The lipid A moiety of lipopolysaccharide forms the outer monolayer of the outer membrane of most gram-negative bacteria. Escherichia coli lipid A is synthesized on the cytoplasmic surface of the inner membrane by a conserved pathway of nine constitutive enzymes. Following attachment of the core oligosaccharide, nascent core-lipid A is flipped to the outer surface of the inner membrane by the ABC transporter MsbA, where the O-antigen polymer is attached. Diverse covalent modifications of the lipid A moiety may occur during its transit from the outer surface of the inner membrane to the outer membrane. Lipid A modification enzymes are reporters for lipopolysaccharide trafficking within the bacterial envelope. Modification systems are variable and often regulated by environmental conditions. Although not required for growth, the modification enzymes modulate virulence of some gram-negative pathogens. Heterologous expression of lipid A modification enzymes may enable the development of new vaccines.

Lipid a modification systems in gram-negative bacteria

Sepsis is one of the leading causes of deaths world-wide and yet there are no therapies available other than ICU treatment. The patient outcome is determined by a complex interplay between the pro and anti-inflammatory responses of the body i.e., a homeostatic balance between these two competing events to be achieved for the patient's recovery. The initial attempts on drug development mainly focused on controlling inflammation, however, without any tangible outcome. This was despite most deaths occurring during the immune paralysis stage of this biphasic disease. Recently, the focus has been shifting to understand immune paralysis (caused by apoptosis and by anti-inflammatory cytokines) to develop therapeutic drugs. In this review we put forth an argument for a proper understanding of the molecular basis of inflammation as well as apoptosis for developing an effective therapy.

/pdf/sepsis-inflammation-is-a-necessary-evil-5726ebfch0.pdf

Sepsis: Inflammation Is a Necessary Evil.

Introduction: Sepsis is thought to be an abnormal inflammatory response to infection. However, most clinical trials of drugs that modulate the inflammatory response of sepsis have been unsuccessful. Emerging genomic evidence shows that the host response in sepsis does not conform to a simple hyper-inflammatory/hypo-inflammatory model. We, therefore, synthesized current genomic studies that examined the host response of circulating leukocytes to human sepsis. Methods: Electronic searches were performed in Medline and Embase (1987 to October 2010), supplemented by additional searches in multiple microarray data repositories. We included studies that (1) used microarray, (2) were performed in humans and (3) investigated the host response mediated by circulating leukocytes. Results: We identified 12 cohorts consisting of 784 individuals providing genome-wide expression data in early and late sepsis. Sepsis elicited an immediate activation of pathogen recognition receptors, accompanied by an increase in the activities of signal transduction cascades. These changes were consistent across most cohorts. However, changes in inflammation related genes were highly variable. Established inflammatory markers, such as tumour necrosis factor-a (TNF-a), interleukin (IL)-1 or interleukin-10, did not show any consistent pattern in their gene-expression across cohorts. The finding remains the same even after the cohorts were stratified by timing (early vs. late sepsis), patient groups (paediatric vs. adult patients) or settings (clinical sepsis vs. endotoxemia model). Neither a distinctive pro/anti-inflammatory phase nor a clear transition from a pro-inflammatory to antiinflammatory phase could be observed during sepsis. Conclusions: Sepsis related inflammatory changes are highly variable on a transcriptional level. We did not find strong genomic evidence that supports the classic two phase model of sepsis.

/pdf/genome-wide-transcription-profiling-of-human-sepsis-a-21txoi56fq.pdf

Genome-wide transcription profiling of human sepsis: a systematic review

Layer-by-Layer (LbL) stepwise self-assembly of the polyelectrolytes poly(allylamine hydrochloride) and poly(styrenesulfonate) was used to create a macromolecular nanoshell around drug nanoparticles (approximately 150 nm in diameter). Dexamethasone, a steroid often used in conjugation with chemotherapy, was chosen as a model drug and was formulated into nanoparticles using a modified solvent-evaporation emulsification method. Measurement of the zeta potential (zeta-potential) after each polyelectrolyte layer was electrostatically added confirmed the successful addition of each layer. Additionally, data acquired from X-ray photon spectroscopy (XPS) indicated the presence of peaks representative of each physisorbed polyelectrolyte layer. Surface modification of the nanoshell was performed by covalently attaching poly(ethylene glycol) (PEG) with a molecular weight of 2000 to the outer surface of the nanoshell. Zeta potential measurements and XPS indicated the presence of PEG chains at the surface of the nanoshell. The polymeric nanoshell on the surface of the drug nanoparticle provides a template upon which surface modifications can be made to create a stealth or targeted drug delivery system.

/pdf/encapsulation-of-drug-nanoparticles-in-self-assembled-555s9rz2ai.pdf

Encapsulation of drug nanoparticles in self-assembled macromolecular nanoshells.

In vitro exposure of liver cells to high concentrations of free fatty acids (FFA) results in fat overload which promotes inflammatory and fibrogenic response similar to those observed in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). Since the mechanisms of this event have not been fully characterized, we aimed to analyze the fibrogenic stimuli in a new in vitro model of NASH. HuH7 cells were cultured for 24 h in an enriched medium containing bovine serum albumin and increasing concentrations of palmitic and oleic acid at a molar ratio of 1:2 (palmitic and oleic acid, respectively). Cytotoxic effect, apoptosis, oxidative stress, and production of inflammatory and fibrogenic cytokines were measured. FFA induces a significant increment in the intracellular content of lipid droplets. The gene expression of interleukin-6, interleukin-8 and tumor necrosis factor alpha was significantly increased. The protein level of interleukin-8 was also increased. Intracellular lipid accumulation was associated to a significant up-regulation in the gene expression of transforming growth factor beta 1, alpha 2 macroglobulin, vascular endothelial growth factor A, connective tissue growth factor, insulin-like growth factor 2, thrombospondin 1. Flow cytometry analysis demonstrated a significant increment of early apoptosis and production of reactive oxygen species. The exposure of hepatocytes to fatty acids elicits inflammation, increase of oxidative stress, apoptosis and production of fibrogenic cytokines. These data support a primary role of FFA in the pathogenesis of NAFLD and NASH.

/pdf/effect-of-intracellular-lipid-accumulation-in-a-new-model-of-osk2fy5j0u.pdf

Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease

Administration of endotoxin (LPS) in humans results in profound physiological responses, including activation of peripheral blood mononuclear cells and the release of inflammatory factors. The time course of the response of selected inflammatory proteins was examined in healthy subjects (n = 6) administered a single intravenous dose of the purified derivative of endotoxin (3.0 ng/kg). Microarray analysis demonstrated changes in the expression of a number of genes, which were confirmed in separate in vitro endotoxin stimulation experiments. Subsequent TaqMan analysis of genes of interest indicated time-dependent changes in the expression of many of these genes. This included pre-B cell enhancing factor, which was identified on microarray analysis as being markedly upregulated following endotoxin stimulation. Protein expression of the genes examined by TaqMan analysis was measured and demonstrated the appearance of tumor necrosis factor (TNF)-α and sTNF-R proteins in the plasma beginning within 1 h after do...

Correlation of protein and gene expression profiles of inflammatory proteins after endotoxin challenge in human subjects.

Get practical!: Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins edited by Andreas D. Baxevanis and B. F. Francis Ouellette

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Correlation of protein and gene expression profiles of inflammatory proteins after endotoxin challenge in human subjects.

Get practical!: Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins edited by Andreas D. Baxevanis and B. F. Francis Ouellette