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81.
Nico A. Jansen Carlos Perez Maarten Schenke Anouk W. van Beurden Anisa Dehghani Rob A. Voskuyl Roland D. Thijs Ghanim Ullah Arn M.J.M. van den Maagdenberg Else A. Tolner 《The Journal of neuroscience》2021,41(3):524
Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of NaV1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting NaV1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS. 相似文献
82.
Paresh Dandona MBBS Sandeep Dhindsa MBBS Husam Ghanim PhD Farid Saad PhD 《Diabetes, obesity & metabolism》2021,23(1):18-28
The role of testosterone in improving sexual symptoms in men with hypogonadism is well known. However, recent studies indicate that testosterone plays an important role in several metabolic functions in males. Multiple PubMed searches were conducted with the use of the terms testosterone, insulin sensitivity, obesity, type 2 diabetes, anaemia, bone density, osteoporosis, fat mass, lean mass and body composition. This narrative review is focused on detailing the mechanisms that underlie the metabolic aspects of testosterone therapy in humans. Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor β subunit, insulin receptor substrate-1, protein kinase B and glucose transporter type 4 in adipose tissue and adenosine 5′-monophosphate-activated protein kinase expression and activity in skeletal muscle. Observational studies show that long-term therapy with testosterone prevents progression from prediabetes to diabetes and improves HbA1c. Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor-2 and decreases expression of the muscle growth suppressors, myostatin and myogenic regulatory factor 4. Testosterone increases haematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on bone. In conclusion, testosterone exerts a series of potent metabolic effects, which include insulin sensitization, maintenance and growth of the skeletal muscle, suppression of adipose tissue growth and maintenance of erythropoiesis and haematocrit. 相似文献
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Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects 总被引:4,自引:0,他引:4
Aims/hypothesis Obesity is associated with insulin resistance and inflammation. The circulating human mononuclear cell (MNC) has been shown
to respond to low-dose insulin infusion. We have now investigated whether in obesity: (1) phosphorylated insulin receptor
beta subunit (p-INSR-β) is reduced in the MNC; (2) pro-inflammatory mediators including inhibitor of kappa light polypeptide
gene enhancer in B cells-kinase beta (IKBKB), suppressor of cytokine signalling-3 (SOCS) and protein kinase C-beta 2 (PRKCB2)
are increased and related to p-INSR-β; and (3) the reduction in MNC p-INSR-β is related to the reduction in insulin sensitivity.
Materials and methods MNCs were prepared from fasting blood samples of 16 normal weight and 16 obese female subjects.
Results Our data show that p-INSR-β is reduced significantly in MNCs from obese subjects compared with that of normal controls. MNCs
from obese subjects have higher IKBKB expression, increased nuclear factor kappa B (NFκB) binding and higher mRNA expression
of TNFAIP1 and IL6 genes. NFκB binding, TNFAIP1 mRNA and plasma C-reactive protein are inversely related to p-INSR-β. PRKCB2 mRNA and protein expression were significantly higher in the obese subjects and were related significantly to pro-inflammatory
mediators but not to p-INSR-β. SOCS3 mRNA expression was markedly elevated and positively related to pro-inflammatory mediators including IKBKB and PRKCB2 on
the one hand and inversely related to p-INSR-β on the other.
Conclusions/interpretation We conclude that in obesity the MNC is characterised by reduced p-INSR-β and increased inflammatory mediators including IKBKB,
PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-β and might mediate the inhibition of p-INSR-β. These data elucidate
the relationship between inflammation and insulin resistance using the MNC as a model.
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users. 相似文献
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Dandona P Mohanty P Ghanim H Aljada A Browne R Hamouda W Prabhala A Afzal A Garg R 《The Journal of clinical endocrinology and metabolism》2001,86(1):355-362
Increased reactive oxygen species generation by the leukocytes of the obese may be responsible for increased oxidative injury to lipids and proteins and, hence, atherosclerosis. We have investigated whether reactive oxygen species generation by leukocytes and other indexes of oxidative damage in the body fall with short-term dietary restriction and weight loss. Nine nondiabetic obese subjects (body mass index, 32.5-64.4 kg/m(2)), not taking any antioxidants, were put on a 1000-Cal diet. Fasting blood samples were taken at 0, 1, 2, 3, and 4 weeks and at 12 weeks after the cessation of dietary restriction. Blood samples were also obtained at 1 and 2 h after administration of 75 g oral glucose at 0 and 4 weeks. Mononuclear cells (MNC) and polymorphonuclear leukocytes (PMN) were isolated, and reactive oxygen species generation was measured. Plasma concentrations of thiobarbituric acid-reactive species (TBARS), 13-hydroxyoctadecadienoic acid (13-HODE), 9-hydroxyoctadecadienoic acid (9-HODE), carbonylated proteins, o-tyrosine, and m-tyrosine as indexes of oxidative damage to lipids, proteins and amino acids, respectively, were measured. Antioxidant vitamins were measured as indexes of antioxidant reserves. Plasma tumor necrosis factor-alpha concentrations were also measured. Mean weight loss was 2.4 +/- 0.6 kg at week 1, 2.5 +/- 1.7 kg at week 2, 3.9 +/- 0.8 kg at week 3, and 4.5 +/- 2.8 kg at week 4 (P < 0.05). Reactive oxygen species generation by PMN fell from 236.4 +/- 95.8 to 150.9 +/- 69.0, 125.9 +/- 24.3, 96.0 +/- 39.9, and 103.1 +/- 35.7 mV at weeks 1, 2, 3, and 4, respectively (P < 0.001). It increased 3 months after the cessation of dietary restriction to 270.0 +/- 274.3 mV. Reactive oxygen species generation by MNC fell from 187.8 +/- 75.0 to 101.7 +/- 64.5, 86.9 +/- 42.8, 63.8 +/- 14.3, and 75.1 +/- 32.2 mV and increased thereafter to 302.0 +/- 175.5 mV at 1, 2, 3, 4, and 16 weeks, respectively (P < 0.005). Reactive oxygen species generation by PMN and MNC increased in response to glucose; the relative increase was greater at 4 weeks than that at week 0 due to a fall in the basal levels of reactive oxygen species generation. Consistent with the fall in reactive oxygen species generation, there was a reduction in plasma TBARS from 1.68 +/- 0.17 micromol/L at week 0 to 1.47 micromol/L at 4 weeks (P < 0.05). The 13-HODE to linoleic acid ratio fell from a baseline of 100% to 56.4 +/- 36.1% at 4 weeks (P < 0.05), and the 9-HODE to linoleic acid ratio fell from a baseline of 100% to 60.5 +/- 37.7% at 4 weeks (P < 0.05). Carbonylated proteins fell from 1.39 +/- 0.27 microgram/mg protein at week 0 to 1.17 +/- 0.12 microgram/mg protein at week 4 (P < 0.05); o-tyrosine fell from 0.42 +/- 0.03 mmol/mol phenylalanine at week 0 to 0.36 +/- 0.02 mmol/mol phenylalanine at 4 weeks (P < 0.005), and m-tyrosine fell from 0.45 +/- 0.04 mmol/mol phenylalanine at week 0 to 0.40 +/- 0.03 mmol/mol phenylalanine at 4 weeks (P < 0.05). The basal concentrations of TBARS, 9-HODE, 13-HODE, carbonylated proteins, o-tyrosine, and m-tyrosine in the obese were significantly greater than those in normal subjects. On the other hand, tumor necrosis factor-alpha concentrations did not change during this 4-week period, nor was there any change in antioxidant vitamins. This is the first demonstration of 1) an increase in reactive oxygen species-induced damage in lipids, proteins, and amino acids in the obese compared with normal subjects; and 2) a decrease in reactive oxygen species generation by leukocytes and oxidative damage to lipids, proteins, and amino acids after dietary restriction and weight loss in the obese over a short period. 相似文献
89.
Because troglitazone has been shown to have antioxidant properties, we investigated whether troglitazone administration to obese subjects causes a reduction in (1) reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs) and mononuclear cells (MNCs) and (2) lipid peroxidation as reflected in the plasma concentrations of 9-hydroxyoctadecadienoic acid (9-HODE) and 13-hydroxyoctadecadienoic acid (13-HODE). Seven obese subjects were given 400 mg/d troglitazone for 4 weeks. Blood samples were obtained before troglitazone administration and at weekly intervals thereafter. Insulin concentrations fell significantly at week 1 and remained low at weeks 2 and 4 (P:<0.001). ROS generation by PMNLs fell to 77.6+/-25.1% of the basal at week 1 and 47.9+/-41.1% at week 4 (P:<0.001). ROS generation by MNCs fell to 59.8+/-15.7% of the basal at week 1 and 35.1+/-17.6% at week 4 (P:<0.001). 9-HODE and 13-HODE concentrations fell significantly from 787.4+/-52.4 and 713. 1+/-44.7 pg/mL to 720.4+/-66.7 (P:<0.004) and 675.2+/-65.0 pg/mL (P:<0.01) after 4 weeks, respectively. Postischemic dilatation of the brachial artery was measured by ultrasonography. The mean percent dilatation after forearm ischemia before and after troglitazone was 5.5+/-3.01% and 8.75+/-3.37% (P:<0.02), respectively. The percent increase in diameter after nitroglycerin was 17.08+/-1.18% before troglitazone, whereas it was 18.9+/-1.91% (P:<0.02) after troglitazone. We conclude that troglitazone has a potent and rapid biological inhibitory effect on ROS generation by PMNLs and MNCs and that it inhibits lipid peroxidation significantly. These changes are associated with a significant improvement in postischemic flow-mediated vasodilation in the brachial artery over a relatively short period of 4 weeks. 相似文献
90.
Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide 总被引:21,自引:0,他引:21
Aljada A Saadeh R Assian E Ghanim H Dandona P 《The Journal of clinical endocrinology and metabolism》2000,85(7):2572-2575
Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelial and other cell types and participates in inflammation and atherosclerosis. It serves as a ligand for leukocyte function-associated antigen-1 on leukocytes and is partially responsible for the adhesion of lymphocytes, granulocytes, and monocytes to cytokine-stimulated endothelial cells and the subsequent transendothelial migration. Its expression on endothelial cells is increased in inflammation and atherosclerosis. As it has been suggested that insulin and hyperinsulinemia may have a role in atherogenesis, we have now investigated whether insulin has an effect on the expression of ICAM-1 on human aortic endothelial cells (HAEC). HAEC were prepared from human aortas by collagenase digestion and were grown in culture. Insulin (100 and 1000 microU/mL) caused a decrease in the expression of ICAM-1 (messenger ribonucleic acid and protein) by these cells in a dose-dependent manner after incubation for 2 days. This decrease was associated with a concomitant increase in endothelial nitric oxide synthase (NOS) expression also induced by insulin. To examine whether the insulin-induced inhibition of ICAM-1 was mediated by nitric oxide (NO) from increased endothelial NOS, HAEC were treated with N(omega)-nitro-L-arginine, a NOS inhibitor. N(omega)-Nitro-L-arginine inhibited the insulin-induced decrease in ICAM-1 expression in HAEC at the messenger ribonucleic acid and protein levels. Thus, the inhibitory effect of insulin on ICAM-1 expression is mediated by NO. We conclude that insulin reduces the expression of the proinflammatory adhesion molecule ICAM-1 through an increase in the expression of NOS and NO generation and that insulin may have a potential antiinflammatory and antiatherosclerotic effect rather than a proatherosclerotic effect. 相似文献