Micro-nanoplastics and cardiovascular diseases: evidence and perspectives.

Emerging evidence indicates that chemical exposures in the environment are overlooked drivers of cardiovascular diseases (CVD). Recent evidence suggests that micro- and nanoplastic (MNP) particles derived largely from the chemical or mechanical degradation of plastics might represent a novel CVD risk factor. Experimental data in preclinical models suggest that MNPs can foster oxidative stress, platelet aggregation, cell senescence, and inflammatory responses in endothelial and immune cells while promoting a range of cardiovascular and metabolic alterations that can lead to disease and premature death. In humans, MNPs derived from various plastics, including polyethylene and polyvinylchloride, have been detected in atherosclerotic plaques and other cardiovascular tissues, including pericardia, epicardial adipose tissues, pericardial adipose tissues, myocardia, and left atrial appendages. MNPs have measurable levels within thrombi and seem to accumulate preferentially within areas of vascular lesions. Their presence within carotid plaques is associated with subsequent increased incidence of cardiovascular events. To further investigate the possible causal role of MNPs in CVD, future studies should focus on large, prospective cohorts assessing the exposure of individuals to plastic-related pollution, the possible routes of absorption, the existence of a putative safety limit, the correspondence between exposure and accumulation in tissues, the timing between accumulation and CVD development, and the pathophysiological mechanisms instigated by pertinent concentrations of MNPs. Data from such studies would allow the design of preventive, or even therapeutic, strategies. Meanwhile, existing evidence suggests that reducing plastic production and use will produce benefits for the environment and for human health. This goal could be achieved through the UN Global Plastics Treaty that is currently in negotiation.

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.

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.).

The Risk of Drug Interactions in Older Primary Care Patients after Hospital Discharge: The Role of Drug Reconciliation.

INTRODUCTION: Drug-drug interactions (DDIs) represent an important clinical problem, particularly in older patients, due to polytherapy, comorbidity, and physiological changes in pharmacodynamic and pharmacokinetic pathways. In this study, we investigated the association between drugs prescribed after discharge from the hospital or clinic and the risk of DDIs with drugs used daily by each patient. METHODS: We performed an observational, retrospective, multicenter study on the medical records of outpatients referred to general practitioners. DDIs were measured using the drug interaction probability scale. Potential drug interactions were evaluated by clinical pharmacologists (physicians) and neurologists. Collected data were analyzed using the Statistical Package for the Social Sciences. RESULTS: During the study, we evaluated 1772 medical records. We recorded the development of DDIs in 10.3% of patients; 11.6% of these patients required hospitalization. Logistic regression showed an association among DDIs, sex, and the number of drugs used (p = 0.023). CONCLUSIONS: This observational real-life study shows that the risk of DDIs is common in older patients. Physicians must pay more attention after hospital discharge, evaluating the treatment to reduce the risk of DDIs.

Prednisone-hydrogen sulfide releasing hybrid shows improved therapeutic profile in asthma.

Introduction: Hydrogen sulfide (H2S) is emerging as an important potential therapeutic option for respiratory inflammatory diseases. In this study, we investigated the effectiveness of a novel corticosteroid derivative, that is chemically linked to an H2S donor, in managing asthma features. Methods: The effects of prednisone (PS), H2S donor (4-hydroxybenzamide; TBZ), and their combination (PS-TBZ) have been evaluated in vitro and in vivo. The in vitro experiments were conducted using lipopolysaccharidestimulated J774 macrophages, while the in vivo experiments utilizing an experimental asthma model. Results: In the in vitro study we found that PS-TBZ exhibited an increased effect compared to the individual parent compounds in modulating the production of inflammatory mediators. TBZ also significantly reduced bronchial contractility and enhanced bronchial relaxation. In the in vivo experiments, where we administered PS, TBZ, or PS-TBZ to ovalbumin-sensitized BALB/c mice, we confirmed that PS-TBZ had a significantly better action in controlling airway hyperreactivity as compared to TBZ or PS alone. Moreover, PS-TBZ was more effective in restoring salbutamol-induced relaxation. The immunohistochemistry analysis demonstrated a significant reduction in the production of α-SMA and procollagen III, indicating the efficacy of PS-TBZ in controlling airway remodeling. Moreover, PS-TBZ also promoted epithelial repair, recovery of the bronchial and parenchyma structure and inhibited mucin production. Discussion: In conclusion, PS-TBZ offers an important opportunity to optimize the beneficial impact of corticosteroids on asthma features.

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.

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.

What Is the Role of Sex-Related Differences in the Effectiveness and Safety of Biological Drugs Used in Patients With Severe Asthma?

Biological drugs are used to treat severe asthma with an improvement of clinical symptoms. Data on sex difference of these drugs in patients with severe asthma are sparse. This study aimed to assess the effects of sex-related differences on biological drugs in patients with severe asthma. In this observational, open-label, prospective, noncontrolled, single-center cohort pilot study, we enrolled adult patients aged >18 years diagnosed with severe asthma and not previously treated with biological drugs. The first clinical end point was the statistical difference (P < .05) in the efficacy of biological drugs evaluated using the asthma control test and spirometry between sexes. The first safety end point was the statistical difference (P < .05) in developing adverse drug reactions between sexes. We enrolled 74 patients with severe asthma (48 women and 26 men) with a mean age of 59.4 (standard deviation, 11.8) years. The mean forced expiratory volume in 1 second was 6.9 (standard deviation, 13.9) for women and 9.4 (standard deviation, 10.7) for men and improved significantly after the treatment (P < .01), with no significant differences in sex (P = .8). Similarly, the asthma control test improved 12 months after the beginning of the treatment without significant differences between men and women (P = .5). The most common drug used was omalizumab (45.9% of the patients; P < .01) without significant differences between sex (P > .05). We did not observe the development of adverse drug reactions during the study. In conclusion, in asthmatic patients, sex does not have a role in either the effectiveness or safety of biological drugs.

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.