The functional link between microsomal prostaglandin E synthase-1 (mPGES-1) and peroxisome proliferator-activated receptor γ (PPARγ) in the onset of inflammation

Many years have elapsed since the discovery of anti-inflammatories as effective therapeutics for the treatment of inflammatory-related diseases, but we are still uncovering their various mechanisms of action. Recent biochemical and pharmacological studies have shown that in different tissues and cell types lipid mediators from thearachidonic acid cascade, play a crucial role in the initiation and resolution of inflammation by shifting from pro-inflammatory prostaglandin (PG)E2 to anti-inflammatory PGD2 and PGJ2. Considering that until now very little is known about the biological effects evoked by microsomal prostaglandin E synthase-1 (mPGES-1) and contextually by peroxisome proliferator-activated receptor γ (PPARγ) modulation (key enzymes involved in PGE2 and PGD2/PGJ2metabolism), in this opinion paper we sought to define the coordinate functional regulation between these two enzymes at the "crossroads of phlogistic pathway" involved in the induction and resolution of inflammation

A cohort study on acute ocular motility disorders in pediatric emergency department

Background: Acute ocular motility disorders (OMDs) in children admitted to Emergency Department (ED) represents a not so rare condition with a wide spectrum of different etiologies. The emergency physician must be skilled in rapidly identifying patients with potentially life threatening (LT) forms, requiring further diagnostic procedures. The aim of the study was to assess characteristics of children with acute Ocular Motility Disorders (OMDs), and to identify "red flags" for recognition of underlying life-threatening (LT) conditions. Methods: A retrospective cohort study evaluated children (2 months-17 years) admitted to a tertiary Emergency Department in 2009-2014. A subgroup analysis was performed comparing children with and without LT conditions. Results: Of 192 visits for OMDs, the isolated strabismus occurred most frequently (55.6%), followed by pupil disorders (31.8%), ptosis (5.2%) and combined OMDs (11.5%). The majority of acute OMDs involved no underlying LT conditions (n = 136) and most of them were infants or toddlers (50%). In a multivariable analysis, LT conditions included especially children over 6 years of age, increasing the odds ratio by 2% for each months of age (p = 0.009). LT etiologies were 16 times more likely in combined OMDs (p = 0.018), were over 13 times more likely to report associated extra-ocular signs/symptoms (p = 0.017) and over 50 times more likely to report co-morbidity (p = 0.017). Conclusion: OMDs are not an uncommon presentation at ED. Although most of them involve non-LT conditions, the ED physician should consider potential "red flags" for appropriate management of children such as age > 6 years, combined OMDs, extra-ocular symptoms and co-morbidity

Interleukin-17A (IL-17A): A silent amplifier of COVID-19

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this "unique" cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy

High Phosphate-Induced JAK-STAT Signalling Sustains Vascular Smooth Muscle Cell Inflammation and Limits Calcification

Vascular calcification (VC) is an age-related complication characterised by calcium-phosphate deposition in the arterial wall driven by the osteogenic transformation of vascular smooth muscle cells (VSMCs). The JAK-STAT pathway is an emerging target in inflammation. Considering the relationship between VC and inflammation, we investigated the role of JAK-STAT signalling during VSMC calcification. Human aortic smooth muscle cells (HASMCs) were cultured in high-inorganic phosphate (Pi) medium for up to 7 days; calcium deposition was determined via Alizarin staining and colorimetric assay. Inflammatory factor secretion was evaluated via ELISA and JAK-STAT members' activation using Western blot or immunohistochemistry on HASMCs or calcified aortas of Vitamin D-treated C57BL6/J mice, respectively. The JAK-STAT pathway was blocked by JAK Inhibitor I and Von Kossa staining was used for calcium deposits in murine aortic rings. During Pi-induced calcification, HASMCs released IL-6, IL-8, and MCP-1 and activated JAK1-JAK3 proteins and STAT1. Phospho-STAT1 was detected in murine calcified aortas. Blocking of the JAK-STAT cascade reduced HASMC proliferation and pro-inflammatory factor expression and release while increasing calcium deposition and osteogenic transcription factor RUNX2 expression. Consistently, JAK-STAT pathway inhibition exacerbates mouse aortic ring calcification ex vivo. Intriguingly, our results suggest an alternative link between VSMC inflammation and VC

Anti-Inflammatory and Anti-Oxidant Activity of Portulaca oleracea Extract on LPS-Induced Rat Lung Injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are classified as two lung complications arising from various conditions such as sepsis, trauma, and lung inflammation. Previous studies have shown that the extract of the leaves of Portulaca oleracea (PO) possesses anti-inflammatory and anti-oxidant activities. In the present study, the effects of PO (50⁻200 mg/kg) and dexamethasone (Dexa; 1.5 mg/kg) on lipopolysaccharide (LPS)-induced ALI were investigated. Subsequentially, the lung wet/dry ratio; white blood cells (WBC); levels of nitric oxide (NO); myeloperoxidase (MPO); malondialdehyde (MDA); thiol groups formation; super oxide dismutase (SOD) and catalase (CAT) activities; and levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, IL-10, prostaglandin E2 (PGE₂), and transforming growth factor (TGF)-β in the broncho alveolar lavage fluid (BALF) were evaluated in order to demonstrate the anti-oxidant and anti-inflammatory activity of PO. Our results show that PO suppresses lung inflammation by the reduction of IL-β, IL-6, TNF-α, PGE₂, and TGF-β, as well as by the increase of IL-10 levels. We also found that PO improves the level of WBC, MPO, and MDA, as well as thiol group formation and SOD and CAT activities, compared with the LPS group. The results of our investigation also show that PO significantly decreased the lung wet/dry ratio as an index of interstitial edema. Taken together, our findings reveal that PO extract dose-dependently displays anti-oxidant and anti-inflammatory activity against LPS-induced rat ALI, paving the way for rational use of PO as a protective agent against lung-related inflammatory disease

Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study

none10noopenSabbatinelli, Jacopo; Castiglione, Stefania; Macrì, Federica; Giuliani, Angelica; Ramini, Deborah; Vinci, Maria Cristina; Tortato, Elena; Bonfigli, Anna Rita; Olivieri, Fabiola; Raucci, AngelaSabbatinelli, Jacopo; Castiglione, Stefania; Macrì, Federica; Giuliani, Angelica; Ramini, Deborah; Vinci, Maria Cristina; Tortato, Elena; Bonfigli, Anna Rita; Olivieri, Fabiola; Raucci, Angel

Repetitive Exposure of IL-17 Into the Murine Air Pouch Favors the Recruitment of Inflammatory Monocytes and the Release of IL-16 and TREM-1 in the Inflammatory Fluids

The infiltration of Th17 cells in tissues and organs during the development of many autoimmune diseases is considered a key step toward the establishment of chronic inflammation. Indeed, the localized and prolonged release of IL-17 in specific tissues has been associated with an increased severity of the inflammatory response that remains sustained over time. The cellular and molecular mechanisms behind these effects are far from being clear. In this study we investigated the effects of two repetitive administration of recombinant IL-17 into the murine air pouch to simulate a scenario where IL-17 is released over time in a pre-inflamed tissue. Consistent with our previous observations, mice receiving a single dose of IL-17 showed a transitory influx of neutrophils into the air pouch that peaked at 24 h and declined at 48 h. Conversely, mice receiving a double dose of the cytokine—one at time 0 and the second after 24 h—showed a more dramatic inflammatory response with almost 2-fold increase in the number of infiltrated leukocytes and significant higher levels of TNF-α and IL-6 in the inflammatory fluids. Further analysis of the exacerbated inflammatory response of double-injected IL-17 mice showed a unique cellular and biochemical profile with inflammatory monocytes as the second main population emigrating to the pouch and IL-16 and TREM-1 as the most upregulated cytokines found in the inflammatory fluids. Most interestingly, mice receiving a double injection of IL-1β did not show any change in the cellular or biochemical inflammatory response compared to those receiving a single injection or just vehicle. Collectively these results shed some light on the function of IL-17 as pro-inflammatory cytokine and provide possible novel ways to target therapeutically the pathogenic effects of IL-17 in autoimmune conditions

Neutralization of IL-17 rescues amyloid-β-induced neuroinflammation and memory impairment

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of T helper 17 cells in the pathogenesis of AD-related neuroinflammation has been reported in several studies, however the role of the main cytokine, IL-17, has not been well addressed. Herein, we investigate the effects of IL-17 neutralizing antibody (IL-17Ab) injected by intracerebroventricular (ICV) or intranasal (IN) routes on amyloid-β-induced neuroinflammation and memory impairment in mice