Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Abstract The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and ≈50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-γ secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016′ inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system

IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut

Summary: Candida albicans is implicated in intestinal diseases. Identifying host signatures that discriminate between the pathogenic versus commensal nature of this human commensal is clinically relevant. In the present study, we identify IL-9 and mast cells (MCs) as key players of Candida commensalism and pathogenicity. By inducing TGF-β in stromal MCs, IL-9 pivotally contributes to mucosal immune tolerance via the indoleamine 2,3-dioxygenase enzyme. However, Candida-driven IL-9 and mucosal MCs also contribute to barrier function loss, dissemination, and inflammation in experimental leaky gut models and are upregulated in patients with celiac disease. Inflammatory dysbiosis occurs with IL-9 and MC deficiency, indicating that the activity of IL-9 and MCs may go beyond host immunity to include regulation of the microbiota. Thus, the output of the IL-9/MC axis is highly contextual during Candida colonization and reveals how host immunity and the microbiota finely tune Candida behavior in the gut. : Deciphering the mechanisms by which Candida albicans promotes either pathology or protective tolerance in the gut could be clinically relevant. Renga et al. show a key role for IL-9 and mast cells in promoting either inflammatory dysbiosis and pathology or tolerance in leaky gut models and human celiac disease. Keywords: IL-9, mast cells, Candida albicans, intestinal inflammation, IDO1, celiac diseas

LCA applicata al trattamento e alla gestione dei rifiuti

Lo studio mira ad individuare quali sono le possibili specificit\ue0 e finalit\ue0 dell\u2019applicazione della metodologia LCA al settore dei rifiuti, attraverso la descrizione di casi applicativi

LCA applicata al trattamento e alla gestione dei rifiuti

l presente lavoro nasce da un\u2019iniziativa del gruppo di lavoro \u201cGestione e trattamento dei rifiuti\u201d della Rete Italiana LCA. L\u2019Associazione Rete Italiana LCA si pone come riferimento in Italia per i principali operatori in materia di Life Cycle Assessment (LCA), favorendo sia la diffusione della metodologia a livello nazionale, sia lo scambio di esperienze applicative tese a sostenere l\u2019approccio del ciclo di vita. In questo contesto il gruppo di lavoro \u201cGestione e trattamento dei rifiuti\u201d ha, tra i suoi scopi, quello di ampliare le conoscenze relative alla specificit\ue0 della metodologia LCA applicata ai processi di gestione e di trattamento dei rifiuti. Lo studio proposto mira nello specifico ad individuare quali sono le possibili specificit\ue0 e finalit\ue0 dell\u2019applicazione della metodologia LCA al settore dei rifiuti, attraverso la descrizione di casi applicativi

Epidemiological features and disease-related concerns of a large cohort of Italian patients with active Crohn\u2019s disease

Background-Aims: The SOLE study was conducted on a large cohort of Italian patients with moderatesevere Crohn\u2019s disease (CD) to assess epidemiological and disease characteristics and their correlation with disease-related worries, treatment satisfaction and adherence, workability. Methods: The following tools were used over 12 months to assess: \u2022 disease-related worries: Rating Form of Inflammatory Bowel Disease Patient Concerns, \u2022 impact on workability: Work Productivity and Activity Impairment-CD, \u2022 satisfaction: Treatment Satisfaction Questionnaire for Medication, \u2022 adherence: Medication Adherence Rating Scale. Results were correlated with demographic and clinical variables with linear regression models. Results: 552 patients with active CD (51% men) were recruited. Higher worries were having an ostomy bag and undergoing surgery. Variables associated with a higher RFIPC score included female sex, higher disease activity, lower treatment adherence (p < 0.001), previous surgical treatments (p = 0.003). 60% of patients claimed difficulties with activities of daily living. Lower VAS scores were reported by patients with disease duration >6years; treatment satisfaction/adherence was higher with anti-TNF- treatment. Decreased hospitalizations during follow-up and improved workability/daily activities occurred with adalimumab, infliximab, azathioprine (p < 0.001). Conclusion: Worries included having an ostomy bag, undergoing surgery, developing cancer: conditions significantly associated with worsened disease activity and low treatment adherence. Higher treatment adherence scores/greater workability improvements were observed in patients treated with anti-TNF- agents

The Aryl Hydrocarbon Receptor (AhR) Mediates the Counter-Regulatory Effects of Pelargonidins in Models of Inflammation and Metabolic Dysfunctions

Pelargonidins are anthocyanidins thought to be beneficial for the human health, although controversies exist over the doses needed and the unclear mechanism of action, along with poor systemic bioavailability. One putative target of pelargonidins is the aryl hydrocarbon receptor (AhR). A synthetic pelargonidin (Mt-P) was synthesized by the methylation of the pelargonidin (the natural compound indicated as P). Mt-P transactivated the AhR with an EC50 of 1.97 µM and was ~2-fold more potent than the natural compound. In vitro Mt-P attenuated pro-inflammatory activities of Raw264.7 macrophage cells in an AhR-dependent manner. In vivo, administration of the Mt-P in Balb/c mice resulted in a dose-dependent attenuation of signs and symptoms of colitis induced by TNBS. A dose of 5 mg/kg Mt-P, but not the natural compound P, reversed intestinal inflammation and increased expression of Tnf-α, Ifn-ƴ, and Il-6, while promoted the expansion of regulatory T cells and M2 macrophages. In C57BL/6J mice fed a high fat diet (HFD), Mt-P attenuated body weight gain, intestinal and liver inflammation, and ameliorated insulin sensitivity, while worsened liver steatosis by up-regulating the liver expression of Cd36 and Apo100b. These effects were abrogated by AhR gene ablation. Mt-P is a synthetic pelargonidin endowed with robust AhR agonist activity that exerts beneficial effects in murine models of inflammation and metabolic dysfunction