NADPH Oxidase-Dependent Production of Reactive Oxygen Species Induces Endoplasmatic Reticulum Stress in Neutrophil-Like HL60 Cells

Reactive oxygen species (ROS) primarily produced via NADPH oxidase play an important role for killing microorganisms in neutrophils. In this study we examined if ROS production in Human promyelocytic leukemia cells (HL60) differentiated into neutrophil-like cells (dHL60) induces ER stress and activates the unfolded protein response (UPR). To cause ROS production cells were treated with PMA or by chronic hyperglycemia. Chronic hyperglycemia failed to induce ROS production and did not cause activation of the UPR in dHL60 cells. PMA, a pharmacologic NADPH oxidase activator, induced ER stress in dHL60 cells as monitored by IRE-1 and PERK pathway activation, and this was independent of calcium signaling. The NADPH oxidase inhibitor, DPI, abolished both ROS production and UPR activation. These results show that ROS produced by NADPH oxidase induces ER stress and suggests a close association between the redox state of the cell and the activation of the UPR in neutrophil-like HL60 cells.     

Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain

Background  

Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3) in both carrageenan- and complete Freund's adjuvant (CFA)-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation.     

Protein structure similarity from principle component correlation analysis

Background  

Owing to rapid expansion of protein structure databases in recent years, methods of structure comparison are becoming increasingly effective and important in revealing novel information on functional properties of proteins and their roles in the grand scheme of evolutionary biology. Currently, the structural similarity between two proteins is measured by the root-mean-square-deviation (RMSD) in their best-superimposed atomic coordinates. RMSD is the golden rule of measuring structural similarity when the structures are nearly identical; it, however, fails to detect the higher order topological similarities in proteins evolved into different shapes. We propose new algorithms for extracting geometrical invariants of proteins that can be effectively used to identify homologous protein structures or topologies in order to quantify both close and remote structural similarities.     

Neutrophil fatty acid composition: effect of a single session of exercise and glutamine supplementation

The fatty acid composition of immune cells appears to contribute to variations of cell function. The independent and combined effects of a single session of exercise (SSE) and glutamine supplementation (GS) on neutrophil fatty acid composition were investigated. Compared to control (no treatment given--i.e. neither SSE or GS), single session of exercise decreased myristic, palmitic and eicosapentaenoic (EPA) acids, and increased lauric, oleic, linoleic, arachidonic (AA) and docosahexaenoic (DHA) acids whereas glutamine supplementation combined with SSE (GS+SSE) increased oleic acid. Polyunsaturated/saturated fatty acid ratio and Unsaturation index were higher in neutrophils from the SSE and GS groups as compared with control. These findings support the proposition that SSE and GS may modulate neutrophil function through alterations in fatty acid composition.     

Conditional random pattern model for copy number aberration detection

Background  

DNA copy number aberration (CNA) is very important in the pathogenesis of tumors and other diseases. For example, CNAs may result in suppression of anti-oncogenes and activation of oncogenes, which would cause certain types of cancers. High density single nucleotide polymorphism (SNP) array data is widely used for the CNA detection. However, it is nontrivial to detect the CNA automatically because the signals obtained from high density SNP arrays often have low signal-to-noise ratio (SNR), which might be caused by whole genome amplification, mixtures of normal and tumor cells, experimental noise or other technical limitations. With the reduction in SNR, many false CNA regions are often detected and the true CNA regions are missed. Thus, more sophisticated statistical models are needed to make the CNAs detection, using the low SNR signals, more robust and reliable.     

Semi-supervised drug-protein interaction prediction from heterogeneous biological spaces

Background

Predicting drug-protein interactions from heterogeneous biological data sources is a key step for in silico drug discovery. The difficulty of this prediction task lies in the rarity of known drug-protein interactions and myriad unknown interactions to be predicted. To meet this challenge, a manifold regularization semi-supervised learning method is presented to tackle this issue by using labeled and unlabeled information which often generates better results than using the labeled data alone. Furthermore, our semi-supervised learning method integrates known drug-protein interaction network information as well as chemical structure and genomic sequence data.

Results

Using the proposed method, we predicted certain drug-protein interactions on the enzyme, ion channel, GPCRs, and nuclear receptor data sets. Some of them are confirmed by the latest publicly available drug targets databases such as KEGG.

Conclusions

We report encouraging results of using our method for drug-protein interaction network reconstruction which may shed light on the molecular interaction inference and new uses of marketed drugs.

     

Effect of indole-3-acetic acid administration by gavage and by subcutaneous injection on rat leukocytes

This study was done to investigate the effect of indole-3-acetic acid (IAA) administered subcutaneously and by gavage on neutrophil function and cytotoxicity in neutrophils and lymphocytes. A gavage administration resulted in an increase in phagocytic capacity in neutrophils in a dose depended manner for 1 mg, 2 mg, 18 mg, and 40 mg of IAA per kg of body mass, respectively, compared with the control. Similarly, subcutaneous administration of IAA at 2, 18, and 40 mg per kg of body mass promoted a significant rise in phagocytosis by neutrophils. H2O2 production in neutrophils from treated rats by gavage was similar to those receiving subcutaneous IAA treatment, and did not show a significant difference between treatments and control. IAA treatment, whether by gavage or subcutaneous, did not produce an alteration in antioxidant enzyme activities or in glucose-6-phosphate dehydrogenase activity of either neutrophils or lymph nodes. Subcutaneous IAA administration did not alter the neutrophil and lymphocyte death as deduced by unaltered membrane integrity, DNA fragmentation and mitochondrial transmembrane potential, compared with controls. In conclusion, IAA administration either subcutaneously or by gavage could increase the phagocytic capacity by neutrophils and this acid administration did not have prooxidant effects or cytotoxic effects on neutrophils and lymphocytes.     

Effect of lipid infusion on metabolism and force of rat skeletal muscles during intense contractions.

The hypothesis that during intense muscle contraction induced by electrical stimulation, long chain fatty acids (LCFA) might reduce mitochondrial ATP/ADP ratio, raising the contribution of glycolysis for ATP production was examined. The effect of a lipid infusion (Lipovenus emulsion) on UCP-3 mRNA level, lactate, glucose-6-phosphate (G-6P) and glycogen content was investigated in rat. Blood samples for determination of free fatty acids and lactate were collected at 0, 30 and 60 min during rest and at 0, 10 and 20 min during muscle contraction. The content of lactate, glycogen and G-6P was also determined in soleus (SO), red gastrocnemius (RG) and white gastrocnemius (WG) muscles collected immediately after muscle contraction period. In addition, the force level was determined during muscle contractions. The effect of Lipovenus emulsion on respiration of mitochondria isolated from rat skeletal muscle, and content of UCP-3 and lactate in cultured skeletal muscle cells was also determined. The in vivo experiments showed that Lipovenus induced a significant increase of UCP-3 mRNA levels. After Lipovenus infusion, lactate level was increased in RG muscle only, whereas the contents of glycogen and G-6P were decreased in both RG and WG muscles (P < 0.05). Lipovenus infusion failed to exert any effect on muscle force performance (P > 0.05). The in vitro experiments showed that Lipovenus infusion induced a significant increase in mitochondrial respiration, but had no effect on UCP-3 content. Lactate concentration was significantly increased in the culture medium of stimulated cells in the control and Lipovenus groups compared with the respective not-stimulated cells (P< 0.05). We concluded that as mitochondrial function becomes limited by the FFA-uncoupling effect, the ATP demand is mainly supplied by anaerobic glucose metabolism preventing an expected decrease in muscle contraction performance.