonary mast cell activation. The in vitro study on RBL-2H3 cells confirms that DHT inhibits mast cell degranulation. In conclusion, our data demonstrate that immunomodulatory effects of DHT on mast cell activation prevent the translation of allergen sensitization into clinical manifestation of asthma.

Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization.

The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function. While high plasma levels of IgE, as sensitization index, were elevated in both sexes, LT levels increased only in lungs of female ovalbumin-sensitized BALB/c mice. Sex-dependent elevated LT levels strictly correlated to an enhanced airway hyperreactivity, pulmonary inflammation and mast cell infiltration/activation in female mice. Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy.

N/OFQ-NOP System and Airways.

Asthma is a heterogeneous chronic inflammatory disease of the airways. The most prevalent form is atopic asthma, which is initiated by the exposure to (inhaled) allergens. Intermittent attacks of breathlessness, airways hyperresponsiveness, wheezing, coughing, and resultant allergen-specific immune responses characterize the disease. Nociceptin/OFQ-NOP receptor system is able to combine anti-hyperresponsiveness and immunomodulatory actions. In particular, N/OFQ is able to inhibit airways microvascular leakage and bronchoconstriction through a presynaptic and non-opioid mechanism of action that blocks tachykinin release. Moreover, it also acts on allergenic sensitization because it is able to modulate the immune response that triggers the development of airway hyperresponsiveness through an interaction on cell membranes of dendritic cells (DCs) that are generally responsible to start and sustain allergic T helper 2 (TH2)-cell responses to inhaled allergens in asthma. In asthmatic patients, sputum showed elevated N/OFQ levels that are related to increased eosinophil counts. The addition of exogenous N/OFQ in sputum obtained from patients with severe asthma attenuated eosinophils migration and release of inflammatory mediators. These observations confirmed that elevated endogenous N/OFQ levels in asthmatic sputum were lower than the ones required to exert beneficial effects, suggesting that supplementation with exogenous N/OFQ may need. In conclusion, the innovative role of N/OFQ in counteracting airways inflammation/hyperresponsiveness opens new potential targets/strategies in asthma treatment.

Role of adiponectin in sphingosine-1-phosphate induced airway hyperresponsiveness and inflammation.

Epidemiological data suggest that obesity represent an important risk factor for asthma, but the link between excess fat and airway hyperresponsiveness (AHR) and inflammation is not fully understood. Recently, a key role in physiopathologic conditions of lungs has been given to adiponectin (Acrp30). Acrp30 is one of the most expressed adipokines produced and secreted by adipose tissue, showing an intriguing relationship with metabolism of sphingolipids. Sphingosine-1-phosphate (S1P) has been proposed as an important inflammatory mediator implicated in the pathogenesis of airway inflammation and asthma. In the present study we analyze the effects of recombinant Acrp30 administration in an experimental model of S1P-induced AHR and inflammation. The results show that S1P is able to reduce endogenous Acrp30 serum levels and that recombinant Acrp30 treatment significantly reduce S1P-induced AHR and inflammation. Moreover, we observed a reduction of Adiponectin receptors (AdipoR1, AdipoR2 and T-cadherin) expression in S1P treated mice. Treatment with recombinant Acrp30 was able to restore Acrp30 serum levels and adiponectin receptors expression. These results could indicate the ability of S1P to modulate the Acrp30 action, by modulating not only the serum levels of the protein, but also its receptors. Taken together, these data suggest that adiponectin could represent a possible biomarker in obesity-associated asthma.

Disodium cromoglycate inhibits asthma-like features induced by sphingosine-1-phosphate.

Compelling evidence suggests the involvement of sphingosine-1-phosphate (S1P) in the pathogenesis of asthma. The systemic administration of S1P causes asthma like features in the mouse involving mast cells. In this study we investigated whether disodium cromoglycate (DSCG), administered as a preventative treatment as in human therapy, could affect S1P effects on airways. BALB/c mice, treated with DSCG, received subcutaneous administration of S1P. Bronchi and pulmonary tissues were collected and functional, molecular and cellular studies were performed. DSCG inhibited S1P-induced airway hyper-reactivity as well as pulmonary inflammation. DSCG decreased the recruitment of solely mast cells and B cells in the lung. IgE serum levels, prostaglandin D2, mucus production and IL-13 were also reduced when mice were pretreated with DSCG. S1P induced pulmonary expression of CD23 on T and B cells, that was reversed by DSCG. Conversely, S1P failed to upregulate CD23 in mast cell-deficient Kit W-sh/W-sh mice. In conclusion we have shown that DSCG inhibits S1P-induced asthma like features in the mouse. This beneficial effect is due to a regulatory action on mast cell activity, and in turn to an inhibition of IgE-dependent T and B cells responses.

New Role of Adult Lung c-kit+ Cells in a Mouse Model of Airway Hyperresponsiveness.

Structural changes contribute to airway hyperresponsiveness and airflow obstruction in asthma. Emerging evidence points to the involvement of c-kit+ cells in lung homeostasis, although their potential role in asthma is unknown. Our aim was to isolate c-kit+ cells from normal mouse lungs and to test whether these cells can interfere with hallmarks of asthma in an animal model. Adult mouse GFP-tagged c-kit+ cells, intratracheally delivered in the ovalbumin-induced airway hyperresponsiveness, positively affected airway remodeling and improved airway function. In bronchoalveolar lavage fluid of cell-treated animals, a reduction in the number of inflammatory cells and in IL-4, IL-5, and IL-13 release, along with an increase of IL-10, was observed. In MSC-treated mice, the macrophage polarization to M2-like subset may explain, at least in part, the increment in the level of anti-inflammatory cytokine IL-10. After in vitro stimulation of c-kit+ cells with proinflammatory cytokines, the indoleamine 2,3-dioxygenase and TGFß were upregulated. These data, together with the increased apoptosis of inflammatory cells in vivo, indicate that c-kit+ cells downregulate immune response in asthma by influencing local environment, possibly by cell-to-cell contact combined to paracrine action. In conclusion, intratracheally administered c-kit+ cells reduce inflammation, positively modulate airway remodeling, and improve function. These data document previously unrecognized properties of c-kit+ cells, able to impede pathophysiological features of experimental airway hyperresponsiveness.

Hydrogen sulfide inhalation ameliorates allergen induced airway hypereactivity by modulating mast cell activation.

Compelling evidence suggests that hydrogen sulfide represents an important gaseous transmitter in the mammalian respiratory system. In the present study, we have evaluated the role of mast cells in hydrogen sulfide-induced effects on airways in a mouse model of asthma. Mice were sensitized to ovalbumin and received aerosol of a hydrogen sulfide donor (NaHS; 100 ppm) starting at day 7 after ovalbumin challenge. Exposure to hydrogen sulfide abrogated ovalbumin-induced bronchial hypereactivity as well as the increase in lung resistance. Concomitantly, hydrogen sulfide prevented mast cell activity as well as FGF-2 and IL-13 upregulation. Conversely, pulmonary inflammation and the increase in plasmatic IgE levels were not affected by hydrogen sulfide. A lack of hydrogen sulfide effects in mast cell deficient mice occurred. Primary fibroblasts harvested from ovalbumin-sensitized mice showed an increased proliferation rate that was inhibited by hydrogen sulfide aerosol. Furthermore, ovalbumin-induced transdifferentiation of pulmonary fibroblasts into myofibroblasts was reversed. Finally, hydrogen sulfide did abrogate in vitro the degranulation of the mast cell-like RBL-2H3 cell line. Similarly to the in vivo experiments the inhibitory effect was present only when the cells were activated by antigen exposure. In conclusion, inhaled hydrogen sulfide improves lung function and inhibits bronchial hyper-reactivity by modulating mast cells and in turn fibroblast activation.

Effects of sex hormones on bronchial reactivity during the menstrual cycle.

BACKGROUND: Many asthmatic women complain of symptom exacerbations in particular periods, i.e. during pregnancy and menstrual cycles (perimenstrual asthma: PMA)". The goal of this study was to study the effect of the luteal and follicular phases of the menstrual cycle on bronchial reactivity (BR) in a group of asthmatic women. METHODS: For this purpose, 36 pre-menopausal women were enrolled and underwent testing for resting pulmonary function, measurement of the diffusing capacity of the lung for carbon monoxide (DLCO), and airway responsiveness to methacholine in the follicular and luteal phases of their menstrual cycles. We also measured plasma hormone levels and levels of cyclic adenosine monophosphate (cAMP; a mediator of bronchial smooth muscle contraction) and testosterone in induced sputum samples. RESULTS: Our study showed that about 30% of the asthmatic women had decreased PC20FEV1.0 in the follicular phase of menstrual cycle with a significant correlation between PC20FEV1.0 and serum testosterone levels. Moreover, marked increases in sputum testosterone levels (mean=2.6-fold increase) together with significant increases in sputum cAMP concentrations (mean=3.6-fold increases) were observed during the luteal phase of asthmatic patients, suggesting that testosterone contributes to the pathophysiology of PMA. We excluded the possibility that testosterone directly inhibits phosphodiesterase (PDE) activity as incubating PDE with testosterone in vitro did not reduce PDE catalytic activity. CONCLUSIONS: In conclusion, our data show that PC20FEV1.0 was decreased in the follicular phase of the menstrual cycle in about 30% of women and was associated with lower cAMP levels in sputum samples, which may contribute to bronchoconstriction. Our results also suggest a link between PMA and testosterone levels. However, whether these findings are of clinical significance in terms of the management of asthma or asthma worsening during the menstrual cycle needs further investigation.

MicroRNA Monitoring in Human Alveolar Macrophages from Patients with Smoking-Related Lung Diseases: A Preliminary Study.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is commonly considered to be a potent driver of non-small cell lung cancer (NSCLC) development and related mortality. A growing body of evidence supports a role of the immune system, mainly played by alveolar macrophages (AMs), in key axes regulating the development of COPD or NSCLC phenotypes in response to harmful agents. MicroRNAs (miRNAs) are small non-coding RNAs that influence most biological processes and interfere with several regulatory pathways. The purpose of this study was to assess miRNA expression patterns in patients with COPD, NSCLC, and ever- or never-smoker controls to explore their involvement in smoking-related diseases. Bronchoalveolar lavage (BAL) specimens were collected from a prospective cohort of 43 sex-matched subjects to determine the expressions of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p and 106a-5p by RT-PCR. In addition, a bioinformatic analysis of miRNA target genes linked to cancer was performed. Distinct and common miRNA expression levels were identified in each pathological group, suggesting their possible role as an index of NSCLC or COPD microenvironment. Moreover, we identified miRNA targets linked to carcinogenesis using in silico analysis. In conclusion, this study identified miRNA signatures in AMs, allowing us to understand the molecular mechanisms underlying smoking-related conditions and potentially providing new insights for diagnosis or pharmacological treatment.

Skeletal muscle oxidative metabolism in an animal model of pulmonary emphysema: formoterol and skeletal muscle dysfunction.

Skeletal muscle dysfunction is a significant contributor to exercise limitation in pulmonary emphysema. This study investigated skeletal muscle oxidative metabolism before and after aerosol exposure to a long-acting ß-agonist (LABA), such as formoterol, in the pallid mouse (B6.Cg-Pldnpa/J), which has a deficiency in serum α(1)-antitrypsin (α(1)-PI) and develops spontaneous pulmonary emphysema. C57 BL/6J and its congener pallid mice of 8-12 and 16 months of age were treated with vehicle or formoterol aerosol challenge for 120 seconds. Morphological and morphometric studies and evaluations of mitochondrial adenosine diphosphate-stimulated respiration and of cytochrome oxidase activity on skeletal muscle were performed. Moreover, the mtDNA content in skeletal muscle and the mediators linked to muscle mitochondrial function and biogenesis, as well as TNF-α and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), were also evaluated. The lungs of pallid mice at 12 and 16 months of age showed patchy areas of airspace enlargements, with the destruction of alveolar septa. No significant differences were observed in basal values of mitochondrial skeletal muscle oxidative processes between C57 BL/6J and pallid mice. Exposure to LABA significantly improved mitochondrial skeletal muscle oxidative processes in emphysematous mice, where the mtDNA content was significantly higher with respect to 8-month-old pallid mice. This effect was compared with a significant increase of PGC-1α in skeletal muscles of 16-month-old pallid mice, with no significant changes in TNF-α concentrations. In conclusion, in emphysematous mice that showed an increased mtDNA content, exposure to inhaled LABA can improve mitochondrial skeletal muscle oxidative processes. PGC-1α may serve as a possible mediator of this effect.

Nociceptin/orphanin FQ receptor activation decreases the airway hyperresponsiveness induced by allergen in sensitized mice.

Several studies suggest that the N/OFQ (nociceptin/orphanin FQ)-NOP (N/OFQ peptide) receptor pathway is involved in airway physiology. We previously demonstrated a modulation of the endogenous N/OFQ levels in allergen-sensitized mice. Here, we investigated the effects of NOP receptor activation in allergen sensitization using a murine model of allergen-induced airway hyperresponsiveness (AHR). BALB/c mice were intraperitoneally treated with the NOP receptor agonist UFP-112, either during the sensitization phase (30 min before ovalbumin administration) or at the end of sensitization process (15 min before bronchopulmonary reactivity evaluation). At day 21 from the first allergen exposure, bronchopulmonary reactivity and total and differential cell count in bronchoalveolar lavage fluid were evaluated. In a separate set of experiments cell proliferation in lymphocytes, cytokine levels, IgE serum levels, and the effect of UFP-112 on IL-13-induced AHR were evaluated. Pretreatment with UFP-112, during the sensitization phase, caused a significant reduction in allergen-induced AHR and total cell lung infiltration. No effect on allergen-induced AHR was observed when the treatment was performed at the end of sensitization process, on tissues harvested from OVA-sensitized mice and on IL-13-induced AHR. The in vitro proliferative response of lymphocytes was significantly reduced by pretreatment during the sensitization phase with UFP-112. This effect was paralleled by a significant modulation of cytokine secretion in pulmonary tissues and lymphocytes. In conclusion, we demonstrated a role for the NOP receptor and N/OFQ pathway in the AHR induced by allergen, probably through a modulation of the immune response that triggers the development of AHR that involves pro- and anti-inflammatory cytokines.

The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients?

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF.

Association between Sex-Related ALOX5 Gene Polymorphisms and Lung Atopy Risk.

Atopy is an exaggerated IgE-mediated immune response to foreign antigens in which metabolic abnormalities of the leukotrienes (LTs) pathway play a crucial role. Recent studies have described sex as a key variable in LT biosynthesis, partly explaining why treatment with anti-LT drugs in atopic subjects leads to better control of symptoms in women. In addition, variability in LT production is often associated with single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase (ALOX5) gene, which encodes the leukotriene-synthesizing enzyme machinery, 5-lipoxygenase (5-LO). This study aimed to investigate whether two SNPs of ALOX5 are implicated in sex differences in allergic diseases in a prospective cohort of 150 age- and sex-matched atopic and healthy subjects. Rs2029253 and rs2115819 were genotyped using allele-specific RT-PCR, and serum levels of 5-LO and LTB4 were measured by ELISA. Both polymorphisms are significantly more common in women than in men, and their influences on LT production vary as a function of sex, leading to a decrease in men's and an increase in women's serum levels of 5-LO and LTB4. These data represent a new resource for understanding sex-related differences in lung inflammatory diseases, partly explaining why women are more likely to develop allergic disorders than men.

Lung microRNAs Expression in Lung Cancer and COPD: A Preliminary Study.

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an impending burden on the healthcare system. Despite increasing attention, the mechanisms underlying tumorigenesis in cancer-related diseases such as COPD remain unclear, making novel biomarkers necessary to improve lung cancer early diagnosis. MicroRNAs (miRNAs) are short non-coding RNA that interfere with several pathways and can act as oncogenes or tumor suppressors. This study aimed to compare miRNA lung expression between subjects with NSCLC and COPD and healthy controls to obtain the miRNA expression profile by analyzing shared pathways. Lung specimens were collected from a prospective cohort of 21 sex-matched subjects to determine the tissue miRNA expression of hsa-miR-34a-5p, 33a-5p, 149-3p, 197-3p, 199-5p, and 320a-3p by RT-PCR. In addition, an in silico prediction of miRNA target genes linked to cancer was performed. We found a specific trend for has-miR-149-3p, 197-3p, and 34a-5p in NSCLC, suggesting their possible role as an index of the tumor microenvironment. Moreover, we identified novel miRNA targets, such as the Cyclin-Dependent Kinase (CDK) family, linked to carcinogenesis by in silico analysis. In conclusion. this study identified lung miRNA signatures related to the tumorigenic microenvironment, suggesting their possible role in improving the evaluation of lung cancer onset.

Plasma glutamine decreases immediately after surgery and is related to incisiveness.

Glutamine (gln) is the most abundant free amino acid in the blood. It is involved in important metabolic and biochemical processes, like cell proliferation and oxidative stress. Previous studies have demonstrated that gln concentration in human plasma decreases in several conditions such as sepsis, ischemia-reperfusion, trauma, major surgery and burn. The aim of the present work was to compare the acute effects of different types of surgical interventions and of anesthetization on blood gln concentration. Plasma samples from 88 subjects (30 males and 58 females) were collected before and after major or minor surgery and the gln concentration was analyzed with high-performance liquid chromatography. The results showed that plasma gln concentration after surgery was lower than pre-surgery values and that in major surgery the decrease of gln was higher than in minor surgery. No significant effect was shown for sex or type of anesthesia. These results demonstrate the importance of a gln supplementation before a surgical intervention and show that the amount of gln supplementation should also be adjusted based on the type of surgery.

Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand?

The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID-19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulnerable to COVID-19 exhibiting severe symptoms, thus characterizing valid therapeutic strategies for better management of the disease is still a challenge.

Oxygen-Ozone Therapy in Cervicobrachial Pain: A Real-Life Experience.

This prospective, open-label clinical study was carried out to evaluate both the efficacy and safety of intramuscular paravertebral injections of an oxygen−ozone (O2−O3) mixture in patients with cervicobrachial pain. We enrolled 540 subjects affected by cervicobrachial pain referred to the Ozone Therapy Ambulatory at the Mater Domini Hospital of Catanzaro (Italy) and to the Center of Pain in Taurianova (Reggio Calabria, Italy). All the subjects (n = 540) completed the treatment and the follow-up visits. The subjects received a mean of 11 cervical intramuscular treatments with an O2−O3 mixture (5 mL) with an O3 concentration of 10 µg/mL bis a week. The improvement of pain was measured by a change in the mean of the Visual Analog Scale (VAS) score from baseline to the end of treatment and during follow-ups. Patient satisfaction was assessed at the end of treatment using the SF-36 Questionnaire. The development of adverse drug reactions was recorded. The mean (±standard deviation) VAS pain score at baseline, at the end of treatment, and during follow-ups showed a significant reduction in pain over time (p < 0.001). All the patients who were enrolled (n: 540) were pain-free after one year. According to the pain distribution, all subjects showed a significant reduction in pain over time in each group (p < 0.05). No significant differences were observed with respect to sex or age. No adverse events were observed during the study. In conclusion, we documented that the intramuscular injection of an O2−O3 mixture is an effective and safe treatment option for patients with cervicobrachial pain.

Circulating MicroRNAs Expression Profile in Lung Inflammation: A Preliminary Study.

BACKGROUND: Bronchial asthma is an inflammatory airway disease with an ever-increasing incidence. Therefore, innovative management strategies are urgently needed. MicroRNAs are small molecules that play a key role in lungs cellular functions and are involved in chronic inflammatory diseases, such as bronchial asthma. This study aims to compare microRNA serum expression between subjects with asthma, obesity, the most common co-morbidity in asthma, and healthy controls to obtain a specific expression profile specifically related to lung inflammation. METHODS: We collected serum samples from a prospective cohort of 25 sex-matched subjects to determine circulating miRNAs through a quantitative RT-PCR. Moreover, we performed an in silico prediction of microRNA target genes linked to lung inflammation. RESULTS: Asthmatic patients had a significant lower expression of hsa-miR-34a-5p, 181a-5p and 146a-5p compared to both obese and healthy ones suggesting microRNAs' specific involvement in the regulation of lungs inflammatory response. Indeed, using in silico analysis, we identified microRNAs novel target genes as GATA family, linked to the inflammatory-related pathway. CONCLUSIONS: This study identifies a novel circulating miRNAs expression profile with promising potentials for asthma clinical evaluations and management. Further and larger investigations will be needed to confirm the potential role of microRNA as a clinical marker of bronchial asthma and eventually of pharmacological treatment response.

Design and synthesis of functionalized 4-aryl-Catechol derivatives as new antiinflammtory agents with in vivo efficacy.

Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases and the discovery of antioxidants is an attractive approach that can simultaneously tackle two or more therapeutic targets of the arachidonic acid cascade. We report that the simple structural variations on the 4-aryl-benzene-1,2-diol side-arm of the scaffold significantly influence the selectivity against 5-LOX vs 12- and 15-LOX. Derivatives 4 a-l were evaluated for their antioxidant activity, using the DPPH, and ferric ion reducing antioxidant power (FRAP) methods. Docking simulations proposed concrete binding of the catechol series to 5-LO. Selected active compound 4-(3,4-dihydroxyphenyl)dibenzofuran (4l) was also tested in different in vivo mouse models of inflammation. 4l (0.1 mg/kg; i.p.) impaired (I) bronchoconstriction in ovalbumin-sensitized mice challenged with acetylcholine, (II) exudate formation in carrageenan-induced paw edema, and (III) zymosan-induced leukocyte infiltration in air pouches. These results pave the way for investigating the therapeutic potential of 4-aryl-benzene-1,2-diol, as novel multitarget therapeutic drugs, able to regulate the complex inflammatory cascade mechanisms.