PPAR γ

The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. PPARγ, a ligand activated transcription factor, has long been studied for its anti-inflammatory actions, but an emerging body of literature is investigating the role of PPARγ and its ligands (including thiazolidinediones, prostaglandins, and oleanolic acids) in all phases of resolution. PPARγ can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. PPARγ and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. PPARγ alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer’s disease, and obesity in animal models. Finally, novel specialized proresolving mediators—eicosanoids with critical roles in resolution—may act through PPARγ modulation to promote resolution, providing another exciting area of therapeutic potential for this receptor

Radiation Induces Metabolic Dysregulation in Pulmonary Fibroblasts

Rationale: Exposure of the lung to ionizing radiation, such as during radiotherapy, can result in pulmonary fibrosis (PF), which has few treatment options. PF is characterized by an accumulation of extracellular matrix proteins that form scar tissue, resulting in dyspnea, disruption of gas exchange, and even death. We and others have shown that metabolic reprogramming is a hallmark of idiopathic pulmonary fibrosis (IPF). IPF lung tissue, and lung fibroblasts treated with TGF-β, exhibit increased aerobic glycolysis with increased expression of lactate dehydrogenase A (LDHA) and excess production of lactate, leading to reduced extracellular pH that activates latent TGF-β. Here, we hypothesized that ionizing radiation would cause aerobic glycolytic metabolic dysregulation in primary human lung fibroblasts. Results: Primary non-fibrotic HLFs exposed to irradiation exhibited significant upregulation of Pyruvate Dehydrogenase Kinase (PDK1 (0.5 – 3-fold, p\u3c0.05) and LDHA (1.4-fold, p\u3c0.05). Cell viability was unaffected by increased radiation dose. Conclusions: Radiation increased fibroblast expression of genes involved in fibrotic phenotypes (αSMA) and aerobic glycolysis (PDK1 and LDHA), in a similar pattern to that seen in IPF fibroblasts. The metabolic changes are closely associated with creating a profibrotic extracellular environment in IPF by promoting an acidic environment. Our evidence suggests this phenomenon can be driven by radiation in lung fibroblasts and affirm that glycolytic reprogramming may also be a hallmark of radiation-induced fibrosis. Further understanding of the common mechanisms that create this metabolic shift could provide novel therapeutics for fibrosis treatment.https://scholarscompass.vcu.edu/gradposters/1158/thumbnail.jp

Impact of abrupt sea ice loss on Greenland water isotopes during the last glacial period

Greenland ice cores provide excellent evidence of past abrupt climate changes. However, there is no universally accepted theory of how and why these Dansgaard–Oeschger (DO) events occur. Several mechanisms have been proposed to explain DO events, including sea ice, ice shelf buildup, ice sheets, atmospheric circulation, and meltwater changes. DO event temperature reconstructions depend on the stable water isotope (δ18O) and nitrogen isotope measurements from Greenland ice cores: interpretation of these measurements holds the key to understanding the nature of DO events. Here, we demonstrate the primary importance of sea ice as a control on Greenland ice core δ18O: 95% of the variability in δ18O in southern Greenland is explained by DO event sea ice changes. Our suite of DO events, simulated using a general circulation model, accurately captures the amplitude of δ18O enrichment during the abrupt DO event onsets. Simulated geographical variability is broadly consistent with available ice core evidence. We find an hitherto unknown sensitivity of the δ18O paleothermometer to the magnitude of DO event temperature increase: the change in δ18O per Kelvin temperature increase reduces with DO event amplitude. We show that this effect is controlled by precipitation seasonality

Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

Peroxisome proliferator-activated receptor gamma (PPARγ) is a multifunctional transcription factor with important regulatory roles in inflammation, cellular growth, differentiation, and apoptosis. PPARγ is expressed in a variety of immune cells as well as in numerous leukemias and lymphomas. Here, we review recent studies that provide new insights into the mechanisms by which PPARγ ligands influence hematological malignant cell growth, differentiation, and survival. Understanding the diverse properties of PPARγ ligands is crucial for the development of new therapeutic approaches for hematological malignancies

Biological controls investigated to aid management of olive fruit fly in California

The widespread and rapid establishment of the olive fruit fly in California required immediate changes in integrated pest management (IPM) programs for olives. After finding that resident natural enemies did not provide adequate control, researchers began a worldwide search for parasitoids, with exploration in the Republic of South Africa, Namibia, India, China and other countries. Parasitoids were shipped to California, and most were studied in quarantine to determine the best species for release. Two parasitoid species — Psyttalia lounsburyi and Psyttalia humilis — are now being released throughout the state’s olive-growing regions, and researchers are studying their effectiveness

Investigating the 8.2 ka event in northwestern Madagascar: Insight from data–model comparisons

The 8.2 ka event is a well-known cooling event in the Northern Hemisphere, but is poorly understood in Madagascar. Here, we compare paleoclimate data and outputs from paleoclimate simulations to better understand it. Records from Madagascar suggest two distinct sub-events (8.3 ka and 8.2 ka), that seem to correlate with records from northern high latitude. This could indicate causal relationships via changes in the Atlantic Meridional Overturning Circulation (AMOC) with changes in moisture source's δ18O, and changes in the mean position of the Inter-Tropical Convergence Zone (ITCZ), as climate modelling suggests. These two sub-events are also apparent in other terrestrial records, but the climatic signals are different. The prominent 8.2 ka sub-event records a clear antiphase relationship between the northern and southern hemisphere monsoons, whereas such relationship is less evident during the first 8.3 ka sub-event. Data–model comparison have also shown a mismatch between the paleoclimate data and the model outputs, the causes of which are more or less understood and may lie in the proxies, in the model, or in both data and model. Knowing that paleoclimate proxies and climate models produce different sets of variables, further research is needed to improve the data–model comparison approach, so that both paleoclimate data and paleoclimate models will better predict the likely climate status of a region during a specified time in the past with minimal uncertainties

Electrophilic PPARγ Ligands Attenuate IL-1β and Silica-Induced Inflammatory Mediator Production in Human Lung Fibroblasts via a PPARγ-Independent Mechanism

Acute and chronic lung inflammation is associated with numerous important disease pathologies including asthma, chronic obstructive pulmonary disease and silicosis. Lung fibroblasts are a novel and important target of anti-inflammatory therapy, as they orchestrate, respond to, and amplify inflammatory cascades and are the key cell in the pathogenesis of lung fibrosis. Peroxisome proliferator-activated receptor gamma (PPARγ) ligands are small molecules that induce anti-inflammatory responses in a variety of tissues. Here, we report for the first time that PPARγ ligands have potent anti-inflammatory effects on human lung fibroblasts. 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO) and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inhibit production of the inflammatory mediators interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), COX-2, and prostaglandin (PG)E2 in primary human lung fibroblasts stimulated with either IL-1β or silica. The anti-inflammatory properties of these molecules are not blocked by the PPARγ antagonist GW9662 and thus are largely PPARγ independent. However, they are dependent on the presence of an electrophilic carbon. CDDO and 15d-PGJ2, but not rosiglitazone, inhibited NF-κB activity. These results demonstrate that CDDO and 15d-PGJ2 are potent attenuators of proinflammatory responses in lung fibroblasts and suggest that these molecules should be explored as the basis for novel, targeted anti-inflammatory therapies in the lung and other organs

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

Assessment of the potential effect of some streams properties on the isolated Aeromonas hydrophila strains susceptibility against some β-Lactams and Sulfamids

The isolation and characterization of A. hydrophila strains were carried out a given stream located in the equatorial zone in Cameroon (Central Africa), during the mild rainy season and the mild dry season. The water physicochemical parameters measured were temperature, pH, electrical conductivity, color, turbidity and suspended solids. It has been noted that bacterial abundances as well as the values of physicochemical parameters undergoes temporal variations. Antimicrobial susceptibility tests showed that the means diameters of inhibition with Oxacillin, Ceftriazone, Penicellin, Sulfamethoxazol-trimethoprim, Chloramphenicol, Imipenem, Amoxicillin-Clavulanic acid and Cefazolin were 6.44, 21, 6.63, 9.58, 15.37, 22.18, 14.29 and 10.26 mm respectively. 100% of strains tested were resistant to Penicillin, 89.47 % resistant to Oxacillin, 68.42% resistant to Sulphamethoxazole-trimetroprim and 63.15% were resistant to Cefazolin. There were 54.60% cases of antibiotic resistance, 24.34 % of intermediate sensitivity and 21.05% of sensitive strains against the tested antibiotics. The encoded redundancy analysis indicates that the percentage of the variation explained on the canonical axes is of 47.8% for the F1 axis and 25.9% for the F2 axis, for an accumulated percentage of 73.7%. The suspended solids, the Ceftriazon and Chloramphenicol are correlated to the F1 axis in positive coordinates, and the Temperature and Amoxicillin-Clavulanic acid in negative coordinates. The correlation test between the water physicochemical characteristics and the inhibition diameters of antibiotics showed some significant correlations (P<0.05). The regulation of bacterial genes would be regulated by complex mechanisms. Although many factors implied are linked to the bacterial cell, others may belong to the closed environment

Mapping and modelling the geographical distribution and environmental limits of podoconiosis in Ethiopia

BACKGROUND Ethiopia is assumed to have the highest burden of podoconiosis globally, but the geographical distribution and environmental limits and correlates are yet to be fully investigated. In this paper we use data from a nationwide survey to address these issues. METHODOLOGY Our analyses are based on data arising from the integrated mapping of podoconiosis and lymphatic filariasis (LF) conducted in 2013, supplemented by data from an earlier mapping of LF in western Ethiopia in 2008-2010. The integrated mapping used woreda (district) health offices' reports of podoconiosis and LF to guide selection of survey sites. A suite of environmental and climatic data and boosted regression tree (BRT) modelling was used to investigate environmental limits and predict the probability of podoconiosis occurrence. PRINCIPAL FINDINGS Data were available for 141,238 individuals from 1,442 communities in 775 districts from all nine regional states and two city administrations of Ethiopia. In 41.9% of surveyed districts no cases of podoconiosis were identified, with all districts in Affar, Dire Dawa, Somali and Gambella regional states lacking the disease. The disease was most common, with lymphoedema positivity rate exceeding 5%, in the central highlands of Ethiopia, in Amhara, Oromia and Southern Nations, Nationalities and Peoples regional states. BRT modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with population density and clay content. Based on the BRT model, we estimate that in 2010, 34.9 (95% confidence interval [CI]: 20.2-51.7) million people (i.e. 43.8%; 95% CI: 25.3-64.8% of Ethiopia's national population) lived in areas environmentally suitable for the occurrence of podoconiosis. CONCLUSIONS Podoconiosis is more widespread in Ethiopia than previously estimated, but occurs in distinct geographical regions that are tied to identifiable environmental factors. The resultant maps can be used to guide programme planning and implementation and estimate disease burden in Ethiopia. This work provides a framework with which the geographical limits of podoconiosis could be delineated at a continental scale