Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 18, Issue 3, 2018

Background: There are controversies regarding the effect of conjugated linoleic acid (CLA) on serum leptin. Objective: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of CLA on serum leptin concentrations. Method: Databases such as Ovid, PubMed/Medline, SCOPUS, Google Scholar, and ISI databases up to January 2017 were searched. The searches included RCTs conducted among human adults, and studies on the effect of conjugated linoleic acid on serum leptin concentrations as outcome variables. The mean difference and standard deviation of leptin changes in the intervention and control groups were used as effect size measures for the meta-analysis. Result: Eleven trials with thirteen effect sizes were pooled in this meta-analysis. CLA supplementations could not reduce serum leptin levels significantly (-0.12 (ng/ml); 95% CI: -1.29, 1.05; P=0.837). However, the impact of CLA supplementation differed by sex and BMI status. Compared with the control group, CLA administration reduced serum leptin levels significantly in trials conducted among male (- 0.86 (ng/ml); 95% CI: -1.11, -0.62; P<0.0001) or overweight individuals (-1.37 (ng /ml); 95% CI: -2.55, -0.20; P=0.022) and lasted for less than 8 weeks (-0.90 (ng/ml); 95% CI: -1.64, -0.17; P=0.0.016). Conclusion: CLA supplementation might be able to decrease circulating leptin levels in studies with duration of less than 8 weeks especially among male and overweight subjects. Additional RCTs that are well controlled for energy intakes may be necessary to explain the cause of short- and long-term effects of conjugated linoleic acid. The protocol was registered with PROSPERO (No. CRD42017059165).

Background and Objective: Infertility is a common disease that in about one third of cases has a female cause and often requires assisted reproduction technologies (ART) to conceive. Also thyroid autoimmunity (TAI), with or without hypothyroidism, is a common disease, particularly in females, and referral for endocrine consultation is not infrequent. Discussion: In the last 15 years a remarkable amount of studies has been published that investigated the pathophysiology of women suffering from TAI, who undergo ART. Due to insufficient sample size, data about the association between infertility and TAI/subclinical hypothyroidism are conflicting. In relation to pregnancy rate, miscarriage, and live births (primary outcomes) data of the literature do not allow to clearly demonstrating an unfavorable impact attributable to TAI/subclinical hypothyroidism; however, secondary outcomes like ovarian reserve or oocytes quality look like worsened. Conclusion: For sure, the therapeutic regimens used for controlled ovarian hyperstimulation (COH) induce a deterioration of thyroid function in patients suffering from TAI [with or without Levothyroxine (LT4) treatment]. This picture places patients in a condition of increased risk of developing untimely TSH elevation during fertilization; then, it is reasonable that a patient, above all if thyroid antibody positive, would have a TSH value <2.5mIU/L before undergoing COH, and that would be strictly monitored to start or increase LT4 treatment, when necessary.

Background: Crigler-Najjar syndrome (CNS, OMIM: 218800) is the paradigm of an inborn error of metabolism and a rare genetic disease with an estimated incidence of 0.6–1.0 per million live births. Discrimination between CNS subtypes is usually done on the basis of the clinical criteria, such as response to phenobarbital treatment and other molecular and functional characteristics. Methods: The identification of four novel pathogenic mutations and the analysis of residual activity of missense in UGT1A1 gene are useful for clinical diagnosis, and may reveal a new insight in enzyme activity, whereas the identification of pathogenic mutations will accelerate genetic counseling for newly identified CNS patients. Results: Phototherapy, orthotropic liver transplantation, liver cell transplantation and gene therapy are treatment choices and candidates to fight back this syndrome. Due to the promising reports of gene therapy in small animal models, gene therapy approaches are expected to continue in preclinical research for developing safe and effective treatment of CNS. Gene transfer vectors using recombinant viruses, such as Adenovirus have been applied successfully in transferring UGT1A1 gene to the liver of Gunn rat model of CNS. Conclusion: In spite of remaining safety and efficiency issues, gene therapy promises to be a realistic treatment modality for CNS during the future decade.

Background and Objective: Excess caloric intake and less energy expenditure (e.g. physical inactivity) are associated with acquired metabolic disorders due to sedentary life style. Pharmacological treatments are less effective in preventing obesity. Type of diet influences the gut microbiome alteration and it is interrelated with obesity, insulin resistance and type 2 diabetes. Modified gut microbiota by the harmful bacterial components (e.g: lipopolysaccharides) is linked with the metabolic endotoxemia (low-grade inflammation) which results in damage to the gut barrier function. Administration of probiotics (lactobacilli and bifidobacteria) as live micro-organisms or fermented products achieves proper gut environment. In addition, administration of prebiotics along with probiotics improves the body weight, abdominal fat and intestinal barrier function. Methods: We compiled all the available literature in the present review in relation to altered gut microbiota by different type of diets, effect of probiotics on obesity and its accompanying diseases in animal and clinical studies. Conclusion: Studies are indicating that anti-hyperglycemic and hyperlipidemic effects of probiotics are strain dependent as well as type of animal models. To improve against metabolic disorders, probiotics, need to be administered through prebiotics and requires more clinical studies in this area.

Background and Objective: Metabolomics is a powerful exploratory tool for discovering new diagnostic molecules or biomarkers due to its ability to highlight several interactions between different biochemical molecules and pathways in composition in health and disease thereby advancing our understanding, to provide evidence based diagnosis and treatment of such a complex disease including polycystic ovarian syndrome (PCOS). The aim of this study was to review available literature on the use of metabolomic approach and to critically evaluate and draw a synthesis to highlight novel biochemical markers for clinical application in PCOS. Method: Studies that applied metabolomic approach to investigate PCOS and those meeting selection criteria were searched and, critically evaluated. Result: Here we highlighted the metabolic reactions and perturbation of some metabolic pathways present in patients with polycystic ovarian syndrome and normal subjects that can allow better understanding of the disorder and help developing a new generation diagnostic and treatment algorithm. Conclusion: A number of disease-related metabolites have been discussed which have extraordinary potential for a clinical utility as diagnostic and treatment monitoring biomarkers.

Background and Objective: Metabolic syndrome (MS) is widespread among middle age people and presents an acute issue in preventive cardiology. A list of conditions associated with MS is quite long and it is constantly growing. Despite the data, described in scientific literature, on general pathogenetic mechanisms, the conditions associated with androgynous status, are not included into the register of MS associated nosologies. Such association is identified in men older than 60 years old and is explained by age related hypoandrogenaemia. However, the issue of occurrence rate of lower urinary tract syndromes (LUTS) in young men with MS and their association of androgen levels remains open. Methods: 62 European men aged from 25 to 40 (30 patients with MS and 32 conditionally healthy persons) were examined. Apart from generally accepted methods of physical and instrumental examination, evaluation of hormonal status (insulin, testosterone, dehydrotestosteron), IPSS-QOI testing and transrectal USI of prostate and bladder were performed. Results: Revealed a high frequency of increasing the size and volume of the prostate gland, the number of points on the IPSS questionnaire, corresponding to the initial manifestation of hyperplastic prostate diseases on the background of insulin resistance and normal androgen levels raises questions about the search for new pathogenetic links of the metabolic syndrome with the processes of induction of prostate growth. Conclusion: Modern standards of examination of patients with MS do not include routine methods for the detection of prostate diseases. The above data raise questions about the need for further study in young patients with verified MS, including IPSS-QOI questionnaire surveying and TRUS.

Background: Until recently, treatment of hypothyroidism has been accomplished using monotherapy of synthetic L-thyroxine (L-T4) sodium tablets that should be taken 30-60 minutes before breakfast. Nowadays, a liquid preparation of levothyroxine is available and can effectively replace tablets without the need of waiting before having breakfast. Evidence of Quality of life (QoL) improvement when shifting from the former to the latter preparation, however, is still lacking. Objective: The study aimed to assess changes in QoL of hypothyroid patients dissatisfied with their therapy with L-T4 sodium tablets who were switched from tablets taken 30-60 minutes before breakfast to liquid L-T4 at breakfast. Methods: A total of 418 consecutive hypothyroid subjects treated by means of L-T4 tablets were asked about their satisfaction/dissatisfaction in order to take the medication 30-60 minutes before having breakfast. Overall, 110 patients (26.3%) complained of the timing of their L-T4 therapy (30-60 minutes before breakfast). A dedicated QoL questionnaire (ThyTSQ), taking just a few minutes to be filled in was then administered to these dissatisfied patients. They were therefore switched to L-T4 to be taken at breakfast. Aiming to avoid TSH elevation due to L-T4 tablets malabsorption caused by meal interference and gastric pH changes, patients were invited to take L-T4 liquid form, as this is claimed to be scarcely affected by the non-fasting state. The questionnaire (ThyTSQ) was administered again at the control visit 3 months later. TSH, FT4, FT3 serum concentrations and metabolic parameters were also recorded. Results: An improved QoL, mainly due to an easier adherence to treatment, was reported by 66.6% of 102 patients who completed the study after shifting from taking medication 30-60 minutes before breakfast to at breakfast ingestion (P<0.01). An overall 10.7% of patients found the liquid formulation distasteful. Mean values of TSH, FT4, FT3, and of metabolic parameters did not significantly change but in eight patients (7.7%) who showed a TSH increase > 2mIU/L. Conclusion: In hypothyroid subjects dissatisfied with L-T4 tablets ingested 30-60 minutes before breakfast, the shift to the same dose of L-T4 in liquid form taken at breakfast improved QoL in the majority of patients, without affecting thyroid function.

Objective: This study was established to investigate the contribution of high mobility group nucleosome-binding protein 1 (HMGN1)/ Toll-like receptor 4 (TLR4) pathway in diabetic nephropathy (DN). And as an intervention of the potential mechanism above, the insulin growth factor 1 receptor (IGF-1R) inhibitor was examined for its therapeutic effect in the diabetic mice. Method: Male C57BL/6J mice were administered streptozotocin(STZ) to induce diabetes and thus divided into 5 groups: the untreated group (DN group), the benazepril-treated group (BEN-DN group), the insulin-treated group (INS-DN group) and the IGF-1R inhibitor-treated group (IGF-DN group). Immunohistochemistry and in situ hybrization were performed to detect the expression of HMGN1 and TLR4 in renal tissue. To evaluate the effect of IGF-1R inhibitor, levels of blood glucose and kidney/ body weight (KW/BW) were measured. And morphological changes and mesangial matrix expansion in kidneys were also detected. Results: Increased expression of HMGN1 and TLR4 in renal tissue of STZ-induced type1 diabetic mellitus (T1DM) mice models was observed. IGF-1R inhibitor attenuate the established nephropathy with reduced expression of TLR4 protein, as revealed by a decrease in mesangial index. Conclusion: IGF-1R inhibitor might have therapeutic potential in DN through inhibition of HMGN1/TLR4 pathway.

Background: A great debate in literature exists nowadays on the role of uric acid as a marker of cardiovascular and metabolic organ damage or a risk factor for cardiovascular and metabolic disease. Methods: The study aimed to determine the relationship among serum uric acid and metabolic syndrome and atherosclerosis, by means of carotid intima media-thickness, in a cohort of 811 otherwise healthy overweight/obese subjects, without overt atherosclerosis not using any kind of drug. Results: Uric acid levels were positively related to male gender, waist circumference, BMI, systolic and diastolic pressure levels, fasting insulin, fasting glucose, HOMA-IR, triglycerides, total cholesterol, LDL cholesterol, the presence of metabolic syndrome and the number of the components of metabolic syndrome and negatively related to HDL cholesterol levels. No correlation was found between uric acid and carotid intima media thickness. At the multiple regression analysis, only waist circumference and triglycerides (positively) and HDL-cholesterol (negatively) maintained an independent association with uric acid as dependent variable, while age, female gender and uric acid showed a significant independent association with metabolic syndrome as dependent variable. Moreover, the analysis of the odd ratios showed that the risk of developing metabolic syndrome was consistent with uric acid levels ranging from 3 mg/dl to 8 mg/dl. Conclusion: The presence of metabolic syndrome does not seem to provide hyperuricemia. By contrast, higher serum uric acid level may predict the risk of metabolic syndrome. Moreover, our results suggest that uric acid cannot be considered a risk factor for early atherosclerosis, at least when assessed using carotid ultrasound.

Background and Objective: The adipose tissue has been recognized as an important endocrine organ, which is metabolically active and expresses and secretes various inflammatory cytokines. Inflammation is involved in obesity-related complications. As such, the present study investigated the correlation between biochemical parameters, serum proinflammatory cytokines and adipokines in individuals with obesity. Methods: Based on the body mass index (BMI), 30 subjects were divided into 3 groups: eutrophic (GC, n = 10), overweight (GOW, n = 10) and obese (GOB, n = 10). Serum glucose, cholesterol (total-C, HDLC and LDL-C), triglycerides, total proteins, uric acid and insulin were determined, as well as cytokines IL-8, TNF-α, IL-1β, and IL-6, leptin and adiponectin. Results: GOB showed the highest glucose, total and LDL-C, triglycerides, uric acid, insulin, leptin, IL- 8, IL-1β, IL-6, TNF-α and lowest adiponectin levels. In general, adiponectin exhibited an inverse correlation with BMI, abdominal circumference, LDL-C, IL-6, TNF-α, leptin and leptin-adiponectin ratio (LAR) and a positive correlation with HDL-C. Leptin was positively correlated with BMI, abdominal circumference, insulin, IL-6, TNF-α and LAR and negatively correlated with HDL-C and adiponectin. The LAR was positively correlated with BMI, waist circumference, insulin, TNF-α and negatively associated with HDL-C. Conclusion: The results confirm that obesity changes the lipid and glycemic profiles of individuals, increases the proinflammatory adipokine levels and reduces those of anti-inflammatory adipokines, promoting a state of chronic inflammation.

Background: TNBS-induced colitis is an experimental immunopathology in rats that shares many features with human inflammatory bowel diseases. Copaiba oleoresin is extracted from plants of the genus Copaifera and is shown to reduce inflammation. Objective: The aim of this study was to investigate the action of copaiba oil (C. reticulata Ducke) on inflammation and oxidative status in the distal colon of colitic rats. Methods: Acute and subchronic colitis were induced in Wistar rats by an intracolonic enema with 2,4,6-trinitrobenzenesulfonic acid (TNBS). The colonic morphology was assessed by histological analysis and the oxidative stress parameters were measured in the intestinal homogenate. The liver damage markers were measured in the plasma. Control and colitic rats were orally treated either with one single dose (acute colitis) of copaiba oil (1.15 g Kg-1) or once a day during seven days (subchronic colitis). Results: The intestinal morphology was severely modified by acute and subchronic colitis, as indicated by the intramural infiltration of polymorphonuclear cells and the increased thickness of all colon layers. The levels of TBARS, protein carbonyl groups and reactive oxygen species (ROS) were increased in the intestine of colitic rats. Copaiba oil did not attenuate the inflammatory damage in acute and subchronic colitis, but it decreased the activity of myeloperoxidase, leukocyte infiltration and oxidative stress in the colon. The level of plasma bilirubin and the activity of alkaline phosphatase were both increased in treated healthy and colitic rats. Conclusion: Copaiba oil decreased oxidative stress and inflammation but did not prevent intestinal damage in the colon of colitic rats. The alterations of plasma markers of hepatic damage caused by the oil seem to be associated to its harmful action on the liver.

Introductıon: Osteoporosis is a common disease, and several factors contribute to its development. Recently, there has been increasing evidence that vitamin K (VK) plays a critical role in maintaining bone strength. Vitamin K serves as a co-factor for the γ-carboxylation of particular proteins to convert specific glutamic acid residues to γ-carboxyglutamic acid residues. This process involves two enzymes, γ-glutamyl carboxylase and vitamin K epoxide reductase (VKORC1). The number of studies investigating the effects of VKORC1 gene mutations on bone mineral density in postmenopausal osteoporosis patients is limited. The aim of this study was to investigate the relationship between the VKORC1 -1639G>A polymorphism and osteoporosis in postmenopausal Turkish women. Methods: The study group consisted of 176 postmenopausal women with osteoporosis and 140 healthy postmenopausal women. The selection criteria for the healthy controls included non-osteoporotic bone mineral density (BMD) and similar demographic characteristics to the osteoporosis group. The genotyping of the VKORC1 -1639G>A polymorphism was conducted using the restriction fragment-length polymorphism method. Results: We found that the genotype frequencies of the GG, GA and AA genotypes were 25.6, 64.2 and 10.2% in the patients and 33.6, 55.8 and 10.7% in the controls, respectively. In the patient and control groups, the genotype distribution of the studied locus was found to be non-compatible with Hardy–Weinberg equilibrium. We found a nonsignificant association between the -1639G>A polymorphism in the VKORC1 gene and osteoporosis in postmenopausal Turkish women. Conclusion: We have shown that the VKORC1 -1639G>A polymorphism is not a risk factor for postmenopausal osteoporosis.