Thyroid hormone status regulates the expression of secretory phospholipases

Thyroid hormone (T3) stimulates various metabolic pathways and the hepatic actions of T3 are mediated primarily through the thyroid hormone receptor beta (TRβ). Hypothyroidism has been linked with low grade inflammation, elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipases (sPLA2) are associated with inflammation, hyperlipidemia and atherosclerosis. Due to potential linkage between thyroid hormone and sPLA2, we investigated the effect of thyroid hormone status on the regulation of secretory phospholipases in mice, rats and human liver. T3 suppressed the expression of the sPLA2 group IIa (PLA2g2a) gene in the liver of BALB/c mice and C57BL/6 transgenic mice expressing the human PLA2g2a. PLA2g2a was elevated with hypothyroidism and high fat diets which may contribute to the low grade inflammation associated with hypothyroidism and diet induced obesity. We also examined the effects of the TRβ agonist eprotirome on hepatic gene regulation. We observed that eprotirome inhibited the expression of selected sPLA2 genes and furthermore the cytokine mediated induction PLA2g2a was suppressed. In addition, eprotirome induced genes involved in fatty acid oxidation and cholesterol clearance while inhibiting lipogenic genes. Our results indicate that in vivo thyroid hormone status regulates the abundance of sPLA2 and the inhibition of PLA2g2a by T3 is conserved across species. By regulating sPLA2 genes, T3 may impact processes associated with atherosclerosis and inflammation and TRβ agonists may ameliorate inflammation and hyperlipidemia.     

Quantifying ‘normal’ shoulder muscle activity during abduction

The purpose of this experiment was to obtain electromyographic (EMG) activity from a sample of healthy shoulders to allow a reference database to be developed and used for comparison with pathological shoulders. Temporal and intensity shoulder muscle activation characteristics during a coronal plane abduction/adduction movement were evaluated in the dominant healthy shoulder of 24 subjects. Surface and intramuscular fine wire electrodes recorded EMG activity from 15 shoulder muscles (deltoid × 3, trapezius × 3, subscapularis × 2, latissimus dorsi, pectoralis major, pectoralis minor, supraspinatus, infraspinatus, serratus anterior and rhomboids) at 2000 Hz for 10 s whilst each subject performed 10 dynamic coronal plane abduction/adduction movements from 0° to 166° to 0° with a light dumbbell. Results revealed that supraspinatus (?.102 s before movement onset) initiated the movement with middle trapezius (?.019 s) and middle deltoid (?.014 s) also activated before the movement onset. Similar patterns were also found in the time of peak amplitude and %MVC with a pattern emerging where the prime movers (supraspinatus and middle deltoid) were among the first to reach peak amplitude or display the highest %MVC values. In conclusion, the most reproducible patterns of activation arose from the more prime mover muscle sites in all EMG variables analysed and although variability was present, there emerged ‘invariant characteristics’ that were considered ‘normal’ for this group of non pathological shoulders. The authors believe that the methodology and certain parts of the analysis in this study can be duplicated and used by future researchers who require a reference database of muscle activity for use as a control group in comparisons to their respective pathological shoulder group.     

Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration

Autophagy is crucial in the turnover of cell components, and clearance of damaged organelles by the autophagic-lysosomal pathway is essential for tissue homeostasis. Defects of this degradative system have a role in various diseases, but little is known about autophagy in muscular dystrophies. We have previously found that muscular dystrophies linked to collagen VI deficiency show dysfunctional mitochondria and spontaneous apoptosis, leading to myofiber degeneration. Here we demonstrate that this persistence of abnormal organelles and apoptosis are caused by defective autophagy. Skeletal muscles of collagen VI-knockout (Col6a1(-/-)) mice had impaired autophagic flux, which matched the lower induction of beclin-1 and BCL-2/adenovirus E1B-interacting protein-3 (Bnip3) and the lack of autophagosomes after starvation. Forced activation of autophagy by genetic, dietary and pharmacological approaches restored myofiber survival and ameliorated the dystrophic phenotype of Col6a1(-/-) mice. Furthermore, muscle biopsies from subjects with Bethlem myopathy or Ullrich congenital muscular dystrophy had reduced protein amounts of beclin-1 and Bnip3. These findings indicate that defective activation of the autophagic machinery is pathogenic in some congenital muscular dystrophies.     

l-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis

Conventional therapies for the treatment of inflammatory bowel disease (IBD) have demonstrated limited efficacy and potential toxicity; therefore, there is a need for novel therapies that can safely and effectively treat IBD. Recent evidence has indicated that amino acids may play a role in maintaining gut health. l-Tryptophan has been shown to reduce oxidative stress and improve neurological states. The objective of this study was to assess the therapeutic effects of l-tryptophan in a porcine model of dextran sodium sulfate (DSS)-induced colitis. DSS was administered to piglets via intragastric catheter for 5 days followed by tryptophan administration at 80% of the daily recommended intake. The severity of colitis was assessed macroscopically and histopathologically, and intestinal permeability was monitored in vivo by d-mannitol analysis. The effect of tryptophan on the local expression of key mediators of inflammation and IBD pathogenesis was examined at the protein and gene expression levels. Supplementation with tryptophan ameliorated clinical symptoms and improved weight gain to feed intake conversion ratios. Histological scores and measurements were also improved, and gut permeability was notably reduced in tryptophan-supplemented animals. Moreover, tryptophan reduced the expression of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, interferon (IFN)-γ, IL-12p40, IL-1β and IL-17, as well as IL-8 and intracellular adhesion molecule-1, and resulted in increased expression of apoptosis initiators caspase-8 and Bax. These results demonstrate that l-tryptophan supplementation can reduce inflammation and enhance the rate of recovery in DSS-induced colitis and may be an effective immunomodulating agent for the treatment of IBD.     

Lipoprotein cofactors located in the outer membrane activate bacterial cell wall polymerases

Most bacteria surround themselves with a peptidoglycan (PG) exoskeleton synthesized by polysaccharide polymerases called penicillin-binding proteins (PBPs). Because they are the targets of penicillin and related antibiotics, the structure and biochemical functions of the PBPs have been extensively studied. Despite this, we still know surprisingly little about how these enzymes build the PG layer in?vivo. Here, we identify the Escherichia coli outer-membrane lipoproteins LpoA and LpoB as essential PBP cofactors. We show that LpoA and LpoB form specific trans-envelope complexes with their cognate PBP and are critical for PBP function in?vivo. We further show that LpoB promotes PG synthesis by its partner PBP in?vitro and that it likely does so by stimulating glycan chain polymerization. Overall, our results indicate that PBP accessory proteins play a central role in PG biogenesis, and like the PBPs they work with, these factors are attractive targets for antibiotic development.     

Autotaxin: a protein with two faces

Autotaxin (ATX) is a catalytic protein, which possesses lysophospholipase D activity, and thus involved in cellular membrane lipid metabolism and remodeling. Primarily, ATX was thought as a culprit protein for cancer, which potently stimulates cancer cell proliferation and tumor cell motility, augments the tumorigenicity and induces angiogenic responses. The product of ATX catalyzed reaction, lysophosphatidic acid (LPA) is a potent mitogen, which facilitates cell proliferation and migration, neurite retraction, platelet aggregation, smooth muscle contraction, actin stress formation and cytokine and chemokine secretion. In addition to LPA formation, later ATX has been found to catalyze the formation of cyclic phosphatidic acid (cPA), which have antitumor role by antimitogenic regulation of cell cycle, inhibition of cancer invasion and metastasis. Furthermore, the very attractive information to the scientists is that the LPA/cPA formation can be altered at different physiological conditions. Thus the dual role of ATX with the scope of product manipulation has made ATX a novel target for cancer treatment.