Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)
. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the ...mechanisms involved are not completely understood
. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14
cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.
•Elemental composition characterized in 14 wines made from an identical clone of Pinot noir.•Concentrations of 47 elements were determined in the wines by ICP–MS.•Several elements, including Mo, Er, ...Na, Li, Cs and Pb, varied by 10-fold the 14 wines.•Wine composition differences are mediated by the soil and microclimate conditions.
Elemental composition was used to characterize and differentiate 14 wines made from the identical clone of Vitis vinifera cv. Pinot noir (clone 667). The vineyards span distances which range from several hundred meters to 1540 km and their elevations vary from near sea level to nearly 500 m. Twenty-seven elements were observed above the limit of quantitation by using inductively coupled plasma mass spectrometry (ICP–MS) in the wines from at least half of the 14 sites. Concentrations of several elements, including Mo, Er, Na, Li, Cs and Pb, varied by 10-fold across the 14 wines. Multiple factor analysis (MFA) of elemental composition with juice chemistry and site characterization show associations consistent with expectations, such as high Ca with high clay content. These results demonstrate that even when grapevine clone and winemaking protocol are controlled, composition differences in wines produced from sites are mediated by diverse soil and microclimate conditions.
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•Fourteen wines made from the identical clone were characterized.•Thirty elements in the wines were quantified with ICP-MS.•Nineteen elements showed reproducibility in wines from at ...least on 8 sites.•Vineyard origin and growing site factors are correlated with elemental profile.
The reproducibility of elemental profile in wines produced across vintages of 2015 and 2016 has been studied using grapes from a single scion clone of Vitis vinifera L. cv. Pinot noir. Grapevines were grown on fourteen different vineyard sites, from Oregon to southern California in the U.S.A., which span distances from approximately hundreds of meters to 1450 km, while elevations range from near sea level to nearly 500 m. The number of elements quantified in the wines made from the 2016 vintage was thirty, by using inductively coupled plasma mass spectrometry (ICP-MS). These data were compared with the twenty-seven elements quantified and previously reported in wines made from 2015 vintage, including twenty-four elements reported in both vintages. The composition of each element was analyzed by analysis of variance with main effect of vineyard. Wines were classified according to vineyard origin and environmental growing site with a combination of factors correlated with the wine elemental profile. The low variability (< 25%) of certain elements in wines from at least eight sites across both vintages, including Group 1 (Cs, K, Na and Rb), Group 2 (Ba, Ca, Mg and Sr), Group 3B (Eu), Group 13 (Al, B and Ga), Group 15 (As and P) and Co, Fe, Mn, Ni and V, demonstrated the reproducibility over the seasons analyzed (2015 and 2016). The comparison of elemental profile of wines across growing seasons demonstrates the opportunity to reproduce one key aspect of wine chemistry across vintages.
Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, ...transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.
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•Sphingolipid drives astrocyte pathogenic activities via cPLA2-MAVS-NF-κB•cPLA2 displaces HK2 from MAVS, limiting the metabolic support of neurons by astrocytes•Miglustat suppresses astrocyte cPLA2-MAVS-NF-κB pro-inflammatory signaling•Miglustat is a candidate drug for repurposing to treat secondary progressive MS
By exploring the immunometabolic pathways that drive pro-inflammatory astrocyte activities, sphingolipid metabolism is identified as a promising therapeutic target in CNS inflammation.
Real-time process metrics are standard for the majority of fermentation-based industries but have not been widely adopted by the wine industry. In this study, replicate fermentations were conducted ...with temperature as the main process parameter and assessed via in-line Oxidation Reduction Potential (ORP) probes and at-line profiling of phenolics compounds by UV-Vis spectroscopy. The California and Oregon vineyards used in this study displayed consistent vinification outcomes over five vintages and are representative of sites producing faster- and slower-fermenting musts. The selected sites have been previously characterized by fermentation kinetics, elemental profile, phenolics, and sensory analysis. ORP probes were integrated into individual fermentors to record how ORP changed throughout the fermentation process. The ORP profiles generally followed expected trends with deviations revealing previously undetectable process differences between sites and replicates. Site-specific differences were also observed in phenolic and anthocyanin extraction. Elemental composition was also analyzed for each vineyard, revealing distinctive profiles that correlated with the fermentation kinetics and may influence the redox status of these wines. The rapid ORP responses observed related to winemaking decisions and yeast activity suggest ORP is a useful process parameter that should be tracked in addition to Brix, temperature, and phenolics extraction for monitoring fermentations.
Malaria is caused by parasite of the genus Plasmodium and is still one of the most important infectious diseases in the world. Several biological characteristics of Plasmodium vivax contribute to the ...resilience of this species, including early gametocyte production, both of which lead to efficient malaria transmission to mosquitoes. This study evaluated the impact of currently used drugs on the transmission of P. vivax. Participants received one of the following treatments for malaria: i) chloroquine 10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3 co-administered with Primaquine 0.5 mg/kg/day for 7 days; ii) Chloroquine 10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3 co-administered with one-dose of Tafenoquine 300 mg on day 1; and iii) Artesunate and Mefloquine 100 mg and 200 mg on day 1, 2 and 3 co-administered with Primaquine 0.5 mg/kg/day for 14 days. Patient blood was collected before treatment and 4 h, 24 h, 48 h and 72 h after treatment. The blood was used to perform a direct membrane feeding assay (DMFA) using Anopheles darlingi mosquitoes. The results showed 100% inhibition of the mosquito infection after 4 h using ASMQ+PQ, after 24 h for the combination of CQ+PQ and 48 h using CQ+TQ. The density of gametocytes declined over time in all treatment groups, although the decline was more rapid in the ASMQ+PQ group. In conclusion, it was possible to demonstrate the transmission-blocking efficacy of the malaria vivax treatment and that ASMQ+PQ acts faster than the two other treatments.
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. ...Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.
The main goal of this work is to evaluate the organic acids (acetic, citric, lactic, malic, tartaric and succinic) profile of fifteen Pinot noir wines from different vineyards by HPLC-DAD. In ...addition, this method was applied to characterize grape juices of ‘Bordeaux grape varieties’ grown in Napa Valley, California, USA and Bolgheri, Tuscany, Italy. The method was validated on grape juices and wines. Organic acids concentrations in wines varied about 2-fold for tartaric, lactic, and acetic acids; 3-fold for malic and citric acids; and 4-fold for succinic acid. In grape juices, the concentrations varied approximately 3-fold for tartaric and citric acids and 8-fold for malic acid. Principal component analysis presented correlations with higher tartaric and malic acids in wines from Russian River Valley AVA and Sonoma Coast AVA regions, which are relatively close to each other. Cabernet sauvignon juices from different regions in the USA and Italy had similar correlations with citric, malic and tartaric acids concentrations. Organic acids profiles obtained in this work are consistent with the literature, thereby demonstrating the reliability of this single methodology for the characterization of a wide variety of grape juices and wines by sampling from different growing regions.
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•Organic acids were profiled in grape juices from ‘Bordeaux grape varieties’.•Organic acids were profiled in Pinot noir wines.•Tartaric acid is correlated in wines from Russian River Valley & Sonoma Coast AVAs.•Tartaric, citric and malic acids levels varied 3, 3 and 8-fold in the grape juices.•Tartaric, lactic and succinic acids concentrations varied 2, 2, and 4-fold in wines.
Obtaining Plasmodium vivax sporozoites is essential for in vitro culture of liver stage parasites, not only to understand fundamental aspects of parasite biology, but also for drug and vaccine ...development. A major impediment to establish high-throughput in vitro P. vivax liver stage assays for drug development is obtaining sufficient numbers of sporozoites. To do so, female anopheline mosquitoes have to be fed on blood from P. vivax-infected patients through an artificial membrane-feeding system, which in turns requires a well-established Anopheles colony. In this study we established conditions to provide a robust supply of P. vivax sporozoites. Adding a combination of serum replacement and antibiotics to the membrane-feeding protocol was found to best improve sporozoite production. A simple centrifugation method appears to be a possible tool for rapidly obtaining purified sporozoites with a minimal loss of yield. However, this method needs to be better defined since sporozoite viability and hepatocyte infection were not evaluated.
Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)
-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence ...of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity
. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.
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