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Medicinal Applications of Bioactive Compounds |
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Medicinal Applications of Bioactive Compounds

Mini Review

Pages: 1 - 6

Physiological and Pathological Roles of Aldose Reductase in Schwann Cells

Kazunori Sango, Koichi Kato, Masami Tsukamoto, Naoko Niimi, Kazunori Utsunomiya and Kazuhiko Watabe

Aldose reductase (AR), the first enzyme in the polyol pathway, is predominantly localized to Schwann cells in the peripheral nervous system (PNS). The exaggerated glucose flux into the pathway via AR in Schwann cells under diabetic conditions is thought to be a major contributing factor in the pathogenesis of diabetic neuropathy, and the restoring effects of AR inhibitors on the neurological symptoms of experimental diabetic animals and patients with diabetes have been investigated. In contrast, however, much less attention has been paid to the physiological functions of AR in the PNS and other tissues (i.e. osmoregulation, aldehyde detoxification, and steroid and catecholamine metabolism). In this paper, we focus on the functional significance of AR in Schwann cells under normal and diabetic conditions. A spontaneously immortalized adult mouse Schwann cell line IMS32 displays distinct Schwann cell phenotypes and high glucose (30 mM)-induced upregulation of AR expression and accumulation of sorbitol and fructose. This cell line can be a useful model to study the physiological and pathological roles of AR in the PNS, especially the interactions between the polyol pathway and other pathogenetic factors of diabetic neuropathy, and the functional redundancy of AR and other enzymes in aldehyde detoxification.

 

Review Article

Pages: 1 - 7

Functional and Morphological Evaluation of the Mesenteric Artery, Kidney and Liver from Obese Rats: Impact of a High Fat Diet plus Fructose

Thalita Rocha, Isabela Ressineti Mendes, Tatiana Mendes Costa, Amanda Gonçalves Ravos, Rudson A Ribeiro Oliveira, Mário Angelo Claudino and Fernanda Bruschi Marinho Priviero

Obesity is a worldwide problem of public health which is taking epidemic proportions. One of the main consequences of obesity is the development of cardiovascular diseases, which in turn, is the main cause of death in Brazil and in the world. Aim: To evaluate functional and morphological changes in the mesenteric artery, kidney and liver in obesity induced by high fat diet plus fructose. Methods: Male Wistar rats were submitted to a normolipidic diet (3.8% of fat–control group) or hyperlipidic diet (59% fat–HFD+F group) associated with fructose (100 mg/ml) in the drinking water during 12 weeks, starting at the 4th week of life. Initial and final body weight and epididymal fat, glucose tolerance and lipidic profile were evaluated. The superior mesenteric artery was removed for functional and histological analysis. Renal and hepatic functions were measured by plasma levels of specific metabolites and enzymes. The kidney and liver were also collected for histology. Results: In HFD+F group, it was observed increased body weight gain, epididymal fat and plasma levels of triglycerides while glucose tolerance was diminished. In the mesenteric artery, endothelium-dependent relaxation was reduced, with no changes in the endothelium-independent relaxation. Morphologically, no changes were seen in the vascular endothelium and smooth muscle. The kidney did not present functional and histological changes whereas the liver presented lipid accumulation, without changes on its function. Conclusion: Our data suggest that the high fat diet plus fructose induced endothelial dysfunction without structural changes on the vascular endothelium and smooth muscle. In this model of obesity, renal function and morphology were preserved while the hepatic tissue showed histological changes which are suggestive of a simple non-alcoholic steatosis.

 

Short Communication

Pages: 1 - 3

A Short Note on Our Study on Gestational Diabetes Mellitus from Bedside to Bench

Jie Yan and Huixia Yang

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Review Article

Pages: 1 - 9

Pulmonary Arterial Hypertension and Insulin Resistance

Elisa A Bradley and David Bradley

The clinical recognition of pulmonary arterial hypertension (PAH) is increasing, and with recent therapeutic advances, short-term survival has improved. In spite of these advances, however, PAH remains a disease with substantial morbidity and long-term mortality. The pathogenesis of PAH involves a complex interaction of local and distant cytokines, growth factors, co-factors, and transcription factors occurring in the right genetic and environmental setting. These factors ultimately lead to the detrimental changes in vascular anatomy and function seen in PAH patients. An important association between obesity/insulin resistance and PAH has recently been identified. Both conditions occur in the presence of a chronic low-grade inflammatory state, and although it is unlikely that a single pathway is solely responsible for the observed association, deficiencies in adiponectin, apolipoprotein E (ApoE) and peroxisome proliferator-activator receptor gamma (PPAR-γ) activity likely play a prominent role. Although incompletely understood, it is clear that further investigation is warranted and the role of weight loss and improved glycemic control in the treatment of at-risk patients with PAH and obesity should be determined.

 

Review Article

Pages: 1 - 7

The Unholy Alliance between Obesity, Type-2 Diabetes, the Sympathetic Nervous System, and Hypertension in Young/Middle-Aged Subjects

JM Cruickshank

There is an obesity/type-2 diabetes (DM2)/hypertension epidemic in developed countries around the world. The purpose of this review is to examine the interrelationships between obesity, DM2 and hypertension in young/middleaged subjects, highlighting the importance of raised sympathetic nerve activity and treatment implications. Central obesity is associated with insulin-resistance, and high plasma insulin and leptin levels. Insulin and leptin act upon the mid-brain, resulting in increased sympathetic nerve activity and blood pressure. Chronically raised sympathetic nerve activity, independent of blood pressure, is a powerful predictor of myocardial infarction in the middle-aged. Weight-loss, via life-style change or bariatric surgery, results in blood pressure reduction. Anti-hypertensive agents that increase sympathetic nerve activity, e.g. diuretics, dihydropyridine calcium antagonists, and angiotensin receptor blockers (ARBs), do not reduce (and may increase) the risk of myocardial infarction in younger/middleaged subjects with hypertension and DM2. Beta-1 blockade, which is effective in regressing and stabilising coronary atheromataous plaque, is preferable to ACE-inhibition, and is the first-line treatment of choice.

 

Research Article

Pages: 0 - 0

The PPAR P12A Locus-Associated Diabetes Risk is Modulated by Central Obesity in Punjabi Sikhs

Anuradha Subramanian, Patrick Dib, Gurpreet S. Wander, Sarju K Ralhan and Dharambir K Sanghera

Background: Several studies have reported a common proline-to-alanine substitution (P12A) in the peroxisome proliferator-activated receptor gamma (PPARγ) gene to be invariably associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and dyslipidemia. The purpose of this study was to determine whether the PPARγ gene (P12A) polymorphism contributes to susceptibility to T2DM and central obesity in Khatri Sikh community from India. Methods: We studied 1711 subjects comprising 1186 individuals from 324 families and 525 unrelated nondiabetic controls. We tested the association between T2D and P12A polymorphism using logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on obesity, glucose homeostasis and lipid traits using multiple linear regression analysis. Results: Our findings could not confirm the association of PPARγ polymorphism with T2DM in this familybased sample. However, the comparison of unrelated controls with affected relatives (n=537) revealed a marginally significant association with this locus with T2DM (odds ratio (OR) 1.48, P=0.016). However, in the data stratified by traits related to abdominal obesity, there was a significant increase in T2DM risk in the individuals with waist circumference (>37 inches, OR 3.51, P=0.005) and waist to hip ratio (>0.95, OR 3.02, P= 0.003) in younger relatives. Conclusions: PPARγ (P12A) locus appears to have profound influence in promoting insulin sensitivity through its interaction with central obesity particularly at younger age.

Review Article

Pages: 1 - 7

The Emerging Role of Sirtuin 1,-3 and -4 in Glucose and Lipid Metabolism and in Diabetes Mellitus

Emin Murat Akbas, Levent Demirtas, Ayd?n Guclu, Fatih Mehmet Erdur, Fatih Ozcicek and Kultigin Turkmen

Diabetes mellitus has been accepted as an epidemic worldwide during the last two decades. Despite the diagnostic tools and therapeutic approaches, the pathophysiology of this metabolic disorder and cellular defensive mechanisms remain mysterious. The maintenance of cellular homeostasis requires well-organized network between glucose, amino acid and lipid metabolism. Sirtuins are a group of nicotinamide adenine dinucleotide dependent proteins that are involved in cellular homeostasis by their deacetylating activity. Among them, sirtuin 1,-3 and -4 have been the most extensively explored. In the present review, we aimed to discuss the role of associated sirtuins in glucose and lipid metabolism and in the pathogenesis and treatment of diabetes mellitus.

 

Mini Review

Pages: 1 - 7

Obesity and Retinopathy in Diabetes

Snježana KaÅ¡telan, Martina TomiÄ?, Antonela GveroviÄ? Antunica and Jasminka Salopek RabatiÄ?

Diabetes mellitus a chronic metabolic disorder is a fast-growing global problem with significant social, health and economic consequences. It is estimated to have affected 366 million people worldwide and is expected to nearly double by 2030 with this rising trend observed for both type 1 and type 2 diabetes. An ageing population and rising prevalence of obesity reaching almost epidemic proportions are the main reasons for this increase. Diabetic retinopathy (DR) a common and progressive microvascular complication of diabetes represents one of the leading causes of vision impairment and blindness in working-age adults in developed countries. Epidemiological and clinical studies have confirmed that the main risk factors for DR are diabetes duration, prolonged poor glycaemic control, hypertension and hyperlipidemia. In addition to the well-known risk factors increasing attention is assigned to obesity specifically due to its frequency and inter-relationship with diabetes. To date this relationship has been examined in a number of epidemiologic studies giving conflicting results with most studies confirming the positive association. Although the underlying pathophysiological mechanisms supporting the relationship between obesity and DR are yet to be defined several biological theories have been suggested comprising the potential involvement of platelet function, blood viscosity, aldose reductase activity, vaso proliferative parameters, oxidative stress and inflammation. Given that weight is changeable and can be modified by lifestyle intervention opens up implications for further research and intervention in order to elucidate the role of obesity and body weight variations on the pathogenesis of DR.

 

Research Article

Pages: 1 - 6

MINOR (NR4A3) Overexpression in Mouse Skeletal Muscle Enhances Insulin Action

Wei Zhang, John Garvey W, Nanlan Luo, W Timothy Garvey and Yuchang Fu

MINOR (Mitogen-Inducible Nuclear Orphan Receptor) is one member of the NR4A3 nuclear orphan receptor family which are immediate early gene products involved in neuroendocrine regulation, neural differentiation, liver regeneration, cell apoptosis, and mitogenic and inflammatory stimulation in different cell types. We have found that MINOR can modulate insulin action and the glucose transport system in 3T3-L1 adipocytes; however, MINOR is highly expressed in skeletal muscle and its function in vivo is not well understood. To determine the role of MINOR in vivo, we have generated a mouse model that has the MINOR gene specifically expressed in the skeletal muscle using a muscle creatine kinase (MCK) promoter, and investigated whether the gene functions of MINOR would be linked to insulin action in vivo since skeletal muscle is one of the primary target tissues for insulin action. We demonstrate that these MCK-MINOR transgenic mice have reduced body weight due to a reduction of fat mass inside the body. Mice with MINOR overexpression also have improved insulin and glucose tolerances, reduced plasma levels of triglyceride, cholesterol and free fatty acid as well as enhanced expression of genes which are related to insulin action and its signaling pathways. Thus, MINOR functions in skeletal muscle act to improve insulin sensitivity and glucose intolerances and regulate insulin action and lipid and energy expenditure process.

 

Review Article

Pages: 1 - 9

Diabetes-Associated Kidney and Vascular Complications: Mechanisms of Disease Progression and Alternative Therapeutic Options

Sara Gallo, Maddalena Gili, Gabriele Togliatto and Maria Felice Brizzi

Vascular complications in diabetes are an emergent health care problem. Accelerated endothelial dysfunction in pathological settings connoted by hyperlipidaemia and hyperglycaemia is a crucial step for the development and the progression of atherosclerosis. Previous data support the central role of Advanced Glycated End-products (AGEs) and oxidation or glycation of Low Dense Lipoproteins (LDLs) in the impaired vascular remodelling associated with diabetes. Hyperglycemia, via NADPH Oxidase (NOX) enzymatic activity, upholds the production of Reactive Oxygen Species (ROS), which in turn mediate tissue damage and long-lasting “metabolic memory”. Nonetheless, in diabetic setting, ROS act as secondary messenger to strictly control stemness of visceral-derived adipose stem cells and to promote transcriptional and post-transcriptional events, also involving small non-coding microRNAs (miRs). In this article we provide an overview on the events elicited by acute and chronic hyperglycemia that account for vascular and kidney diseases. The deleterious effects of LDL and fatty acids on endothelial progenitor cells in condition connoted by hyperglycemia are also discussed. Moreover, as current therapeutic approaches failed to improve endothelial dysfunction/disease progression and consequently long-term outcomes in diabetics with vascular complications, particular attention has been devoted to describe efforts made to identify novel therapeutic options, for the management of one of the most relevant health care problems world wide. Finally, as targeting of epigenetic mechanisms is a future challenge, relevant data supporting their deep involvement in long-lasting “metabolic memory” have been also addressed.

 

Research Article

Pages: 1 - 5

DNA Oxidative Damage is Correlated with JNK Activation in Hepatocytes from Rats with Experimental Insulin Resistance

Zagayko AL, Kravchenko GB, Krasilnikova OA and KochubeyJu I

Oxidative stress was improved as the main complication for a variety of pathological conditions. The present study was aimed to investigate the effect of insulin resistance development on c-Jun-N-terminal kinases (JNK) activity and DNA/RNA oxidative damage in rat’s liver under fructose rich diet. Total JNK, phosphorylated JNK-1 and JNK-2 ([pThr183/Tyr185] c-Jun N-terminal protein kinase (pJNK1/2), and 8-hydroxy-2`-deoxyguanosine (8-OHdG) amounts were measured in hepatocyte lysate. Glucose, insulin, free fatty acids, and triacylglicerols concentration and thiobarbituric acid reactive substances concentrations were measured in blood plasma. Catalase and superoxide dismutase activity, and thiobarbituric acid reactive substances (TBARS) were determined in liver homogenate. Fructose rich diet in rats provoked the insulin resistance that is accompanied by deep metabolic abnormalities detected in our study. These metabolic abnormalities induced by fructose overload are associated with an enhanced oxidative stress which appears to deregulate the JNK pathway. Consequently, accumulation of DNA/RNA oxidative damage stress marker – 8-OHdG– in hepatocytes positively correlates with JNK activity in the cells.

 

Review Article

Pages: 1 - 5

Calcitonin and Parathyrin are Glucoregulating Hormones

Moisa SS and Nozdrachev AD

The comprehensive literature data and our findings about calcium-regulating hormones participant in the glucose metabolism is analyzed. It is showed calcitonin hyperglycemic effect and its mechanisms, established contra-insulin effect of calcitonin to insulin under the pre-receptor, cell level and liver. It is ascertained the impairment of glucose metabolism under calcitonin - hyperglycemia, insulin resistance and glucose intolerance. It is showed the data of combinative effect of calcitonin and calcium antagonists on glucose metabolism. It is discussed calcitonin diabetogenic effect and the role of calcium antagonists in the correction of hyperglycemia and tissue's insulin resistance. It was revealed the effect of parathyrin on glucose, occurring in decreasing the glucose level and increases glucose tolerance. It is concluded about participant of calcium-regulating hormones in the regulation of glucose metabolism.

 

Mini Review

Pages: 1 - 4

Review of Vaccine Induced Immune Overload and the Resulting Epidemics of Type 1 Diabetes and Metabolic Syndrome, Emphasis on Explaining the Recent Accelerations in the Risk of Prediabetes and other Immune Mediated Diseases

J Barthelow Classen MD

There has been an epidemic of inflammatory diseases that has paralleled the epidemic on iatrogenic immune stimulation with vaccines. Extensive evidence links vaccine induced immune over load with the epidemic of type 1 diabetes. More recent data indicates that obesity, type 2 diabetes and other components of metabolic syndrome are highly associated with immunization and may be manifestations of the negative feedback loop of the immune system reacting to the immune overload. The epidemic of diabetes/prediabetes appears to be accelerating at a time when the prevalence of obesity has stabilized, indicating that the negative feedback system of the immune system has been over whelmed. The theory of vaccine induced immune overload can explain the key observations that have confounded many competing hypothesis. The current paper reviews the evidence that vaccine induced immune overload explains the disconnect between the increase in prediabetes and nonalcoholic fatty liver at a time when the obesity epidemic is waning in children.

 

Review Article

Pages: 1 - 7

Hypothalamic Alterations in Obesity

Simone van de Sande-Lee and Licio A Velloso

Obesity is a major public health problem. Excess adiposity reflects an imbalance between food intake and energy expenditure, resulting from complex interactions between genetic and environmental factors. In animals and humans, the control of energy homeostasis is performed by the Central Nervous System (CNS) through neuroendocrine connections, in which circulating peripheral hormones such as leptin and insulin provide a signal to specialized neurons of the hypothalamus reflecting body fat stores, and inducing appropriate responses to maintain the stability of these stores. Obesity is commonly associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways and results in hyperphagia, decreased energy expenditure and ultimately obesity. Recent evidence, obtained from neuroimaging studies and analysis of inflammatory markers in the cerebrospinal fluid of obese subjects, suggest that similar alterations may be also found in humans. In this review, we briefly present the mechanisms involved with deterioration of homeostatic control of energy balance in animal models of obesity and the current evidence of hypothalamic dysfunction in obese humans.

 

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Citations: 3919

Molecular and Genetic Medicine received 3919 citations as per Google Scholar report

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