Prenatal Exposure To Magnetic Field Increases Dopamine Levels In The Striatum Of Offspring

1. The putative effects of prenatal exposure to magnetic field (MF) have recently received much interest. In the present study, mice were exposed to a MF of 50 mT during gestation (0-19 days). 2. After the exposure was terminated, mothers and offspring were returned to normal laboratory conditions. We then determined changes in striatal levels of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the offspring. 3. Our results indicate that prenatal exposure to MF increases levels of DA and DOPAC in the striatum at 4, 8 and 12 weeks postnatally.     

Assessment of Offspring Development and Behavior Following Gestational Exposure to Inhaled Methanol in the Rat

The prospect of widespread human exposure associated with itsuse as an alternative fuel has sparked concern about the toxicpotential of inhaled methanol (MeOH). Previous studies haverevealed congenital malformations in rats following inhaledMeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5,727–736)but these studies did not include postnatal behavioral assessment.In the present study, pregnant Long–Evans rats were placedin exposure chambers containing 15,000 ppm MeOH or air for 7hr/day on Gestational Days (GD) 7–19. The total alveolardose of methanol was estimated at about 6.1 g/kg/day, for atotal dose of about 42.7 g/kg for the entire study. Maternalbody weights were recorded daily and blood methanol concentrationswere determined at the end of exposure on GD 7, 10, 14, and18. Following birth (Postnatal Day 0 [PND 0]), a number of testswere performed at various points in development, including:offspring mortality and body wt (PND 1, 3), motor activity (PND13–21, 30, 60), olfactory learning (PND 18), behavioralthermoregulation (PND 20–21), T-maze learning (PND 23–24),acoustic startle response (PND 24, 60), reflex modfficationaudiometry (PND 60), pubertal landmarks (PND 31–56), passiveavoidance (PND 72), and visual-evoked potentials (PND 160).Maternal blood MeOH levels, measured from samples taken within15 mm after removal from the exposure chamber, declined fromabout 3.8 mg/ml on the first day of exposure to 3.1 mg/ml onthe 12th day of exposure. MeOH transiently reduced maternalbody wt (4–7%) on GD 8–10, and offspring BW (5%)on PND 1. No other test revealed significant effects of MeOH.Prenatal exposure to high levels of inhaled MeOH appears tohave little effect on this broad battery of tests beyond PND1 in the rat.     

The therapeutic potential of GPR120: a patent review

Introduction: Type 2 diabetes (T2D) is a complex metabolic disorder characterized by persistent hyperglycemia and a wide range of underlying metabolic defects. The prevalence and incidence of T2D are expected to dramatically increase in the near-future and consequently, there is a significant medical need for diabetes care. Many targets are under investigation to lower the plasma glucose levels or increase the insulin sensitivity. Despite newer drug classes emerging as viable long-term treatment options for the management of T2D, achieving an optimal glycemic control along with sufficient effectiveness over the course of the disease remains a challenge. In this regard, among several G-protein-coupled receptors (GPCRs), GPR120 and GPR40 have recently been considered as viable targets for diabetes and metabolic disorders.

Areas covered: This article reviews the current literature on the discovery and development of GPR120 agonists in diabetes and metabolic disorders and updates on the published patents in this field. The patent study for this review has been carried out using multiple electronic databases including SciFinder and Thomson Reuters Integrity.

Expert opinion: A paradigm shift in the treatment of diabetes is needed, wherein a single therapeutic agent could target diabetes and its associated disorders such as high plasma glucose level and inflammation, with excellent safety and tolerability profile. In this regard, agonists of GPR120 or dual-agonist GPR120 and GPR40 are highly anticipated as therapeutic approaches for the treatment of diabetes on the basis of their novel glucose-dependent mechanism of action.     

Rimonabant: the evidence for its use in the treatment of obesity and the metabolic syndrome

Introduction:

Obesity and overweight affect over 1 billion people worldwide and are leading causes of morbidity and mortality. Clinical features of obesity converge with those of the metabolic syndrome and type 2 diabetes, greatly increasing the risk of long-term adverse outcomes.

Aims:

To review the evidence on rimonabant, a novel CB1 receptor antagonist, for the treatment of obese and overweight patients.

Evidence review:

There is clear evidence that rimonabant 20 mg/day in conjunction with a hypocaloric diet causes a mean weight loss of 4.6 kg in obese and overweight patients after 1 year’s treatment, with approximately 50% of patients achieving a weight loss of ≥5%. One study demonstrated that weight loss is maintained for up to 2 years. The drug also improves lipid and glycemic cardiovascular risk factors, including high-density lipoprotein cholesterol and insulin resistance, and reduces waist circumference, thus reducing the prevalence of metabolic syndrome. Treatment of obese and overweight diabetic patients with rimonabant decreases glycosylated hemoglobin (HbA_1c), including patients previously untreated for diabetes. The effect of rimonabant appears to be partly independent of weight loss.Rimonabant 20 mg/day is generally well tolerated, with mild to moderate transient adverse effects including nausea, diarrhea, dizziness, and anxiety. Approximately 14% of patients receiving rimonabant 20 mg/day discontinued due to adverse effects, primarily depressed mood, although overall rates of depression did not differ significantly compared with placebo.

Place in therapy:

The evidence supports the use of rimonabant 20 mg/day along with dietary modification to reduce cardiovascular risk factors in obese and overweight patients, including those with diabetes. The drug is contraindicated in patients receiving antidepressants. Long-term data on cardiovascular outcomes, morbidity, and mortality are eagerly awaited.     

西布曲明对肥胖伴糖脂代谢异常的治疗作用

目的 :观察西布曲明 (可秀 )对肥胖伴糖尿病、脂代谢异常患者的治疗作用。方法 :将体重指数大于 2 5kg·m-2 无药物及相关疾病的影响者纳入观察对象 ,测西布曲明干预前后的体重、腰围、腹围、臀围、血脂、空腹 (FBS)和餐后 2h的血糖 (2PBS)、胰岛素、糖化血红蛋白等指标的变化。结果 :(1 ) 41例肥胖患者经西布曲明干预后腹围、体脂含量、体脂重量治疗前后比较 ,差异有显著性 (P <0 .0 1 ) ;(2 )其中1 8例糖代谢异常患者空腹血糖 (FBS)、餐后 2h血糖 (2PBS)、腹围、体重治疗前后比较 ,差异有显著性(P <0 .0 1 )。INS(胰岛素 )、HbAIC(糖化血红蛋白 )有改变 ,但差异无显著性 (P >0 .0 5 )。 (3 )TG(甘油三脂 )、CHO(总胆固醇 )、LDL(高密度脂蛋白 )、HDL(低密度脂蛋白 ) ,差异有显著性 (P <0 .0 5 )结论 :西布曲明具有降低体重 ,改善糖、脂代谢异常的作用。对于降低心血管疾病的危险因素高脂血症有显著疗效     

Prenatal Exposure to Phthalates and Intrauterine Inflammation: A Unifying Hypothesis

We read with great interest the recent paper by Xu et al. (2005),showing that phthalates alter rat placental essential fattyacids (EFA) homeostasis via peroxisome proliferator-activated     

Hydrogen sulfide and the metabolic syndrome

The metabolic syndrome is a group of abnormalities including obesity, high blood pressure, hyperinsulinemia, high blood glucose levels and hyperlipidemia that together greatly increase the risk of developing cardiovascular disease and Type 2 diabetes. Hydrogen sulfide (H₂S) is a vasodilatory gasotransmitter mediator in the cardiovascular system, proposed as an endothelium-derived relaxing factor. A lack of H₂S and its synthesizing enzyme, cystathionine γ-lyase, in the vasculature causes hypertension, whereas an increase in the pancreas reduces insulin secretion. Thus, research is making inroads to determine whether H₂S is involved in the pathogenesis of the metabolic syndrome. Several laboratories are synthesizing and testing clinically used drugs that release H₂S. Some of these compounds are being tested for effectiveness in the metabolic syndrome.     

Therapeutic utilities of fibroblast growth factor 19

Introduction: Diabetes and associated metabolic conditions have reached pandemic proportions worldwide and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 is a distinctive member of the FGF family that functions as an endocrine hormone.

Areas covered: An up-to-date report on the exciting findings related to the involvement of FGF19 in the regulation of glucose, bile acid metabolism and energy expenditure. The role of FGF receptors in these different activities. The therapeutic potential of FGF19 and the engineering opportunities for removing undesirable mitogenic activity.

Expert opinion: The ability of FGF19 to regulate bile acid homeostasis, gallbladder filling and tumor development and its potent ability to normalize glucose, lipid and energy homeostasis have made it a potential therapeutic target for the treatment of patients with gallstones, cancer and metabolic diseases, among others. Its potential utility as a novel therapeutic for both type 1 and type 2 diabetes is of particular interest. The ability to separate the undesired mitogenic activity from its potent metabolic activities has opened new opportunities for the development of potential therapeutic molecules based on FGF19 in treating various conditions associated with metabolic syndrome.     

Prenatal Exposure to Nicotine: Effects on Prepulse Inhibition and Central Nicotinic Receptors

The present experiment examined effects of prenatal nicotine exposure (6 mg/kg/day via osmotic minipump) throughout gestation on prepulse inhibition of the acoustic startle response (PPI) and on the density of nicotinic acetylcholine receptors (nAchRs) in the brains of 5-week-old Sprague–Dawley rats. A total of 117 male and 103 female offspring were used. Prenatal nicotine reduced subsequent percent PPI to a 98 dB stimulus in female but not in male offspring. There was an inverse correlation between the percent of PPI and nAchR density in the cortex of male rats and the striatum of female rats.     

Exposure to an environmentally relevant mixture of organochlorine compounds and polychlorinated biphenyls Promotes hepatic steatosis in male Ob/Ob mice

Hepatic steatosis is recognized as an independent risk factor for the development of cardiovascular disease. While obesity and type 2 diabetes are well‐established risk factors in the development of hepatic steatosis, recent studies have revealed exposure to mixtures of persistent organic pollutants (POPs), which are environmental contaminants in various fatty foods, can promote steatosis. Thus, the present study was designed to determine if exposure to a defined mixture of prevalent polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides or their metabolites promote hepatic steatosis in a genetically induced model of type 2 diabetes, the leptin‐deficient ob/ob mouse. Male C57BL/6J wild type (WT) or ob/ob mice were administered an environmentally relevant mixture of PCBs and OCs for 7 weeks via oral gavage. Exposure to POPs did not significantly alter fasting serum glucose or insulin levels. However, POPs exposure significantly increased hepatic triglyceride content in ob/ob animals, while decreasing serum triglyceride levels. This POPs‐mediated increase in hepatic triglyceride content did not appear to be associated with significantly increased inflammation in either the liver or adipose. Exposure to POPs significantly induced the expression of cytochrome P450 3a11 in WT animals, yet the expression of this cytochrome was significantly downregulated in ob/ob animals regardless of POPs exposure. Taken together, the present data indicate exposure to an environmentally relevant mixture of both PCBs and OC pesticides in ob/ob mice promotes hepatic steatosis while decreasing hypertriglyceridemia, which demonstrates exposure to a defined mixture of POPs alters systemic lipid metabolism in a genetically induced model of obesity and type 2 diabetes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1399–1411, 2017.     

Metabolic syndrome: nature,therapeutic solutions and options

Introduction: Metabolic syndrome (MetS) defines the clustering in an individual of multiple metabolic abnormalities, based on central obesity and insulin resistance. In addition to its five components, prothrombotic and proinflammatory states are essential features. The significance of MetS lies in its close association with the risk of type 2 diabetes and cardiovascular disease (CVD). This field being an evolving one necessitated the current review.

Areas covered: The areas covered in this review include the so far unproven concept that enhanced low-grade inflammation often leads to dysfunction of the anti-inflammatory and atheroprotective properties of apolipoprotein A – I (apoA-I) and HDL particles, which further increases the risk of diabetes and CVD. It was emphasized that lifestyle modification is essential in the prevention and management of MetS, which includes maintenance of optimal weight by caloric restriction, adherence to a diet that minimizes postprandial glucose and triglyceride fluctuations, restricting alcohol consumption, smoking cessation and engaging in regular exercise. Drug therapy should target the dyslipoproteinemia and the often associated hypertension or dysglycemia. Statins are the drugs of first choice, to be initiated in patients with MetS at high 10-year cardiovascular risk. Such treatment is inadequate if fasting serum triglycerides remain at > 150 mg/dl, when niacin should be combined. Fibrates, omega 3 fatty acids, metformin, angiotensin-converting enzyme inhibitors and pioglitazone are additional options in drug therapy.

Expert opinion: Research on MetS in subpopulations prone to impaired glucose tolerance and insulin resistance has indicated that proinflammatory state and oxidative stress are often prominently involved in MetS, to the extent that evidence of impaired function of HDL and apo A-I particles is discernible by biological evidence of functional defectiveness via outcomes studies and/or correlations with inflammatory and anti-inflammatory biomarkers. A sex difference has been clear in this development.     

Effects of Prenatal Exposure to Sheesha Smoke: Response of Juvenile Rats to Novel Environment

Abstract

The traditional tobacco smoking known as sheesha, hubble-bubble, or hoaka is a process by which a tobacco-fruit mixture is drawn through a long tube, then passed through a water trap, before its inhalation by the smoker. Recently sheesha has gained substantial popularity among pregnant woman as a safer alternative to cigarette smoking. The aim of the present work is to examine the effect of prenatal exposure to sheesha smoke on growth and locomotor activities of juvenile rats. Two-day-pregnant rats were exposed daily to sheesha smoke for 10 minutes up to day 18 pregnancy. The effect of sheesha smoke on gestation period, progeny number, and body weight was determined. The ambulatory and stereotype behavior of offspring were measured at the age of 30 days. Results show that passive exposure to sheesha smoke during pregnancy had no effects on the gestational period, number of pups, birth weight, and body weight growth. The total ambulatory activity of exposed rats was 21.1% lower than that of matched control, P = .08. The decline rate of ambulatory activity in exposed rats was 27.6% lower than that of nonexposed, P = .09. The total stereotype movements in exposed rats were 26% lower than that of nonexposed, P = .029. The decline rate of the stereotype movements in the exposed rats was 10-fold lower than that of nonexposed, P = .00006. It was concluded that prenatal exposure to sheesha smoke lowers the response of rats tc novel environments.     

肠道细菌与肥胖及2型糖尿病关系的研究进展

摘要：肠道菌群是定植在肠道的微生物群,其微生态平衡受生活环境、生活方式、饮食习惯及药物等多种因素影 响而发生改变,这些改变是多种疾病发生的病理基础。越来越多的证据显示,肠道菌群中的硬壁菌门、变形菌门、放 线菌门及拟杆菌门等,可通过免疫、代谢及生物钟途径参与肥胖及2型糖尿病（T2DM）的发生发展,目前肠道菌群与 肥胖及T2DM的关系已成为研究热点。本文就两者的相关研究进展进行综述,望有助于进一步阐明肥胖及T2DM的 发病机制,并为寻找两者的治疗靶点提供一些新的思路。     

Exposure to Perfluorooctane Sulfonate during Pregnancy in Rat and Mouse: Maternal and Prenatal Evaluations

Table 3 for     

Pharmacotherapy of obesity: emerging drugs and targets

Background: Obesity and its associated morbidities are the effects of imbalance between energy intake and expenditure. Present drugs either regulate food intake by acting on neural circuits or reduce nutrient absorption from gut. These approaches have shown moderate success, with several safety concerns, leaving an unmet need for effective and safe therapy for obesity. Objective: To provide a brief background on obesity, summarize approved drugs and give an overview of emerging therapeutic targets, their potential benefits and disadvantages. Methods: A review based on information available from medical literature. Conclusions: Potential anti-obesity targets investigated can be classified into five broad categories: i) decreasing appetite through central action; ii) increasing metabolic rate or affecting metabolism through peripheral action; iii) modulating gut peptide receptors; iv) modulating targets to affect overall cardiometabolic parameters; and v) combination therapies directed against several targets.