Lipoxygenase pathway in islet endocrine cells. Oxidative metabolism of arachidonic acid promotes insulin release

Metabolism of arachidonic acid (AA) via the cyclooxygenase pathway reduces glucose-stimulated insulin release. However, metabolism of AA by the lipoxygenase pathway and the consequent effects on insulin secretion have not been simultaneously assessed in the endocrine islet. Both dispersed endocrine cell-enriched pancreatic cells of the neonatal rat, as well as intact islets of the adult rat, metabolized [(3)H]AA not only to cyclooxygenase products (prostaglandins E(2), F(2alpha), and prostacyclin) but also to the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE). 12-HETE was identified by coelution with authentic tritiated or unlabeled 12-HETE using four high performance liquid chromatographic systems under eight mobile-phase conditions and its identity was confirmed by gas chromatography/mass spectrometry using selected ion monitoring. The predominant effect of exogenous AA (5 mug/ml) was to stimulate insulin release from pancreatic cells grown in monolayer. This effect was concentration- and time-dependent, and reversible. The effect of AA upon insulin release was potentiated by a cyclooxygenase inhibitor (indomethacin) and was prevented by either of two lipoxygenase inhibitors (5,8,11,14-eicosatetraynoic acid [ETYA] and BW755c). In addition, glucose, as well as two structurally dissimilar agents (the calcium ionophore A23187 and bradykinin), which activate phospholipase(s) and thereby release endogenous AA in several cell systems, also stimulated insulin secretion. The effects of glucose, glucagon, bradykinin and high concentrations of A23187 (5 mug/ml) to augment insulin release were blocked or considerably reduced by lipoxygenase inhibitors. However, a lower concentration of the ionophore (0.25 mug/ml), which did not appear to activate phospholipase, was resistant to blockade. Exogenous 12-HETE (up to 2,000 ng/ml) did not alter glucose-induced insulin release. However, the labile intermediate 12-hydroperoxy-ETE increased insulin release. Furthermore, diethylmaleate (which binds intracellular glutathione and thereby impedes conversion of the lipoxygenase intermediates hydroperoxy-ETE and leukotriene A(4) to HETE and leukotriene C(4), respectively) potentiated the effect of glucose and of exogenous AA. Finally, 5,6-epoxy, 8,11,14-eicosatrienoic acid (a relatively stable epoxide analogue of leukotriene A(4)) as well as two other epoxy-analogues, potentiated glucose-induced insulin release. We conclude that dual pathways of AA metabolism exist in islet endocrine cells and have opposing regulatory effects on the beta cell-an inhibitory cyclooxygenase cascade and a stimulatory lipoxygenase cascade. Labile products of the latter pathway may play a pivotal role in stimulus-secretion coupling in the islet.     

Role for macrophage migration inhibitory factor in acute respiratory distress syndrome

The critical role of macrophage migration inhibitory factor (MIF) in mediating inflammatory lung injury in acute respiratory distress syndrome (ARDS) has been raised recently. The present study has identified enhanced MIF protein expression in alveolar capillary endothelium and infiltrating macrophages in lung tissues from ARDS patients. The possibility that MIF up-regulates its synthesis in an autocrine fashion in ARDS was tested using cultured endothelial cells stimulated with MIF and a murine model of lipopolysaccharide (LPS)-induced acute lung injury. MIF induced significant MIF and tumour necrosis factor (TNF)-alpha synthesis in cultured endothelial cells and the effect was blocked by neutralizing anti-MIF antibody. A similar blocking effect was observed when MIF-stimulated endothelial cells were pretreated with neutralizing anti-TNF-alpha antibody or glucocorticoid, supporting the notion that MIF induced TNF-alpha production via an amplifying pro-inflammatory loop. Treatment with anti-MIF or glucocorticoid effectively attenuated pulmonary pathology and the synthesis of MIF or TNF-alpha in mice with LPS-induced acute lung injury. Mildly augmented expression of aquaporin 1 (AQP1) was also detected in alveolar capillary endothelium in ARDS. In vitro studies revealed that both MIF and TNF-alpha induced a small increase of AQP1 synthesis in cultured endothelial cells. These findings suggest that MIF plays a crucial pathological role leading to alveolar inflammation in ARDS. Anti-MIF and early glucocorticoid therapy may represent a novel therapeutic approach for reducing alveolar inflammation in ARDS.     

Microencapsulated Genetically Engineered Lactobacillus plantarum 80 (pCBH1) for Bile Acid Deconjugation and Its Implication in Lowering Cholesterol

Cholesterol is known to be a major risk factor for coronary heartdisease (CHD). Current treatments for elevated blood cholesterolinclude dietary management, regular exercise, and drug therapywith fibrates, bile acid sequestrants, and statins. Suchtherapies, however, are often suboptimal and carry a risk forserious side effects. This study shows that microencapsulatedLactobacillus plantarum 80 (pCBH1) cells can efficientlybreak down and remove bile acids, and establishes a basis fortheir use in lowering blood serum cholesterol. Results show thatmicroencapsulated LP80 (pCBH1) is able to effectively break downthe conjugated bile acids glycodeoxycholic acid (GDCA) andtaurodeoxycholic acid (TDCA) with bile salt hydrolase (BSH)activities of 0.19 and 0.08μmol DCA/mg CDW/hrespectively. This article also summarizes the physiologicalinterrelationship between bile acids and cholesterol and predictsthe oral doses of microencapsulated Lactobacillusplantarum 80 (pCBH1) cells required for lowering cholesterol.     

Gender differences in adolescent depression: do symptoms differ for boys and girls?

BACKGROUND: Limited prior research suggests that depressed women are more likely to experience certain symptoms of depression than are depressed men. The purpose of this study was to examine whether such gender differences in depressive symptoms are present during adolescence. METHODS: The Childhood Version of the Schedule for Affective Disorders and Schizophrenia and the Beck Depression Inventory were administered to adolescents presenting for evaluation at an outpatient clinic (n=383; ages 11.9 to 20.0). RESULTS: Depressed girls and boys had similar symptom prevalence and severity ratings for most depressive symptoms. However, depressed girls had more guilt, body image dissatisfaction, self-blame, self-disappointment, feelings of failure, concentration problems, difficulty working, sadness/depressed mood, sleep problems, fatigue, and health worries than depressed boys on some comparisons. In contrast, depressed boys had higher clinician ratings of anhedonia, depressed morning mood, and morning fatigue. LIMITATIONS: Longitudinal research is needed to test whether such relatively gender-specific symptoms play different roles in the onset, maintenance, or remittance of depression for boys and girls. CONCLUSIONS: These findings indicate that, in general, the experience of depression is highly similar for adolescent girls and boys. However, some gender differences previously found among depressed adults appear to be present by adolescence, possibly suggesting somewhat distinct etiologies for depression among males and females.     

Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway

Dysfunctional endothelial cell activation and cytokines are implicated in preterm labor, a condition commonly treated with the tocolytic agent, magnesium sulfate (MgSO(4)). Based on recent findings showing the inflammatory effects of magnesium deficiency, we examined the effect of MgSO(4) on human umbilical vein endothelial cell (HuVEC) inflammatory responses in vitro. HuVECs isolated from term umbilical cords were incubated with MgSO(4) prior to stimulation with lipopolysaccharide (LPS) and then assessed for endothelial cell activation. Endothelial cell supernatants were assayed for inflammatory mediator production (interleukin-8; IL-8), and endothelial cell-associated intercellular adhesion molecule (ICAM-1) expression was determined. In the absence of LPS stimulation, MgSO(4) had no effect on HuVEC responses. Treatment of HuVECs with MgSO(4) prior to LPS stimulation inhibited inflammatory mediator production (p<0.05) and cell adhesion molecule expression (p<0.05) in a dose-dependent manner. Mechanistic studies showed that MgSO(4) reduced NFkappaB nuclear translocation and protected cytoplasmic IkappaBalpha from degradation in LPS-treated HuVECs. In conclusion, MgSO(4) inhibits endothelial cell activation, as measured by levels of IL-8 and ICAM-1 expression, via NFkappaB. Our results support the hypothesis that MgSO(4) treatment may function as an anti-inflammatory agent during preterm labor.     

Amino acid catabolism: a pivotal regulator of innate and adaptive immunity

Enhanced amino acid catabolism is a common response to inflammation, but the immunologic significance of altered amino acid consumption remains unclear. The finding that tryptophan catabolism helped maintain fetal tolerance during pregnancy provided novel insights into the significance of amino acid metabolism in controlling immunity. Recent advances in identifying molecular pathways that enhance amino acid catabolism and downstream mechanisms that affect immune cells in response to inflammatory cues support the notion that amino acid catabolism regulates innate and adaptive immune cells in pathologic settings. Cells expressing enzymes that degrade amino acids modulate antigen-presenting cell and lymphocyte functions and reveal critical roles for amino acid- and catabolite-sensing pathways in controlling gene expression, functions, and survival of immune cells. Basal amino acid catabolism may contribute to immune homeostasis that prevents autoimmunity, whereas elevated amino acid catalytic activity may reinforce immune suppression to promote tumorigenesis and persistence of some pathogens that cause chronic infections. For these reasons, there is considerable interest in generating novel drugs that inhibit or induce amino acid consumption and target downstream molecular pathways that control immunity. In this review, we summarize recent developments and highlight novel concepts and key outstanding questions in this active research field.     

The effect of age on knowledge of HIV/AIDS and risk related behaviours among army personnel

Background

HIV/AIDS has been described as the fourth largest cause of death globally and leading cause of death in Africa^. HIV/AIDS has been a devastating inferno for nearly 30 years, and has particularly impacted countries in sub-Saharan Africa^. In most African countries, it has been reported that the HIV infection amongst the military has been shown to be about 2 to 5 times higher than their civilian counterparts.

Objective

To address the knowledge level of HIV/AIDS and risk-related behaviours in military personnel, a well-described high risk groups for HIV/AIDS.

Methods

A cross-sectional study among army personnel in 82 Division Nigerian Army Headquarters Enugu, which has a population of about 1777. A random sampling in all the departments of 82 Division Nigerian Army Headquarters was done using the ballot method to select the respondents. Approval for the study was obtained from the General Officer in Command (GOC) of the 82 Division Nigerian Army Headquarters Enugu.

Results

There were no significant differences between the risk related behavior variables when comparisons were made between those under 30 years, and those 30 years and above. Furthermore, more respondents under 30 years (48.0%) did not seek medical treatment when infected with another STI before having sex again as against 45% of those above 30 years. Most of the respondents (9.1%) under the age of 30 years believed that HIV/AIDS could be contracted through mosquito bites as against 2.8% of those above 30 years.

Conclusion

The knowledge level of HIV/AIDS among the army personnel was high, though misconceptions about transmission modes like getting HIV through the bites of mosquitoes and casual body contacts were noted, especially among those under 30 years of age.