Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors

Peroxisome proliferator-activated receptors (PPARα, -β/δ, and -γ) are a subfamily of nuclear receptors that plays key roles in glucose and lipid metabolism. PPARγ is the molecular target of the thiazolidinedione class of antidiabetic drugs that has many side effects. PPARγ is also activated by long chain unsaturated or oxidized/nitrated fatty acids, but its relationship with the medium chain fatty acids remains unclear even though the medium chain triglyceride oils have been used to control weight gain and glycemic index. Here, we show that decanoic acid (DA), a 10-carbon fatty acid and a major component of medium chain triglyceride oils, is a direct ligand of PPARγ. DA binds and partially activates PPARγ without leading to adipogenesis. Crystal structure reveals that DA occupies a novel binding site and only partially stabilizes the AF-2 helix. DA also binds weakly to PPARα and PPARβ/δ. Treatments with DA and its triglyceride form improve glucose sensitivity and lipid profiles without weight gain in diabetic mice. Together, these results suggest that DA is a modulating ligand for PPARs, and the structure can aid in designing better and safer PPARγ-based drugs.     

Initiation and progression of mechanical damage in the intervertebral disc under cyclic loading using continuum damage mechanics methodology: A finite element study

It is difficult to study the breakdown of disc tissue over several years of exposure to bending and lifting by experimental methods. There is also no finite element model that elucidates the failure mechanism due to repetitive loading of the lumbar motion segment. The aim of this study was to refine an already validated poro-elastic finite element model of lumbar motion segment to investigate the initiation and progression of mechanical damage in the disc under simple and complex cyclic loading conditions. Continuum damage mechanics methodology was incorporated into the finite element model to track the damage accumulation in the annulus in response to the repetitive loading. The analyses showed that the damage initiated at the posterior inner annulus adjacent to the endplates and propagated outwards towards its periphery under all loading conditions simulated. The damage accumulated preferentially in the posterior region of the annulus. The analyses also showed that the disc failure is unlikely to happen with repetitive bending in the absence of compressive load. Compressive cyclic loading with low peak load magnitude also did not create the failure of the disc. The finite element model results were consistent with the experimental and clinical observations in terms of the region of failure, magnitude of applied loads and the number of load cycles survived.     

Inhibitory effects of Robo2 on nephrin: a crosstalk between positive and negative signals regulating podocyte structure

Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit-diaphragm protein that functions in the kidney glomerular filtration barrier. Here, we report that Robo2 is expressed at the basal surface of mouse podocytes and colocalizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin?polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture.     

Spore germination based assay for monitoring antibiotic residues in milk at dairy farm

Spore germination based assay involves the transformation of dormant spores of Bacillus stearothermophilus 953 into active vegetative cells. The inhibition of germination process specifically in presence of antibiotic residues was used as a novel approach for monitoring target contaminants in milk. The indicator organism i.e., B. stearothermophilus 953 was initially allowed to sporulate by seeding in sporulation medium and incubating at 55 °C for 18 ± 2 h. The spores exhibited a typical chain behavior as revealed through phase contrast microscopy. The minimal medium inoculated with activated spores was incubated at 64 °C for 2-3 h for germination and outgrowth in presence of specific germinant mixture containing dextrose, whey powder and skimmed milk powder added in specific ratio along with reconstituted milk as negative control and test milk samples. The change in color of the medium from purple to yellow was used as criteria for detection of antibiotic residues in milk. The efficiency of the developed assay was evaluated through a surveillance study on 228 samples of raw, pasteurized and dried milks and results were compared with AOAC approved microbial receptor assay. The presence of antibiotic level was 10.08 % at Codex maximum residual limit having false positive result only in 0.43 % of the samples. The results of the present investigation suggest that developed spore based assay can be a practical solution to dairy industry for its application at farm level, milk processing units, independent testing and R & D centres in order to comply with the legal requirements set by Codex.     

Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis

Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.     

Inhibitory effect of Terminalia chebula Retz. fruit extracts on digestive enzyme related to diabetes and oxidative stress

Terminalia chebula fruit extracts were prepared sequentially with hexane, ethyl acetate, methanol and methanol-water (70:30) and tested for their α-glucosidase inhibitory and antioxidant potential. The study resulted in the formulation of an extract with high α-glucosidase inhibitory potential (IC(50) 0.19 ± 0.03 μg mL(-1)) enriched with hydrolysable tannins. Also, each of the extract was chemically characterized by reversed-phase high-performance liquid chromatography on the basis of their marker compounds chebulagic acid, chebulinic acid and corilagin in order to give explanation to the significant activity shown by the extracts. The antioxidant potential of the highly active extract was evaluated in the cellular level also using superoxide dismutase, glutathione S-transferase and induced oxidative stress assays. The results indicated the possibility of using the extract as a nutraceutical health supplement in the management of type 2 diabetes.     

Lipid signaling in Drosophila photoreceptors

Drosophila photoreceptors are sensory neurons whose primary function is the transduction of photons into an electrical signal for forward transmission to the brain. Photoreceptors are polarized cells whose apical domain is organized into finger like projections of plasma membrane, microvilli that contain the molecular machinery required for sensory transduction. The development of this apical domain requires intense polarized membrane transport during development and it is maintained by post developmental membrane turnover. Sensory transduction in these cells involves a high rate of G-protein coupled phosphatidylinositol 4,5 bisphosphate [PI(4,5)P(2)] hydrolysis ending with the activation of ion channels that are members of the TRP superfamily. Defects in this lipid-signaling cascade often result in retinal degeneration, which is a consequence of the loss of apical membrane homeostasis. In this review we discuss the various membrane transport challenges of photoreceptors and their regulation by ongoing lipid signaling cascades in these cells. This article is part of a Special Issue entitled Lipids and Vesicular Transport.     

Effect of temperature on the survival of Aconophora compressa Walker (Hemiptera: Membracidae): implications for weed biocontrol

Abstract  In weed biocontrol, similarity of abiotic factors between the native and introduced range of a biocontrol agent is critical to its establishment and effectiveness. This is particularly the case for weeds that have a wide geographical distribution in the native range. For such weeds, the choice of a specialist insect that has narrow tolerance limits to important abiotic factors can diminish its ability to be an effective biocontrol agent. The membracid Aconophora compressa was introduced in Australia from Mexico for biocontrol of Lantana camara , a plant with a wide climatic tolerance. In this study we investigated the effect of constant and alternating temperatures on A. compressa survival. Longevity of adults and nymphs declined with increasing temperatures, and at 39°C individuals survived for less than a day. At lower temperatures, nymphs survived longer than adults. Survival at alternating temperatures was longer than at constant temperatures, but the general trend of lower survival at higher temperatures remained. Spatially and temporally, the climatic tolerance of A. compressa appears to be a subset of that of lantana, thereby limiting its potential impact.