Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma

<p>Abstract</p> <p>Background</p> <p>While glucocorticoids are currently the most effective therapy for asthma, associated side effects limit enthusiasm for their use. Peroxisome proliferator-activated receptor-γ (PPAR-γ) activators include the synthetic thiazolidinediones (TZDs) which exhibit anti-inflammatory effects that suggest usefulness in diseases such as asthma. How the ability of TZDs to modulate the asthmatic response compares to that of glucocorticoids remains unclear, however, because these two nuclear receptor agonists have never been studied concurrently. Additionally, effects of PPAR-γ agonists have never been examined in a model involving an allergen commonly associated with human asthma.</p> <p>Methods</p> <p>We compared the effectiveness of the PPAR-γ agonist pioglitazone (PIO) to the established effectiveness of a glucocorticoid receptor agonist, dexamethasone (DEX), in a murine model of asthma induced by cockroach allergen (CRA). After sensitization to CRA and airway localization by intranasal instillation of the allergen, Balb/c mice were challenged twice at 48-h intervals with intratracheal CRA. Either PIO (25 mg/kg/d), DEX (1 mg/kg/d), or vehicle was administered throughout the period of airway CRA exposure.</p> <p>Results</p> <p>PIO and DEX demonstrated similar abilities to reduce airway hyperresponsiveness, pulmonary recruitment of inflammatory cells, serum IgE, and lung levels of IL-4, IL-5, TNF-α, TGF-β, RANTES, eotaxin, MIP3-α, Gob-5, and Muc5-ac. Likewise, intratracheal administration of an adenovirus containing a constitutively active PPAR-γ expression construct blocked CRA induction of Gob-5 and Muc5-ac.</p> <p>Conclusion</p> <p>Given the potent effectiveness shown by PIO, we conclude that PPAR-γ agonists deserve investigation as potential therapies for human asthma.</p

The peroxisome: still a mysterious organelle

More than half a century of research on peroxisomes has revealed unique features of this ubiquitous subcellular organelle, which have often been in disagreement with existing dogmas in cell biology. About 50 peroxisomal enzymes have so far been identified, which contribute to several crucial metabolic processes such as β-oxidation of fatty acids, biosynthesis of ether phospholipids and metabolism of reactive oxygen species, and render peroxisomes indispensable for human health and development. It became obvious that peroxisomes are highly dynamic organelles that rapidly assemble, multiply and degrade in response to metabolic needs. However, many aspects of peroxisome biology are still mysterious. This review addresses recent exciting discoveries on the biogenesis, formation and degradation of peroxisomes, on peroxisomal dynamics and division, as well as on the interaction and cross talk of peroxisomes with other subcellular compartments. Furthermore, recent advances on the role of peroxisomes in medicine and in the identification of novel peroxisomal proteins are discussed

Nancy Cunard's English journey

This essay analyses Nancy Cunard's contribution to the struggle for racial justice in England and her work with the black communities in Liverpool and London (whose histories and experiences differ radically from their counterparts in the United States) in the 1940s. It chronicles for the first time her campaign to safeguard the African collections in the Liverpool Museum and her specific contribution to the archive of black British history. This includes not only the monumental the Negro Anthology (1934) but also the tract, The White Man's Duty (1943) arguing for an end to British imperialism and for race relations legislation. Cunard is situated within a history of the Communist left in Britain and the United States. Her insistence on the primacy of race differentiates her from other white left activists in her day for whom issues of gender and race were or secondary importance compared to those of class (Cunard, 1944). Using unpublished archive material from the Harry Ransom Center in Austin, Texas I show that Cunard's work constitutes one segment in the rich and varied mosaic of black cultural activity in the 1930s and 1940s and discuss how Cunard knew and worked alongside some of the key figures in the black British politics of her day including Una Marson, Learie Constantine, John Carter, Harold Moody, Rudolph Dunbar and Paul Robeson. A prolific writer, publisher and political activist, Cunard presented a white readership with documentation which prompted them to question their own prejudice and rendered problematic the imaging of black people as fixed embodiments of a Eurocentric sense of reality. Cunard's work in the 1930s and 1940s predates the sailing of the Empire Windrush and the accelerated immigration to Britain from the Commonwealth after the Nationality Act of 1948. It adds to our knowledge of earlier black history, narratives, settlements, and anti-racist struggles

TRB3 is stimulated in diabetic kidneys, regulated by the ER stress marker CHOP, and is a suppressor of podocyte MCP-1

The prevalence of diabetic nephropathy continues to rise, highlighting the importance of investigating and discovering novel treatment strategies. TRB3 is a kinase-like molecule that modifies cellular survival and metabolism and interferes with signal transduction pathways. Herein, we report that TRB3 expression is increased in the kidneys of type 1 and type 2 diabetic mice. TRB3 is expressed in conditionally immortalized podocytes; however, it is not stimulated by elevated glucose. The diabetic milieu is associated with increased oxidative stress and circulating free fatty acids (FFA). We show that reactive oxygen species (ROS) such as H2O2 and superoxide anion (via the xanthine/xanthine oxidase reaction) as well as the FFA palmitate augment TRB3 expression in podocytes. C/EBP homologous protein (CHOP) is a transcription factor that is associated with the endoplasmic reticulum stress response. CHOP expression increases in diabetic mouse kidneys and in podocytes treated with ROS and FFA. In podocytes, transfection of CHOP increases TRB3 expression, and ROS augment recruitment of CHOP to the proximal TRB3 promoter. MCP-1/CCL2 is a chemokine that contributes to the inflammatory injury associated with diabetic nephropathy. In these studies, we demonstrate that TRB3 can inhibit basal and stimulated podocyte production of MCP-1. In summary, enhanced ROS and/or FFA associated with the diabetic milieu induce podocyte CHOP and TRB3 expression. Because TRB3 inhibits MCP-1, manipulation of TRB3 expression could provide a novel therapeutic approach in diabetic kidney disease

Thiazolidinedione-induced fluid retention is independent of collecting duct alphaENaC activity.

Thiazolidinediones are agonists of peroxisome proliferator-activated receptor gamma (PPARgamma) that can induce fluid retention and weight gain through unclear mechanisms. To test a proposed role for the epithelial sodium channel ENaC in thiazolidinedione-induced fluid retention, we used mice with conditionally inactivated alphaENaC in the collecting duct (Scnn1a(loxloxCre) mice). In control mice, rosiglitazone did not alter plasma aldosterone levels or protein expression of ENaC subunits in the kidney, but did increase body weight, plasma volume, and the fluid content of abdominal fat pads, and decreased hematocrit. Scnn1a(loxloxCre) mice provided functional evidence for blunted Na+ uptake in the collecting duct, but still exhibited rosiglitazone-induced fluid retention. Moreover, treatment with rosiglitazone or pioglitazone did not significantly alter the open probability or number of ENaC channels per patch in isolated, split-open cortical collecting ducts of wild-type mice. Finally, patch-clamp studies in primary mouse inner medullary collecting duct cells did not detect ENaC activity but did detect a nonselective cation channel upregulated by pioglitazone. These data argue against a primary and critical role of ENaC in thiazolidinedione-induced fluid retention

Preliminary application of DNA barcoding toward the detection of viable plant propagules at an initial, international point-of-entry in Georgia, USA

© 2020, Springer Nature Switzerland AG. Over 90% of global commercial trade occurs between seaports, which are initial points-of-entry for nonnative, potentially invasive propagules. As such, there is a need to develop means to both rapidly intercept and identify propagules as they arrive. Here, we focus on plant propagules that are assumed to be non-native, in seed form. Because standard morphological techniques alone are laborious and require taxonomic expertise, we sought to address if identification through barcoding of the plastid DNA (rbcL + matK genes) of plant seeds could improve current processes in the early detection and rapid response to prevent entry/establishment of nonnative plant species. This research conducted a preliminary foray to evaluate the utility of widely accepted plant plastid DNA barcodes to identify plant propagules (seeds, hereafter) collected from the air-intake grilles of refrigerated shipping containers of a single agricultural commodity arriving at the Port of Savannah, Georgia, USA. We ask four questions: (1) Can DNA barcoding be used to detect seeds collected from shipping containers at the port? (2) What is the genetic composition of propagules entering the port? (3) How do morphological identifications compare to those based on genetic analysis? (4) Are nonnative invasive plant species present on shipping containers entering the Port of Savannah? This research collected 11,044 seeds from 628 refrigerated shipping containers between 2015 and 2017. Seeds were then morphologically sorted into Seed Types. Barcoding of the matK and rbcL gene regions of the plastid genomes directly isolated from seeds resulted in poor amplification. This is likely due to a host of potential confounding factors. Therefore, we germinated seeds and utilized leaf-tissues for sequencing of these two gene regions. From BLASTn analyses, results returned top hits for a variety of species, with up to 22 possible nonnative plant species and one definite Federal Noxious Weed. This work investigates the interception application of DNA barcoding to improve agro- and bio-security issues posed by nonnative and invasive species. Though this study required the germination of the seeds to obtain leaf-tissue suitable for our DNA barcoding method, we effectively demonstrated seed viability. Our seed identification process was lengthy and understandably not feasible for real-time application. Therefore, we seek to improve our methods for future applications by testing other approaches that may better complement morphological identification. Next reasonable steps include improved extraction protocols, metabarcoding to generate DNA barcode sequences directly from groups of seeds harvested from shipping containers and implementing other next-generation sequencing techniques