This study describes the effect of novel 6-Arylbenzimidazo[1,2-c]quinazoline derivatives as tumor necrosis factor alpha (TNF-α) production inhibitors.The newly synthesized compounds were tested for their in vitro ability to inhibit the lipolysaccharide (LPS) induced TNF-α secretion in the human promyelocytic cell line HL-60.The compound 6-Phenyl-benzimidazo[1,2-c]quinazoline, coded as G1, resulted as the most potent inhibitor and with no significant cytotoxic activity.Thus, 6-Arylbenzimidazo[1,2-c]quinazoline derivatives may have a potential as anti-inflammatory agents.
Introduction: Endothelial Lipase (EL), enzyme that modulates HDL metabolism, is overregulated by inflammatory-cytokines. Type 2 Diabetes (DM2) has been associated with a subclinical inflammation, so it has been ruled that these patients could have high levels of EL. The objectives of the research are to determine the effect of glucose in the expression of EL in culturing cells and evaluate the relation between the levels of EL and the metabolic control in patients with DM2. Method: During 24 hours, human endothelial cells (HUVEC) were stimulated with different concentrations of glucose (5.5, 25 and 50 mmol/L), the effect was evaluated over the expression of EL. In DM2 patients levels of EL, glucose and HbA1c were measured. We had a control group (8) to determine the levels of enzyme. EL was measured by immune transference, and the results were expressed by arbitrary units(AU). Results: In HUVEC cells, the expression of EL was directly proportional extracellular glucose (p < 0.05). 24 diabetic patients were evaluated (15 females and 9 males) average age from 60 ± 9,7 years old. The studied group showed levels of EL bigger than the control group (14911AU and 10250, 18AU) respectively (p < 0.05). We found no relation between glucose, HbA1c and EL. Conclusion: In HUVEC cells there is a direct relation between extracell glucose and EL. The diabetic patients had higher levels of EL than the control group, but these was not related with glucose or HbA1c, these shows the existence of other factors that participate in the increasement of EL.
Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study, we evaluated the chronic effects of TNFα, IL-6, and IL-1β on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNFα treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ΔΨ m , increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1β decreased maximal respiratory capacity, they had no effect on ΔΨ m and varied effects on ATP turnover, proton leak, or basal respiration. Only TNFα treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis, including PGC-1α and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNFα exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology.
Direct and indirect evidence emphasizes the participation of classical protein kinase C (cPKC) in the development and function of the mammary gland. This work shows that there are changes not only in total cPKC activity during the lactogenic cycle, but also in the relative amounts of the soluble and particulate cPKC activities and that the time-course of these two events are not the same. The time-course of translocation from the cytoplasm to the plasma membrane suggests that the soluble and particulate forms of the enzyme may be associated with growth and differentiation of the tissue, respectively. Phosphorylation patterns also show characteristic and significant differences throughout the development of the gland. These results suggest that both total mammary cPKC activity and its subcellular forms change in accordance with the proliferative and differentiative stages of the mammary gland, and that the enzyme translocation occurs during the transition from pregnancy to lactation.
GDM, characterized by an alteration of glucose regulation which is first detected during pregnancy, is associated with elevated blood glucose, insulin resistance, pro‐inflammatory agents, and increased nitric oxide (NO) synthesis. Our purpose was to assess supplementation of mothers with GDM with 600 mg/day DHA (randomized to receive DHA or placebo, corn oil) (week 24 of pregnancy‐delivery, GDM mothers, n=31). Blood samples were collected at weeks 24 and 36 in pregnancy. At delivery, blood from the mother and umbilical cord were collected to assess transfer of DHA from mother to fetus and placental tissue for NO synthesis. DHA supplementation significantly increased maternal red blood cell (RBC) DHA concentration but not fetal RBC DHA. Supplementation reduced fasting glucose in GDM compared to controls and insulin resistance tended to decrease substantially more in supplemented mothers than controls. Inflammatory markers were not different between the groups, likely explained on the basis of small sample size. Placental endothelial cells from controls had increased L‐arginine utilization and elevated NO synthesis compared to the DHA supplementation group. We hypothesize that DHA decreased expression of L‐arginine transport protein and/or diminished activity of endothelial NO synthase. In conclusion, DHA supplementation of women with GDM demonstrated favorable effects regarding glucose metabolism and the NO synthetic pathway compared to controls, underscoring the importance of this n‐3 long chain fatty acid in pregnancy complicated by diabetes. (Fondo Nacional de Innovacion en Salud de Chile and Nestle)
Insulin resistance is associated with obesity but mechanisms controlling this relationship in humans are not fully understood. Studies in animal models suggest a linkage between adipose reactive oxygen species (ROS) and insulin resistance. ROS oxidize cellular lipids to produce a variety of lipid hydroperoxides that in turn generate reactive lipid aldehydes that covalently modify cellular proteins in a process termed carbonylation. Mammalian cells defend against reactive lipid aldehydes and protein carbonylation by glutathionylation using glutathione-S-transferase A4 (GSTA4) or carbonyl reduction/oxidation via reductases and/or dehydrogenases. Insulin resistance in mice is linked to ROS production and increased level of protein carbonylation, mitochondrial dysfunction, decreased insulin-stimulated glucose transport, and altered adipokine secretion. To assess protein carbonylation and insulin resistance in humans, eight healthy participants underwent subcutaneous fat biopsy from the periumbilical region for protein analysis and frequently sampled intravenous glucose tolerance testing to measure insulin sensitivity. Soluble proteins from adipose tissue were analyzed using two-dimensional gel electrophoresis and the major carbonylated proteins identified as the adipocyte and epithelial fatty acid-binding proteins. The level of protein carbonylation was directly correlated with adiposity and serum free fatty acids (FFAs). These results suggest that in human obesity oxidative stress is linked to protein carbonylation and such events may contribute to the development of insulin resistance.
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