Adipose tissue release of interleukin-6 (IL-6) and asymmetric dimethyl arginine (ADMA): Implications for obesity associated metabolic disease.

Obesity is associated with the development of various metabolic diseases. Adipose tissue-derived factors may underlie this relationship. Two novel adipose signals associated with increased risk of coronary heart disease were investigated; interleukin-6 (IL-6) and the endogenous nitric oxide inhibitor, asymmetric dimethyl arginine (ADMA). The effect of the cyclo-oxygenase (COX) pathway on basal adipose IL-6 production was examined. Basal COX-2 expression was detected in adipose tissue explants. There was a dose-dependent decrease in adipose IL-6 release by a non-selective COX inhibitor, aspirin. Cyclic AMP, and not Ca2+, was the intracellular mediator of IL-6 release. PGE2 EP2 and 4 signalling is mediated by elevation in intracellular cAMP and agonists for these receptors elevated IL-6. Thus, basal IL-6 secretion occurs through increased COX-2 mediated PGE2 release signalling via EP4 receptors and elevated intracellular cAMP. The role of the COX pathway was also investigated in adipogenesis. Aspirin and SC-560, a selective COX-1 inhibitor, inhibited adipocyte differentiation mainly by down-regulating adipogenic transcription factors. However, NS-398, a COX-2 selective inhibitor, was found to have no such effect. Thus, adipogenesis was found to be regulated by a COX-1 mediated mechanism. ADMA, an endogenous NO inhibitor, is cleared mainly by catabolism by DDAH. Significant amounts of DDAH 1 and 2 mRNA and protein were expressed in mouse and human adipose tissue and adipocytes. In human subjects, the abdominal sub-cutaneous adipose tissue released ADMA in vivo and circulating levels in morbid obesity were elevated. Furthermore, weight loss increased adipose DDAH expression and decreased systemic ADMA levels. In vitro studies also showed a direct correlation between the amount of adipose tissue and its release of ADMA. Thus, genetic, dietary and pharmacological disruption of DDAH altered adipose ADMA release. In conclusion, this work showed that two important enzymes, COX and DDAH, in adipose tissue have the capacity to modulate cardiovascular risk in obesity by their regulation of IL-6 synthesis, adipogenesis and the release of ADMA

Effects of copper reduction on angiogenesis-related factors in recurrent glioblastoma cases

Purpose: To evaluate the therapeutic effects of copper reduction on angiogenesis-related factors in patients with glioblastoma multiforme treated by gamma knife radiosurgery. Materials and Methods: In the present block randomized, placebo-controlled trial, fifty eligible patients with a diagnosis of glioblastoma multiforme who were candidates for gamma knife radiosurgery were randomly assigned into two groups to receive daily either 1gr penicillamine and a low copper diet or placebo for three months. The intervention started on the same day as gamma knife radiosurgery. Serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF) and copper levels were measured at baseline and after the intervention. The serum copper level was used as the final index of compliance with the diet. In order to control probable side effects of intervention, laboratory tests were conducted at the beginning, middle and end of the study. Results: The patients had a mean age and Karnofsky Performance Scale of 43.7 years and 75 respectively. Mean serum copper levels were significantly reduced in intervention group. Mean survival time was 18.5 months in intervention group vs. 14.9 in placebo group. VEGF and IL-6 levels in the intervention group were also significantly reduced compared to the placebo group and TNF-α increased less. Conclusions: It seems that reducing the level of copper in the diet and dosing with penicillamine leads to decline of angiogenesis-related factors such as VEGF, IL-6 and TNF-α. Approaches targeting angiogenesis may improve survival and can be used as a future therapeutic strategy

Effects of zinc supplementation on serum adiponectin concentration and glycemic control in patients with type 2 diabetes

Background: Previous studies have suggested that zinc is involved in insulin homeostasis. Adiponectin is a well-known adipokine with anti-diabetic, anti-atherogenic, and anti-inflammatory properties. The aim of this study was to investigate the effect of zinc supplementation on glycemic control, and the potential mediating role of adiponectin, in patients with type 2 diabetes. Methods: In this randomized double-blind placebo-controlled clinical trial, 60 patients with diabetes, 30-60 years, were randomized to receive either 30 mg/d zinc (as zinc gluconate) or placebo for 12 weeks. Circulating levels of adiponectin, zinc, glucose homeostasis parameters, and lipid profiles, as well as anthropometric parameters and dietary intakes, were assessed. Results: About 53.3 of the patients had zinc insufficiency at baseline. Serum zinc levels improved significantly in the intervention than control group following 12 weeks supplementation (P < 0.001). Adiponectin (1.23 ± 2.23 μg/ml, P = 0.006) and insulin (3.6 ± 4.66 μIU/ml, P = 0.001) levels increased significantly compared to baseline in the zinc group; but this change was not significant compared with the control group. Following supplementation, there were no significant differences in glycemic control and anthropometric parameters between the two groups. Serum HDL levels increased significantly in the zinc (5.37 ± 14.8 mg/dl) compared to control (-1.53 ± 6.9 mg/dl) group following supplementation (P = 0.039). Conclusion: Despite a significant increase in serum zinc level, no improvement was observed in glycemic control, following 12 weeks supplementation with 30 mg/d zinc (as zinc gluconate). Zinc supplementation restored adiponectin concentrations partly within the intervention group, and increased HDL levels compared to the control group. The current findings did not support improvement in glucose homeostasis following zinc supplementation in patients with type 2 diabetes under the present study design. © 2019 Elsevier Gmb

The effect of a hydrolyzed collagen-based supplement on wound healing in patients with burn: A randomized double-blind pilot clinical trial

Introduction: Burn is among the most severe forms of critical illness, associated with extensive and prolonged physical, metabolic and mental disorders. The aim of this study was to assess the effect of an oral, low-cost, and accessible collagen-based supplement on wound healing in patients with burn. Methods: In this randomized double-blind controlled pilot clinical trial, 31 men, 18�60 years, with 20�30 total body surface area burn were studied. Patients were randomly assigned to receive either a collagen-based supplement (1000 kcal) or an isocaloric placebo, for 4 weeks. Serum pre-albumin, rate of wound healing, length of hospital stay, and anthropometries were assessed at baseline, and the end of week 2 and 4. Results: Serum pre-albumin was significantly higher at week 2 (29.7 ± 13.6 vs. 17.8 ± 7.5 mg/dL, P = 0.006) and week 4 (35.1 ± 7.6 vs. 28.3 ± 8.2 mg/dL, P = 0.023) in collagen than control group. Changes in pre-albumin concentration were also significantly higher in collagen group at week 2 (13.9 ± 9.8 vs. �1.9 ± 10.3 mg/dL, P < 0.001) and week 4 (19.2 ± 7.5 vs. 8.5 ± 10.1 mg/dL, P = 0.002). The Hazard ratio of wound healing was 3.7 times in collagen compared to control group (95 CI: 1.434�9.519, P = 0.007). Hospital stay was clinically, but not statistically, lower in collagen than control group (9.4 ± 4.6 vs. 13.5 ± 7 days, P = 0.063). There were no significant differences in weight, body mass index, dietary energy and protein intakes between the two groups. Conclusion: The findings showed that a hydrolyzed collagen-based supplement could significantly improve wound healing and circulating pre-albumin, and clinically reduce hospital stay in patients with 20�30 burn. © 2019 Elsevier Ltd and ISB

Effect of fish oil on circulating asymmetric dimethylarginine and adiponectin in overweight or obese patients with atrial fibrillation

Obesity and adipose-derived peptides might be involved in the pathogenesis of atrial fibrillation (AF). Adiponectin plays a major role in the modulation of several metabolic pathways, and asymmetric dimethylarginine (ADMA) has been suggested to be predictive of AF and associated adverse events. The aim of this study was to investigate the effect of fish oil supplementation on circulating adiponectin and ADMA in overweight or obese patients with persistent AF. In this randomized, double-blind, placebo-controlled trial, 80 overweight or obese (body mass index (BMI) � 25 kg/m2) patients with persistent AF were randomly assigned to two groups to receive either 2 g/day fish oil or placebo, for 8 weeks. Serum levels of adiponectin and ADMA, and anthropometric indexes were measured. This study showed that serum adiponectin concentrations increased significantly following fish oil supplementation compared with the placebo group (13.15 ± 7.33 vs. 11.88 ± 6.94 µg/ml; p =.026). A significant reduction was also observed in serum ADMA levels in the fish oil compared with the placebo group following the intervention (0.6 ± 0.13 vs. 0.72 ± 0.15 µmol/L; p =.001). The changes in serum adiponectin and ADMA concentrations remained significant after adjustments for baseline values, age, sex, and changes of BMI and waist circumference (p =.011 and p =.001, respectively). In conclusion, 8 weeks supplementation with fish oil increased serum adiponectin and decreased ADMA concentrations in overweight or obese patients with persistent AF. As adiponectin and ADMA are suggested to be involved in many pathways associated with AF, the current findings might be promising in the clinical management of this disease, an issue that needs further investigations. © 2020 The Authors. Food Science & Nutrition published by Wiley Periodicals, Inc

Increased efficacy of a garlic supplement on knee osteoarthritis symptoms in patients with obesity

Background: Obesity is a major risk factor for the incidence, progression, and poor outcomes of osteoarthritis (OA). It is unknown if obese patients could have different outcomes with complementary interventions. This study investigated joint symptoms following supplementation with a garlic tablet in obese women with knee OA. Methods: In this secondary analysis of a randomized, double-blind, placebo-controlled trial, 50 obese (BMI � 30 Kg/m2) women with knee OA received either a 1000 mg garlic supplement or placebo for 12 weeks. The outcomes were joint symptoms, measured using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and pain severity based on a visual analogue scale (VAS). Results: Garlic supplementation decreased WOMAC total score (29.2 ± 14.5 vs. 36.4 ± 14.3, P = 0.013), joint stiffness (1.3 ± 1.3 vs. 2.5 ± 2, P = 0.019), and physical function (20.5 ± 10.9 vs. 24.8 ± 10.3, P = 0.018) in the garlic compared with the control group. Pain severity decreased marginally (2 ± 3.1 vs. 0.4 ± 2.8, P = 0.073) in the garlic than the control group, which seemed to be clinically important. Additionally, all joint clinical outcomes improved remarkably in the garlic group compared to the baseline. There were no significant changes in anthropometric indices, body composition, and reported dietary intakes between the two groups at the end of the trial. Conclusions: A 12-week 1000 mg garlic supplementation exerted significant improvements in joint symptoms in the obese women with knee OA. Future studies should address the potential better response of obese patients to interventions as well as relevant underlying mechanisms. The study was registered with the Iranian Registry of Clinical Trials (http://www.irct.ir, registration code IRCT201307179543N2). © 2020 Elsevier Gmb

Effects of Selenium Supplementation on Asymmetric Dimethylarginine and Cardiometabolic Risk Factors in Patients with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is characterized by various reproductive and cardiometabolic disorders. Asymmetric dimethylarginine (ADMA) is associated with cardiovascular, metabolic, and hormonal status. Selenium, a micronutrient with antioxidant properties, could affect multiple physiological pathways. This study aimed to investigate the effect of selenium supplementation on ADMA, cardiometabolic risk factors, and hormonal status in women with PCOS. In this randomized, double-blind, placebo-controlled clinical trial, 66 women with PCOS, aged 18�45 years, were randomly assigned to receive either 200 μg/day selenium or placebo, for 12 weeks. Circulating concentrations of ADMA, testosterone, sex hormone-binding globulin (SHBG), lipid profiles, and glycemic parameters were assessed at baseline and following supplementation. ADMA concentration decreased significantly compared to baseline values (85.14 ± 75 to 56.4 ± 38.64 ng/l, p = 0.02) in the selenium group. This change was marginally significant compared with the placebo group (28.74 ± 68.63 vs. � 1.77 ± 52.88 ng/l, p = 0.056). Serum testosterone levels declined significantly in the intervention compared to the placebo group (0.01 ± 0.17 vs. � 0.08 ± 0.18 ng/ml, p = 0.038). Pre- to post-Apo-B100/Apo-A1 ratio declined considerably in the intervention group (0.72 ± 0.16 to 0.65 ± 0.16, p = 0.003). No further differences were observed in SHBG, lipid profiles, Apo-A1, Apo-B100, Apo-B100/Apo-A1 ratio, and glycemic control between the two groups at the end of the study. Selenium supplementation for 12 weeks had beneficial effects on reduction of circulating ADMA and total testosterone levels in women with PCOS. No significant improvements were seen in other cardiometabolic risk factors. The effects of selenium supplementation on hormonal, reproductive, and cardiometabolic disorders, considering the potential mediating role of ADMA, should be further investigated. © 2019, Springer Science+Business Media, LLC, part of Springer Nature

Effect of single-dose injection of vitamin D on immune cytokines in ulcerative colitis patients: a randomized placebo-controlled trial

Ulcerative colitis (UC) is a chronic recurrent inflammation of the colon. It has been proposed that the UC pathogenesis may be related to vitamin D deficiency and/or vitamin D administration in UC patients may have an ameliorating effect on the intestinal inflammation. The aim of this study was to assess the effect of vitamin D on the serum levels of immune cytokines in UC patients. In this double-blind randomized controlled trial, 90 mild-to-moderate UC patients were assigned to get either a single muscular injection of 7.5 mg vitamin D3 or 1 mL normal saline as placebo. Three months later serum levels of IL-4, IL-10, IL-12p70, IFN-γ, and TNF-α were measured. Two group variables were compared using independent t-test and analysis of covariance (ANCOVA). There was a significant increase in vitamin D only in the vitamin D group. Compared to placebo, vitamin D had significant decreasing effects on serum TNF-α, IFN-γ, and IL12p70 levels, but it had no significant effect on serum levels of IL4 and IL10. Vitamin D seems to inhibit Th1 immune responses and have no effect on Th2 responses. The findings of this study support several in vitro studies, which suggest a therapeutic immunomodulatory potential of vitamin D. © 2019 APMIS. Published by John Wiley & Sons Lt

White adipose tissue browning in critical illness: A review of the evidence, mechanisms and future perspectives

Observational studies suggest better clinical outcomes following critical illness in patients with overweight and obesity (obesity paradox). An understanding of the morphologic, physiologic and metabolic changes in adipose tissue in critical illness may provide an explanation. Recent studies have demonstrated the transformation of white to brown-like adipocytes due to the �browning process,� which has been of interest as a potential novel therapy in obesity during the last decade. The characteristics of the browning of white adipose tissue (WAT) include the appearance of smaller, multilocular adipocytes, increased UCP1 mRNA expression, mitochondrial density and respiratory capacity. These changes have been identified in some critical illnesses, which specifically refers to burns, sepsis and cancer cachexia in this study. The pathophysiological nature of WAT browning, underlying mechanisms, main regulators and potential benefits and harms of this process are interesting new areas that warrants further investigations. In this review, we discuss emerging scientific discipline of adipose tissue physiology in metabolic stress, available data, gaps of knowledge and future perspectives. Future investigations in this field may provide insights into the underlying mechanisms and clinical aspects of browning that may further our understanding of the proposed obesity paradox following critical illness, which may in turn open up opportunities for novel therapies to save lives and improve recovery. © 2020 World Obesity Federatio

Vitamin D suppresses proangiogenic factors in patients with ulcerative colitis: A randomized double blind placebo controlled clinical trial

Background: Angiogenesis and inflammation are involved in the pathogenesis of ulcerative colitis (UC). This study aimed to assess the effect of vitamin D on serum levels of proangiogenic factors, visfatin and vascular endothelial growth factor (VEGF), in patients with UC. Materials and methods: Ninety patients were randomized to receive either a single intramuscular injection of 300,000 IU vitamin D or normal saline. Visfatin, VEGF, and 25-hydroxyvitamin D 25(OH)D concentrations were assessed before and 90 days after the intervention. Results: There were no significant differences in visfatin and VEGF levels between the two groups following supplementation. In patients with vitamin D insufficiency, visfatin increase was significantly lower in the intervention versus placebo group. There was an inverse correlation between serum 25(OH)D and visfatin in the subgroup with vitamin D insufficiency. Conclusion: Vitamin D might be beneficial in decreasing proangiogenic factors such as visfatin in UC patients with low 25(OH)D levels. © 2020 Elsevier Lt