The effect of exercise training on intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review and meta-analysis.

This systematic review and meta-analysis determined the impact of structured exercise training, and the influence of associated weight loss, on intrahepatic triglyceride (IHTG) in individuals with non-alcoholic fatty liver disease (NAFLD). It also examined its effect on hepatic insulin sensitivity in individuals with or at increased risk of NAFLD. Analyses were restricted to studies using magnetic resonance spectroscopy or liver biopsy for the measurement of IHTG and isotope-labelled glucose tracer for assessment of hepatic insulin sensitivity. Pooling data from 17 studies (373 exercising participants), exercise training for one to 24 weeks (mode: 12 weeks) elicits an absolute reduction in IHTG of 3.31% (95% CI: -4.41 to -2.22%). Exercise reduces IHTG independent of significant weight change (-2.16 [-2.87 to -1.44]%), but benefits are substantially greater when weight loss occurs (-4.87 [-6.64 to -3.11]%). Furthermore, meta-regression identified a positive association between percentage weight loss and absolute reduction in IHTG (ß = 0.99 [0.62 to 1.36], P < 0.001). Pooling of six studies (94 participants) suggests that exercise training also improves basal hepatic insulin sensitivity (mean change in hepatic insulin sensitivity index: 0.13 [0.05 to 0.21] mg m-2  min-1 per µU mL-1 ), but available evidence is limited, and the impact of exercise on insulin-stimulated hepatic insulin sensitivity remains unclear.

Performance of the Gen-Probe AMPLIFIED Chlamydia Trachomatis Assay in detecting Chlamydia trachomatis in endocervical and urine specimens from women and urethral and urine specimens from men attending sexually transmitted disease and family planning clinics.

The Gen-Probe AMPLIFIED Chlamydia Trachomatis Assay (AMP CT) uses transcription-mediated amplification and hybridization protection assay procedures to qualitatively detect Chlamydia trachomatis rRNA in urine, endocervical swab, and urethral specimens. The performance of the AMP CT was compared to that of cell culture for endocervical swab and urine specimens from women and urethral and urine specimens from men. Analysis of specimens with discrepant results was performed by a combination of reculture, direct fluorescent-antibody (DFA) staining of specimen sediment, and amplification which targeted a different chlamydial rRNA. A total of 800 urine samples were tested by the AMP CT (607 from women and 193 from men), and 7. 1% were positive for C. trachomatis, with a sensitivity of 91.2% and a specificity of 99.6% upon discrepant analysis. A total of 926 swab specimens were tested by culture and AMP CT (717 endocervical swab specimens and 209 urethral swab specimens from men), and 7.7% were positive for C. trachomatis, with a sensitivity and specificity of 100% upon discrepant analysis. The AMP CT is a sensitive and specific nucleic acid hybridization assay for the detection of C. trachomatis in endocervical swab specimens from women, urethral swab specimens from men, and urine specimens from men and women.

Regulation of activin type I receptor function by phosphorylation of residues outside the GS domain.

Activin signals through a heteromeric complex of receptor serine kinases by inducing type II receptor-mediated phosphorylation, and consequent activation, of the type I receptor. Type I receptor phosphorylation occurs at a glycine- and serine-rich site in the juxtamembrane domain; phosphorylation at that site correlates with signaling. Investigation of type I activin receptor mutants impaired for GS domain phosphorylation revealed that, in the presence of elevated amounts of type II activin receptor, GS domain phosphorylation is not required for signaling. The type I receptor showed activin-dependent phosphorylation of several tryptic phosphopeptides, suggesting that phosphorylation of receptor I at sites both within and outside the GS domain is required for full signaling.

Formation and activation by phosphorylation of activin receptor complexes.

Activin is a protein growth and differentiation factor that initiates intracellular events through the activation of a complex of transmembrane protein serine kinases. Two subfamilies of receptor serine kinases, type I and type II, have been identified, and both receptor types may be required to generate a transmembrane signal. Investigation of the interaction between various activin receptors (ActRs) revealed that ActRs I and II could exist in a stable complex and that formation of that complex between transiently overexpressed molecules was not regulated by ligand. Analysis of phosphorylation suggested that activin induced phosphorylation of receptor I, probably at residues within a conserved glycine and serine-rich sequence in the juxtamembrane region referred to as the GS domain. Phosphorylation of the GS domain was dependent upon a functional ActRII. Introduction of an activin type I receptor, ALK4, into the mink lung epithelial cell line, L17, conferred activin responsiveness on those cells. Mutation of specific combinations of serines and threonines in the core sequence of the ALK4 GS domain to alanine rendered that receptor incompetent for signaling. Mutation of the same sets of residues to glutamic acid produced molecules that supported activin signaling but that did not display elevated basal signaling anticipated for a constitutively active receptor. However, mutation of a threonine residue in the carboxy-terminal half of the GS domain, T206, to glutamic acid yielded receptors with constitutive activity. Taken together, these results support a role for phosphorylation of type I ActRs in the generation of a biological signal.

Differential induction of the mitogen-activated protein kinase pathway by bacterial lipopolysaccharide in cultured monocytes and astrocytes.

We recently reported that cyclic AMP (cAMP) specifically inhibits lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1 beta) transcription initiation in astrocytic cells but enhances the LPS induction of IL-1 beta in monocytic cells. The purpose of this study was to determine how cAMP differentially regulates LPS-induced IL-1 beta transcription in these two cell types. Two essential components of the mitogen-activated protein (MAP) kinase signal-transduction pathway, extracellular-signal-regulated kinase (ERK2; p41 mapk) and Raf-1, have been shown to be targets of LPS stimulation in other cell types, and therefore may be linked to the regulation of IL-1 beta transcription. In the human astrocytic cell line, U-373MG, LPS was found to strongly activate (and cAMP to inhibit) both ERK2 and Raf-1. In the human monocytic cell line, THP-1, LPS minimally activated ERK2 and did not activate Raf-1. These findings suggest that, in astrocytic cells, elevated intracellular cAMP levels may negatively regulate LPS activation of IL-1 beta via the MAP kinase signalling pathway. In contrast, this pathway is not significantly activated by LPS in monocytic cells, thus inhibition by elevated intracellular cAMP levels would not affect IL-1 beta transcription.

Protein synthesis-dependent induction of interleukin-1 beta by lipopolysaccharide is inhibited by dexamethasone via mRNA destabilization in human astroglial cells.

Dexamethasone inhibits lipopolysaccharide-induced synthesis of the cytokine, interleukin-1 beta, in cerebrospinal fluid of patients with bacterial meningitis. Along with monocytes, astrocytes are capable of producing lipopolysaccharide-induced interleukin-1 beta in the central nervous system. The objective of this study was to investigate the induction of interleukin-1 beta mRNA by lipopolysaccharide, and the inhibition of this process by dexamethasone, in human astrocytes using the astrocytoma cell line U-373MG as a model system. Dexamethasone-mediated inhibition of induction of interleukin-1 beta mRNA by lipopolysaccharide required a functional glucocorticoid receptor. In contrast to monocytes, lipopolysaccharide induction of interleukin-1 beta mRNA in U-373MG cells required de novo protein synthesis. Dexamethasone also had no effect on lipopolysaccharide-induced interleukin-1 beta transcriptional initiation in U-373MG cells. U-373MG cells were similar to monocytes, however, with respect to the ability of dexamethasone to decrease interleukin-1 beta mRNA half-life. These findings demonstrate that the mode of lipopolysaccharide induction of interleukin-1 beta mRNA, and inhibition of this process by dexamethasone, can vary in different cell types.

Inhibition of lipopolysaccharide-induced IL-1 beta transcription by cyclic adenosine monophosphate in human astrocytic cells.

The response to LPS includes synthesis by monocytes of the inflammatory mediator IL-1 beta. Although the intracellular signaling pathways activated by LPS that lead to IL-1 beta production have been studied extensively in monocytes, these pathways have not been investigated in astrocytes, an important source of IL-1 beta in the central nervous system. cAMP has been implicated in LPS signaling as a positive regulator of IL-1 beta mRNA accumulation in monocytes. In this study, we demonstrate that in human astrocytes (both fetal and the astrocytoma cell line, U-373 MG), agents that elevate intracellular cAMP decrease LPS-induced IL-1 beta mRNA accumulation. Elevated intracellular cAMP does not affect IL-1 beta mRNA stability, but inhibits LPS-induced transcription initiation of IL-1 beta in U-373 MG cells. Elevated intracellular cAMP may be a negative feedback regulatory mechanism to inhibit IL-1 beta production employed by astrocytes that (unlike monocytic cells) lack a glycosyl-phosphatidylinositol (GPI)-anchored form of the LPS receptor, CD14. Whether cAMP inhibits an LPS-inducible signaling pathway or negatively affects cAMP-dependent transcription factors remains to be determined.