The effect of weight loss on serum concentrations of FAS and tumour necrosis factor alpha in obese women

INTRODUCTION: Apoptosis can influence both adipose tissue mass and its distribution. The suprafamily of tumour necrosis factor (TNF) receptors stimulate apoptosis. The aim of the study was to assess serum concentrations of tumour necrosis factor alpha (TNF-alpha), TNF soluble receptors (sTNFRs) and FAS in obese subjects and to examine the changes in these parameters after weight loss. MATERIAL AND METHODS: The study group consisted of 23 obese women without additional disease aged 36.6 +/- 10.9 years. These were examined before and after three-month weight reduction treatment consisting of a diet of 1000 kcal/day and physical exercise. The control group comprised 17 lean healthy women aged 40.3 +/- 5.5 years. Blood samples were taken in the morning after an overnight fast. Serum concentrations of TNF-alpha, sTNFRs and FAS were measured by enzyme linked immunosorbent assay (ELISA). Serum concentrations of insulin were measured by RIA. Serum concentrations of glucose, total cholesterol, HDL cholesterol and triglycerides were measured by an enzymatic procedure. RESULTS: The mean weight loss over the three-month treatment was 11.4 +/- 3.1 kg. Following weight loss, serum TNF-alpha concentrations decreased significantly (7.3 +/- 3.0 vs. 5.4 +/- 1.6 pg/ml; p < 0.005) and concentrations of sTNFRs increased significantly (1222.6 +/- 211.8 vs. 1325.6 +/- 261.6 pg/ml; p < 0.05 and 1881.5 +/- 337.2 vs. 2057.4 +/- 358.7 pg/ml; p < 0.05 respectively). However, no changes in serum concentrations of FAS were observed after weight loss. CONCLUSION: We observed increased serum concentrations of TNF-alpha but not of FAS in obese women. The concentrations of TNF decreased and those of sTNFRs increased after weight loss. However, the weight reduction therapy did not change serum concentrations of FAS.     

Effects of body weight loss on serum progesterone concentrations of non-lactating dairy cows

The objective was to evaluate serum concentrations of nonesterified fatty acids (NEFA), cortisol, insulin, and progesterone (P4) of dairy cows maintaining or mobilizing body weight (BW). Eleven non-lactating, non-pregnant, and ovariectomized Gir × Holstein cows were stratified by BW and body condition score (BCS), and randomly assigned to: 1) BW loss (six cows; LOSS) and 2) BW maintenance (five cows; MAINT). Treatments were achieved through a grazing schedule using three pastures. From Days −7 to 1 of the study, all cows were maintained in Pasture A (12 kg of dry matter/cow daily). From Days 2 to 30, LOSS cows were maintained in Pasture B (less than 1.0 kg of dry matter/cow daily), whereas MAINT cows were maintained in Pasture C (12 kg of dry matter/cow daily). However, from Days 3 to 30 of the study, cows from both treatments were regrouped daily into Pasture A from 0600 to 1200 h to allow LOSS cows to consume, on average, 4.5 kg/d of forage dry matter. On Day −66 of the study, all cows received an intravaginal drug releasing device containing 1.9 g of P4 (replaced every 14 d and removed on Day 3). Cow BW and BCS were assessed on Day 0 and 30 and blood samples were collected daily from Days 0 to 30 at 0600 and 1200 h. Changes in BW and BCS were greater (P ≤ 0.05) in LOSS cows compared to MAINT cows. Within samples collected at 0600 h, serum NEFA concentrations were often greater (P < 0.05) in LOSS cows compared to MAINT after Day 14. Serum P4 concentrations were greater (P < 0.05) on Days 21 and 22, and tended (P < 0.10) to be greater on Days 16, 23, and 24 of the study in LOSS cows compared to MAINT. In conclusion, BW loss was associated with increased circulating concentrations of P4 in non-lactating ovariectomized dairy cows; this was mainly attributed to fat mobilization and consequent release of P4 stored in adipose tissues.     

Competitive antagonism of nitric oxide synthetase causes weight loss in mice.

These studies demonstrate that the competitive antagonist of nitric oxide synthesis, L-NG-nitro-arginine methyl ester (NO Arg ME), produces an L-arginine reversible decrease in food intake in mice. NO Arg ME also blocked the feeding effect of the potent orexigenic peptide, neuropeptide Y. NO Arg ME produced weight loss when administered over 5 days. The studies suggest that nitric oxide is a physiological modulator of food intake and that nitric oxide synthetase inhibitors may be useful in the management of obesity.     

Dynamics of diurnal changes in serum concentration of TNF-alpha soluble receptors in gastrointestinal cancer patients

The objective of the study was to investigate the dynamic changes in soluble TNFalpha p-55 and p-75 receptors in serum of advanced cancer patients during 24 hours. The group examined consisted of 42 patients suffering from advanced gastrointestinal neoplasms (colorectal, gastric and pancreatic cancer). Serum levels of the cytokine and both receptors in cancer patients were measured using ELISA type kits 6 times a day (8.00 a.m., 2.00 p.m., 6.00 p.m., 10.00 p.m., 2.00 a.m. and again 8.00 a.m.) as well as in healthy controls. The levels of TNFalpha and its soluble receptors were substantially increased in the examined group and displayed statistically significant circadian fluctuations. The presence of circadian rhythm of the cytokine was proved (acrophase - 00.36 a.m.), however no diurnal rhythm of soluble TNF receptors was observed. The concentration of p-55 receptor was distinctly lower then p-75. The peak p-55 value appeared at 10.00 p.m. while the p-75 reached its minimum level at the same time. Although there was no statistical correlation between the receptor concentrations the shapes of both curves remained inversely proportional. The present results may suggest the presence of complex self-regulation mechanisms in advanced gastrointestinal cancer patients.     

The effect of hypertension on serum nitric oxide and vascular endothelial growth factor concentrations. A study in DOCA-Salt hypertensive ovariectomized rats

CardioVascular Disease (CVD) accounts for considerable mortality and morbidity in developed countries. Most of the common forms of CVD, such as hypertension, are caused by functional and structural changes in endothelial function. This study was designed to study the effect of hypertension on serum Nitric Oxide (NO) and Vascular Endothelial Growth Factor (VEGF) concentrations in DOCA-Salt hypertensive ovariectomized rats. Thirty female rats were ovariectomized. Blood samples were taken and the animals were divided into hypertensive and control groups. Hypertension was induced by DOCA-Salt method. DOCA was injected 30 mg/kg of body weight subcutaneously, twice a week with NaCl 1% instead of tap water for drinking throughout the experiment. The control group received normal saline injection with usual drinking water. Results showed that serum NO concentration in DOCA-Salt hypertensive rats was lower than the control group (18.35 +/- 5.31, 45.01 +/- 12.54 micromol/l, respectively) (p < 0.05). Also, the mean serum VEGF concentration was raised after induced hypertension (120.55 +/- 8.11 vs. 88.58 +/- 2.24 pg/ml) (p < 0.05). In conclusion, reduced serum NO and increased serum VEGF concentrations in hypertensive animals support the concept of endothelial dysfunction in hypertensive subjects.     

一氧化氮对过氧化氢所致听力损失的保护作用

通过全耳蜗灌流法在体观察一氧化氮(N0)能否通过一氧化氮/环磷酸鸟苷(NO/cGMP)途径对抗过氧化氢这种氧自由基所致的听力损失。实验选用耳廓反射灵敏、无耳毒性药物使用史的健康杂色豚鼠(250-350 g)50只,雌雄不拘,随机分为5组,每组10只动物,分别行全耳蜗灌流人工外淋巴液;过氧化氢(H2O2);L-精氨酸(合成NO的底物);H2O2+L-精氨酸;H2O2+L-精氨酸+L-NNA(一氧化氮合成酶的抑制剂),均灌流2 h。通过圆窗龛电极,每隔30 min记录复合动作电位(compound action potential,CAP:由短声Click诱发)阈值,耳蜗微音器电位(cochlear microphonic,CM;由短纯音Tone Burst诱发)幅度,了解耳蜗功能的变化,并分离取出耳蜗基底膜并制备基底膜硬铺片,通过碘化毗啶(PI)和Hoecbst双染色方法,观察耳蜗组织各类细胞损伤情况。结果显示,灌流H2O2+L-精氨酸组的CAP阈移和CM下降幅度值明显低于单独灌流H2O2组,差异有显著性(氏P<0.05);前者形态学观察未见明显的细胞损伤,后者可见大量坏死红染的细胞。H2O1+L-精氨酸+L-NNA组CAP阈移和CM下降幅度与单独灌流H2O2组比较无统计学差异。实验结果提示NO可能通过NO/cGMP途径部分对抗过氧化氢所致的听力损失。     

Effect of psoriasis activity on VEGF and its soluble receptors concentrations in serum and plaque scales

Vascular endothelial growth factor (VEGF) demonstrating pro-angiogenic activity promote new blood vessel formation in psoriatic lesions. The aim of this study was to evaluate the serum concentrations of VEGF, its soluble receptors (sVEGF R1 and R2) and VEGF content in scales of patients with psoriasis. To analyze possible association with activity of the disease, serum and scales from plaques were collected from 59 patients with exacerbated chronic plaque-type psoriasis. Mean concentrations of VEGF and sVEGF R1 in sera of patients were respectively two and four times higher than in healthy controls. Serum VEGF and sVEGF R1, but not sVEGF R2 demonstrated significant correlation with psoriasis area and severity index (PASI). There was also significant correlation between VEGF levels in serum and scales. Serum sVEGF R1 concentration was significantly elevated even in patients with low psoriasis activity (PASI < 10), whereas increase of serum VEGF became significant in patients with medium activity (PASI: 10–20). Levels of serum VEGF and sVEGF R1 were the highest in patients with PASI > 20. We confirmed association of both serum and scales VEGF concentrations with degree of psoriasis activity and demonstrated predominant increase of sVEGF R1 vs. VEGF in serum of patients with low psoriasis activity.     

Effect of psoriasis activity on VEGF and its soluble receptors concentrations in serum and plaque scales

Vascular endothelial growth factor (VEGF) demonstrating pro-angiogenic activity promote new blood vessel formation in psoriatic lesions. The aim of this study was to evaluate the serum concentrations of VEGF, its soluble receptors (sVEGF R1 and R2) and VEGF content in scales of patients with psoriasis. To analyze possible association with activity of the disease, serum and scales from plaques were collected from 59 patients with exacerbated chronic plaque-type psoriasis. Mean concentrations of VEGF and sVEGF R1 in sera of patients were respectively two and four times higher than in healthy controls. Serum VEGF and sVEGF R1, but not sVEGF R2 demonstrated significant correlation with psoriasis area and severity index (PASI). There was also significant correlation between VEGF levels in serum and scales. Serum sVEGF R1 concentration was significantly elevated even in patients with low psoriasis activity (PASI<10), whereas increase of serum VEGF became significant in patients with medium activity (PASI: 10-20). Levels of serum VEGF and sVEGF R1 were the highest in patients with PASI>20. We confirmed association of both serum and scales VEGF concentrations with degree of psoriasis activity and demonstrated predominant increase of sVEGF R1 vs. VEGF in serum of patients with low psoriasis activity.     

Circulating TNF-alpha and its soluble receptors during experimental acute pancreatitis

Clinical and experimental studies have shown increased concentrations of TNF-alpha and its soluble receptors in serum of patients with acute pancreatitis. In this work, we have investigated the time-course of TNF-alpha and its soluble receptors during taurocholate-induced acute pancreatitis. In addition, since TNF-alpha itself could mediate the shedding of its receptors, we have assessed the effect of inhibiting TNF-alpha production on the release of soluble TNF-alpha receptors in experimental acute pancreatitis. Our results indicate that soluble receptors are released in the early stages of the disease and this increase is concomitant with the release of TNF-alpha, which is mainly bound to specific proteins. The increased concentrations of its receptors strongly suggest that they could be these binding proteins. Inhibition of TNF-alpha generation with pentoxifylline abrogated the shedding of sTNF-alphaR1, but had no effect on sTNF-alphaR2. This finding suggests that the shedding of sTNF-alphaR1 is induced by TNF-alpha itself, but in the case of sTNF-alphaR2, the shedding appears to be induced by another mechanism.     

The effect of nitric oxide on glucose metabolism

Nitric oxide (NO) is an important bioactive signaling molecule that mediates a variety of normal physiological functions, which, if altered, could contribute to the genesis of many pathological conditions, including diabetes. In this study, we examined the possible diabetogenicity of NO by noting differences in the cellular binding of insulin in dogs treated with the NO donor, S-nitrosoglutathione (GSNO) compared to captopril-treated controls. GSNO administration resulted in an abnormality in glucose metabolism which was attributed to decreased binding of insulin to its receptor on the cell membrane of mononuclear leucocytes, 11.60 ± 0.60% in GSNO-treated dogs compared with 18.10 ± 1.90% in captopril-treated control (p < 0.05). The decreased insulin binding was attributed to decreased insulin receptor sites per cell, 21.43 ± 2.51 × 10⁴ in GSNO-treated dogs compared with 26.60 ± 1.57 × 10⁴ in captopril-treated controls (p < 0.05). Average affinity analysis of the binding data demonstrated that this decrease in insulin binding was also due to a decrease in average affinity of the receptor on mononuclear leucocytes for insulin. This was evident by a decrease in empty and filled site affinities in GSNO-treated dogs compared with that of captopril-treated dogs (p < 0.05). It appears that GSNO is exerting its effect by decreasing the number of insulin receptor sites and/or decreasing the average receptor affinity. These results provide evidence for a novel role of NO as a modulator of insulin binding and the involvement of NO in the aetiology of diabetes mellitus. (Mol Cell Biochem 263: 29–34, 2004)     

The effect of nitric oxide on glucose metabolism

Nitric oxide (NO) is an important bioactive signaling molecule that mediates a variety of normal physiological functions, which, if altered, could contribute to the genesis of many pathological conditions, including diabetes. In this study, we examined the possible diabetogenicity of NO by noting differences in the cellular binding of insulin in dogs treated with the NO donor, S-nitrosoglutathione (GSNO) compared to captopril-treated controls. GSNO administration resulted in an abnormality in glucose metabolism which was attributed to decreased binding of insulin to its receptor on the cell membrane of mononuclear leucocytes, 11.60 +/- 0.60% in GSNO-treated dogs compared with 18.10 +/- 1.90% in captopril-treated control (p < 0.05). The decreased insulin binding was attributed to decreased insulin receptor sites per cell, 21.43 +/- 2.51 x 10(4) in GSNO-treated dogs compared with 26.60 +/- 1.57 x 10(4) in captopril-treated controls (p < 0.05). Average affinity analysis of the binding data demonstrated that this decrease in insulin binding was also due to a decrease in average affinity of the receptor on mononuclear leucocytes for insulin. This was evident by a decrease in empty and filled site affinities in GSNO-treated dogs compared with that of captopril-treated dogs (p < 0.05). It appears that GSNO is exerting its effect by decreasing the number of insulin receptor sites and/or decreasing the average receptor affinity. These results provide evidence for a novel role of NO as a modulator of insulin binding and the involvement of NO in the aetiology of diabetes mellitus.     

Inhibitory effect of nitric oxide on dopamine transporters: interneuronal communication without receptors

Previously we observed that Nomega-nitro-L-arginine methyl ester (l-NAME) decreased the striatal dopamine (DA) release in microdialysis experiments and this effect was completely diminished in the presence of the DA uptake inhibitor nomifensine, indicating that the effect was mediated via the DA transporter. The aim of the present work was to study the direct effect of nitrergic compounds on DA uptake. We measured the uptake of [3H]DA in striatal slices and found that the nitric oxide (NO) generator sodium nitroprussid (100 microM) decreased the uptake by 66%. In contrast, the NO synthase inhibitor L-NAME (100 microM) increased the DA uptake by 80%, while the inactive D-NAME had no effect on uptake. Our data indicate that NO exerts an inhibitory effect on DA transporters. Since the production of NO by neuronal NO synthase is closely related to the activation of NMDA receptors, the level of NO around synapses reflects the activity of glutamatergic neurotransmission. The strength of excitatory input, therefore, can be nonsynaptically signaled by NO to the surrounding dopaminergic neurons via the inhibitory tone on transporters. The concomitant elevation of DA concentration around the activated synapse represents the response of dopaminergic system, which can adapt to the changing excitatory activity without receiving glutamatergic input and without expressing glutamate receptors. Thus, the effect of NO on transporters represents a new form of interneuronal communication, a nonsynaptic interaction without receptors.     

TNF-alpha controls intracellular mycobacterial growth by both inducible nitric oxide synthase-dependent and inducible nitric oxide synthase-independent pathways

The role of TNF-alpha in the control of mycobacterial growth in murine macrophages was studied in vitro. Infection of macrophages from TNF-alpha gene disrupted (TNF-knockout (KO)) mice with recombinant Mycobacterium bovis bacillus Calmette Guérin (BCG) expressing the vector only (BCG-vector) resulted in logarithmic growth of the intracellular bacilli. Infection with BCG-secreting murine TNF-alpha (BCG-TNF) led to bacillary killing. Killing of BCG-TNF was associated with rapid accumulation of inducible NO synthase (iNOS) protein and the production of nitrite. The uncontrolled growth of BCG-vector was associated with low iNOS expression but no nitrite production. Thus, iNOS expression appears to be TNF-alpha independent but iNOS generation of NO requires TNF-alpha. In cultures of TNF-KO macrophages infected with BCG-TNF, inhibition of iNOS by aminoguanidine (AMG) abolished the killing of the bacilli. However, the growth of the organisms was still inhibited, suggesting an iNOS-independent TNF-alpha-mediated growth inhibition. To confirm this, macrophages from iNOS-KO mice were infected with either BCG-vector or BCG-TNF. As expected, no nitrite was detected in the culture medium. TNF-alpha was detected only when the cells were infected with BCG-TNF. In the iNOS-KO macrophages, the growth of BCG was inhibited only in the BCG-TNF infection. These results suggest that in the absence of iNOS activity, TNF-alpha stimulates macrophages to control the growth of intracellular BCG. Thus, there appears to be both a TNF-alpha-dependent-iNOS-dependent killing pathway as well as a TNF-alpha-dependent-iNOS-independent growth inhibitory pathway for the control of intracellular mycobacteria in murine macrophages.     

The generation of nitric oxide by G protein-coupled receptors

The highly reactive free radical gas, nitric oxide, serves a variety of biomodulatory functions and has been implicated in a growing array of physiological and pathophysiological states. The striking differences between this labile substance and other, more conventional, signaling molecules highlight the tight degree of nitric oxide regulation that is required in order to maintain appropriate cellular homeostasis. The generation of nitric oxide represents a common component of the signal transduction pathways of a number of chemical signaling molecules that act via binding to G protein-coupled receptors. This review focuses on the relationship between this receptor superfamily, the generation of nitric oxide via the actions of the nitric oxide synthases and some of the inter- and intracellular roles of nitric oxide.     

The arachidonic acid effect on platelet nitric oxide level

Arachidonic acid can act as a second messenger regulating many cellular processes among which is nitric oxide (NO) formation. The aim of the present study was to investigate the molecular mechanisms involved in the arachidonic acid effect on platelet NO level. Thus NO, cGMP and superoxide anion level, the phosphorylation status of nitric oxide synthase, the protein kinase C (PKC), and NADPH oxidase activation were measured. Arachidonic acid dose-dependently reduced NO and cGMP level. The thromboxane A₂ mimetic U46619 behaved in a similar way. The arachidonic acid or U46619 effect on NO concentration was abolished by the inhibitor of the thromboxane A₂ receptor SQ29548 and partially reversed by the PKC inhibitor GF109203X or by the phospholipase C pathway inhibitor U73122. Moreover, it was shown that arachidonic acid activated PKC and decreased nitric oxide synthase (eNOS) activities. The phosphorylation of the inhibiting eNOSthr495 residue mediated by PKC was increased by arachidonic acid, while no changes at the activating ser1177 residue were shown. Finally, arachidonic acid induced NADPH oxidase activation and superoxide anion formation. These effects were greatly reduced by GF109203X, U73122, and apocynin. Likely arachidonic acid reducing NO bioavailability through all these mechanisms could potentiate its platelet aggregating power.     

The effect of weight loss on serum concentration of interleukine-6 (IL-6) and insulin resistance

INTRODUCTION: Interleukine-6 (IL-6) is one of the cytokines, excreting by adipocytes, which increases in obesity. These cytokines participate in very complicated mechanisms of developing insulin resistance that accompany obesity. The aim of the study was to: 1) evaluate the influence of weight loss on insulin resistance and serum concentration of IL-6, 2) evaluate the hypothetical association between serum concentration of IL-6 and the improvement of insulin sensitivity in obese women after weight loss. MATERIAL AND METHODS: The study involved 27 obese women (age 40.3 +/- 11.1 year; BMI 37.4 +/- 5.2 kg/m(2)) with insulin resistance diagnosed using HOMA index, without concomitant diseases and without any medication. All the patients participated in complex weight reduction treatment (diet, physical activity and psychotherapy). Before and after weight reduction therapy weight and height were measured, body composition was determined using bioimpedance analysis. Serum concentration of glucose was determined by enzymatic procedure, serum concentration of insulin was measured by radioimmunoassay, serum concentration of IL-6 was measured by ELISA. HOMA index was calculated with formula. RESULTS: The mean weight loss after 3-month was 9.2 +/- 4.5 kg (approximately 10% of initial weight). After weight reduction significant decreases in HOMA index, insulin and IL-6 concentrations was observed. However, no correlations between changes in insulin concentrations, HOMA index and decrease of IL-6 concentration were showed. We observed significant correlations between DeltaHOMA and DeltaBMI (r = 0.48; p = 0.012) and Delta percentage fat mass (r = 0.39; p < 0.05). CONCLUSIONS: A moderate weight loss improves insulin sensitivity and decreases serum concentrations of IL-6. However improvement of insulin sensitivity is the effect of fat mass reduction and does not change serum concentration of IL-6.