Exhaled nitric oxide (NO) originates from the upper airways, and takes action, to varying extents, in regulation, protection and defense, as well as in noxious processes. Nitric oxide retains ...important functions in a wide range of physiological and pathophysiological processes of the human body, including vaso-regulation, antimicrobial activity, neurotransmission and respiration. This review article reports the ongoing investigations regarding the source, biology and relevance of NO within upper respiratory tract. In addition, we discuss the role of NO, originating from nasal and paranasal sinuses, in inflammatory disorders such as allergic rhinitis, sinusitis, primary ciliary dyskinesia, and cystic fibrosis.
In COVID-19 clinical symptoms can persist even after negativization also in individuals who have had mild or moderate disease. We here investigated the biomarkers that define the post-COVID-19 ...clinical state analyzing the exhaled breath condensate (EBC) of 38 post COVID-19 patients and 38 sex and age-matched healthy controls via nuclear magnetic resonance (NMR)-based metabolomics. Predicted gene-modulated microRNAs (miRNAs) related to COVID-19 were quantified from EBC of 10 patients and 10 controls. Finally, clinical parameters from all post-COVID-19 patients were correlated with metabolomic data. Post-COVID-19 patients and controls showed different metabolic phenotype ("metabotype"). From the metabolites, by using enrichment analysis we identified miRNAs that resulted up-regulated (hsa-miR146a-5p) and down-regulated (hsa-miR-126-3p and hsa-miR-223-3p) in post-COVID-19. Taken together, our multiomics data indicate that post-COVID-19 patients before rehabilitation are characterized by persistent inflammation, dysregulation of liver, endovascular thrombotic and pulmonary processes, and physical impairment, which should be the primary clinical targets to contrast the post-acute sequelae of COVID-19.
Chronic obstructive pulmonary disease (COPD) is an increasing cause of global morbidity and mortality, with poor long-term outcomes and chronic disability. COPD is a condition with a wide spectrum of ...clinical presentations, with different phenotypes being identified even among patients with comparable degrees of airflow limitation. Considering the burden of COPD in terms of social and economic costs, in recent years growing attention has been given to the need for more personalized approaches and patienttailored rehabilitation programs. In this regard, the systematic analysis of metabolites in biological matrices, namely metabolomics, may become an essential tool in phenotyping diseases. Through the identification and quantification of the small molecules produced during biological processes, metabolomic profiling of biological samples has thus been proposed as an opportunity to identify novel biomarkers of disease outcome and treatment response. Exhaled breath condensate (EBC) and plasma/serum are fluid pools, which can be easily extracted and analyzed. In this review, we discuss the potential clinical applications of the metabolomic profiling of EBC and plasma/serum in COPD.
Background Epidemiologic and clinical evidence supports the existence of an obesity-related asthma phenotype. No distinct pathophysiologic elements or specific biomarkers have been identified thus ...far, but increased oxidative stress has been reported. Objective We aimed at verifying whether metabolomics of exhaled breath condensate from obese asthmatic (OA) patients, lean asthmatic (LA) patients, and obese nonasthmatic (ONA) subjects could recognize specific and statistically validated biomarkers for a separate “asthma-obesity” respiratory metabolic phenotype, here defined as “metabotype.” Methods Twenty-five OA patients, 30 ONA subjects, and 30 mild-to-moderate LA age-matched patients participated in a cross-sectional study. Nuclear magnetic resonance (NMR) profiles were analyzed by using partial least-squares discriminant analysis, and the results were validated with an independent patient set. Results From NMR profiles, we obtained strong regression models that distinguished OA patients from ONA subjects (quality parameters: goodness-of-fit parameter R 2 = 0.81 and goodness-of-prediction parameter Q 2 = 0.79), as well as OA patients from LA patients ( R 2 = 0.91 and Q 2 = 0.89). The all-classes comparison ( R 2 = 0.86 and Q 2 = 0.83) indicated that OA patients possess a respiratory metabolic profile fully divergent from those obtained in the other patient groups. We also identified specific biomarkers for between-class separation, which are independent from clinical bias. They are involved in the methane, pyruvate, and glyoxylate and dicarboxylate metabolic pathways. Conclusions NMR-based metabolomics indicates that OA patients are characterized by a respiratory metabolic fingerprint fully different from that of patients independently affected by asthma or obesity. Such a phenotypic difference strongly suggests unique pathophysiologic pathways involved in the pathogenesis of asthma in adult obese subjects. Furthermore, the OA metabotype could define a strategy for patient stratification based on unbiased biomarkers, with important diagnostic and therapeutic implications.
Nothing is known about the potential implication of gut microbiota in skeletal muscle disorders. Here, we provide evidence that fecal microbiota composition along with circulating levels of ...short‐chain fatty acids (SCFAs) and related metabolites are altered in the mdx mouse model of Duchenne muscular dystrophy (DMD) compared with healthy controls. Supplementation with sodium butyrate (NaB) in mdx mice rescued muscle strength and autophagy, and prevented inflammation associated with excessive endocannabinoid signaling at CB1 receptors to the same extent as deflazacort (DFZ), the standard palliative care for DMD. In LPS‐stimulated C2C12 myoblasts, NaB reduces inflammation, promotes autophagy, and prevents dysregulation of microRNAs targeting the endocannabinoid CB1 receptor gene, in a manner depending on the activation of GPR109A and PPARγ receptors. In sum, we propose a novel disease‐modifying approach in DMD that may have benefits also in other muscular dystrophies.
Synopsis
Changes in gut microbiota composition are found to be associated with an excess of endocannabinoid system activity and increased expression of cannabinoid CB1 receptors, suggesting a novel pathological mechanism implicated in the severity and progression of Duchenne muscular dystrophy.
Fecal microbiota, along with circulating levels of short‐chain fatty acids and ketone bodies, are dysregulated in the mdx mouse model of Duchenne muscular dystrophy (DMD).
Supplementation with sodium butyrate (NaB) in mdx mice rescues muscle strength and impaired autophagy, and also halts inflammation.
NaB prevents the dysregulation of endocannabinoid system activity.
In LPS‐stimulated C2C12 myoblasts, NaB reduces inflammation, promotes autophagy, and prevents the dysregulation of microRNAs targeting the endocannabinoid CB1 receptor gene in a manner depending on the activation of GPR109A and PPARγ receptors.
Changes in gut microbiota composition are found to be associated with an excess of endocannabinoid system activity and increased expression of cannabinoid CB1 receptors, suggesting a novel pathological mechanism implicated in the severity and progression of Duchenne muscular dystrophy.
Ammonia is a potent neurotoxin that is detoxified mainly by the urea cycle in the liver. Hyperammonemia is a common complication of a wide variety of both inherited and acquired liver diseases. If ...not treated early and thoroughly, it results in encephalopathy and death. Here, we found that hepatic autophagy is critically involved in systemic ammonia homeostasis by providing key urea-cycle intermediates and ATP. Hepatic autophagy is triggered in vivo by hyperammonemia through an α-ketoglutarate–dependent inhibition of the mammalian target of rapamycin complex 1, and deficiency of autophagy impairs ammonia detoxification. In contrast, autophagy enhancement by means of hepatic gene transfer of the master regulator of autophagy transcription factor EB or treatments with the autophagy enhancers rapamycin and Tat-Beclin-1 increased ureagenesis and protected against hyperammonemia in a variety of acute and chronic hyperammonemia animal models, including acute liver failure and ornithine transcarbamylase deficiency, the most frequent urea-cycle disorder. In conclusion, hepatic autophagy is an important mechanism for ammonia detoxification because of its support of urea synthesis, and its enhancement has potential for therapy of both primary and secondary causes of hyperammonemia.
Endothelial dysfunction has been proposed to play a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its post-acute sequelae. Flow-mediated dilation (FMD) is recognized as an ...accurate clinical method to assess endothelial function. Thus, we performed a meta-analysis of the studies evaluating FMD in convalescent COVID-19 patients and controls with no history of COVID-19.
A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the random effects method, differences between cases and controls were expressed as mean difference (MD) with 95% confidence intervals (95% CI). The protocol was registered on PROSPERO with reference number CRD42021289684.
Twelve studies were included in the final analysis. A total of 644 convalescent COVID-19 patients showed significantly lower FMD values as compared to 662 controls (MD: −2.31%; 95% CI: −3.19, −1.44; p < 0.0001). Similar results were obtained in the sensitivity analysis of the studies that involved participants in either group with no cardiovascular risk factors or history of coronary artery disease (MD: −1.73%; 95% CI: −3.04, −0.41; p = 0.010). Interestingly, when considering studies separately based on enrolment within or after 3 months of symptom onset, results were further confirmed in both short- (MD: −2.20%; 95% CI: −3.35, −1.05; p < 0.0001) and long-term follow-up (MD: −2.53%; 95% CI: −4.19, −0.86; p = 0.003). Meta-regression models showed that an increasing prevalence of post-acute sequelae of COVID-19 was linked to a higher difference in FMD between cases and controls (Z-score: −2.09; p = 0.037).
Impaired endothelial function can be documented in convalescent COVID-19 patients, especially when residual clinical manifestations persist. Targeting endothelial dysfunction through pharmacological and rehabilitation strategies may represent an attractive therapeutic option.
Key messages
The mechanisms underlying the post-acute sequelae of coronavirus disease 2019 (COVID-19) have not been fully elucidated.
Impaired endothelial function can be documented in convalescent COVID-19 patients for up to 1 year after infection, especially when residual clinical manifestations persist.
Targeting endothelial dysfunction may represent an attractive therapeutic option in the post-acute phase of COVID-19.
In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory ...response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline.
KEY MESSAGE
Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients.
The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung.
The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.
In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key ...role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.
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Breathomics, the multidimensional molecular analysis of exhaled breath, includes analysis of exhaled breath with gas-chromatography/mass spectrometry (GC/MS) and electronic noses (e-noses), and ...metabolomics of exhaled breath condensate (EBC), a non-invasive technique which provides information on the composition of airway lining fluid, generally by high-resolution nuclear magnetic resonance (NMR) spectroscopy or MS methods. Metabolomics is the identification and quantification of small molecular weight metabolites in a biofluid. Specific profiles of volatile compounds in exhaled breath and metabolites in EBC (breathprints) are potentially useful surrogate markers of inflammatory respiratory diseases. Electronic noses (e-noses) are artificial sensor systems, usually consisting of chemical cross-reactive sensor arrays for characterization of patterns of breath volatile compounds, and algorithms for breathprints classification. E-noses are handheld, portable, and provide real-time data. E-nose breathprints can reflect respiratory inflammation. E-noses and NMR-based metabolomics of EBC can distinguish patients with respiratory diseases such as asthma, COPD, and lung cancer, or diseases with a clinically relevant respiratory component including cystic fibrosis and primary ciliary dyskinesia, and healthy individuals. Breathomics has also been reported to identify patients affected by different types of respiratory diseases. Patterns of breath volatile compounds detected by e-nose and EBC metabolic profiles have been associated with asthma phenotypes. In combination with other -omics platforms, breathomics might provide a molecular approach to respiratory disease phenotyping and a molecular basis to tailored pharmacotherapeutic strategies. Breathomics might also contribute to identify new surrogate markers of respiratory inflammation, thus, facilitating drug discovery. Validation in newly recruited, prospective independent cohorts is essential for development of e-nose and EBC NMRbased metabolomics techniques.
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