New potentials for 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase inhibitors: Possible applications in retarding diabetic complications

The prevalence of diabetes mellitus is increasing all over the world and it is apparent that treatment of diabetic complications has the same importance as primary diabetes treatment and glycemic control. Diabetic complications occur as a result of prolonged hyperglycemia and its consequences, such as advanced glycation end products and reactive oxygen species. Impairment of lipid profile is also contributed to worsening diabetic complications. Therefore, it seems that the application of lipid-lowering agents may have positive effects on reversing diabetic complications besides glycemic control. Statins, a group of lipid-lowering compounds, have been shown to exert antioxidant, immunomodulatory, anti-inflammatory, and antiproliferative properties beyond their lipid-lowering effects. Furthermore, they have been reported to improve diabetic complications with different pathways. In this review, we will discuss the clinical importance, molecular biology of the most important microvascular/macrovascular diabetic complications, possible application of statins and their mechanism of action in retarding these complications.     

Protective effects of plant-derived natural products on renal complications

Diabetic nephropathy is the leading cause of renal failure worldwide. This debilitating disorder has several underlying pathophysiologic mechanisms, and therefore a variety of pharmacologic agents have been developed to prevent or treat diabetic nephropathy; however, synthetic drugs may possess unfavorable side effects. In response to this, the global use of herbal-based pharmacologic agents is increasing among diabetic patients. Numerous studies have reported therapeutic benefits of herbal-based compounds against diabetes-induced renal dysfunction. These agents can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress, inflammation, apoptosis, necrosis, and nitric oxide deprivation that lead to vascular injuries. In the current study, we have reviewed the beneficial properties of the most common herbal agents used in renal complications and diabetic nephropathy.     

Advanced glycation end products and diabetic retinopathy

Studies have established hyperglycemia as the most important factor in the progress of vascular complications. Formation of advanced glycation end products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that hyperglycemia contributes to the pathogenesis of diabetic complications including retinopathy. However, their role in diabetic retinopathy remains largely unknown. This review discusses the chemistry of AGEs formation and their patho-biochemistry particularly in relation to diabetic retinopathy. AGEs exert deleterious effects by acting directly to induce cross-linking of long-lived proteins to promote vascular stiffness, altering vascular structure and function and interacting with receptor for AGE, to induce intracellular signaling leading to enhanced oxidative stress and elaboration of key proinflammatory and prosclerotic cytokines. Novel anti-AGE strategies are being developed hoping that in next few years, some of these promising therapies will be successfully evaluated in clinical context aiming to reduce the major economical and medical burden caused by diabetic retinopathy.     

AMPK in microvascular complications of diabetes and the beneficial effects of AMPK activators from plants

BackgroundDiabetes mellitus is a multifactorial disorder with the risk of micro- and macro-vascular complications. High glucose-induced derangements in metabolic pathways are primarily associated with the initiation and progression of secondary complications namely, diabetic nephropathy, neuropathy, and retinopathy. Adenosine monophosphate-activated protein kinase (AMPK) has emerged as an attractive therapeutic target to treat various metabolic disorders including diabetes mellitus. It is a master metabolic regulator that helps in maintaining cellular energy homeostasis by promoting ATP-generating catabolic pathways and inhibiting ATP-consuming anabolic pathways. Numerous pharmacological and plant-derived bioactive compounds that increase AMP-activated protein kinase activation has shown beneficial effects by mitigating secondary complications namely retinopathy, nephropathy, and neuropathy.PurposeThe purpose of this review is to highlight current knowledge on the role of AMPK and its activators from plant origin in diabetic microvascular complications.MethodsSearch engines such as Google Scholar, PubMed, Science Direct and Web of Science are used to extract papers using relevant key words. Papers mainly focusing on the role of AMPK and AMPK activators from plant origin in diabetic nephropathy, retinopathy, and neuropathy was chosen to be highlighted.ResultsAccording to results, decrease in AMPK activation during diabetes play a causative role in the pathogenesis of diabetic microvascular complications. Some of the plant-derived bioactive compounds were beneficial in restoring AMPK activity and ameliorating diabetic microvascular complications.ConclusionAMPK activators from plant origin are beneficial in mitigating diabetic microvascular complications. These pieces of evidence will be helpful in the development of AMPK-centric therapies to mitigate diabetic microvascular complications.     

Narrative review of the effects of antidiabetic drugs on albuminuria

Diabetes mellitus is the most prevalent metabolic disorder worldwide. Glycemic control is the main focus of antidiabetic therapy. However, there are data suggesting that some antidiabetic drugs may have intrinsic beneficial renal effects and protect against the development and progression of albuminuria, thus minimizing the risk of diabetic nephropathy. These pharmacological agents can suppress upstream molecular pathways involved in the pathophysiology of diabetes-induced renal dysfunction such as oxidative stress, inflammatory responses, and apoptosis. In this narrative review, the pathophysiology of albuminuria in patients with diabetic nephropathy is discussed. Furthermore, the renoprotective effects of antidiabetic drugs, focusing on albuminuria, are reviewed.     

糖尿病肾病的发病机制和药物干预研究进展

糖尿病肾病作为糖尿病最严重的并发症之一,也是糖尿病患者最主要的死亡原因之一。糖尿病肾病的发病机制主要与代谢紊乱、 血流动力学紊乱、氧化应激、炎症及遗传因素等相关。综述糖尿病肾病发病机制及相关药物治疗的研究新进展,为糖尿病肾病的早期干 预和治疗提供参考。     

A review of the anti-inflammatory properties of antidiabetic agents providing protective effects against vascular complications in diabetes

The global prevalence of Type 2 diabetes mellitus and its associated complications are growing rapidly. Although the role of hyperglycemia is well recognized in the pathophysiology of diabetic complications, its exact underlying mechanisms are not fully understood. In this regard, accumulating evidence suggests that the role of inflammation appears pivotal, with studies showing that most diabetic complications are associated with an inflammatory response. Several classes of antidiabetic agents have been introduced for controlling glycemia, with evidence that these pharmacological agents may have modulatory effects on inflammation beyond their glucose-lowering activity. Here we review the latest evidence on the anti-inflammatory effects of commonly used antidiabetic medications and discuss the relevance of these effects on preventing diabetic complications.     

The effects of microRNAs in activating neovascularization pathways in diabetic retinopathy

Diabetic retinopathy (DR) is one of the major complications of diabetes mellitus that causes diabetic macular edema and visual loss. DR is categorized, based on the presence of vascular lesions and neovascularization, into non-proliferative and proliferative DR. Vascular changes in DR correlate with the cellular damage and pathological changes in the capillaries of blood-retinal barrier. Several cytokines have been involved in inducing neovascularization. These cytokines activate different signaling pathways which are mainly responsible for the complications of DR. Recently; microRNAs (miRNAs) have been introduced as the key factors in the regulation of the cytokine expression which plays a critical role in neovascularization of retinal cells. Some studies have demonstrated that changing levels of miRNAs have essential role in the pathophysiology of vascular changes in patients with DR. The aim of this study is to identify the effects of miRNAs in the pathogenesis of DR via activating neovascularization pathways.     

Molecular mechanisms by which aerobic exercise induces insulin sensitivity

Insulin resistance is a key feature of Type 2 diabetes and an important therapeutic target to address glycemic control to prevent diabetic complications. Lifestyle advice is the first step in the ADA/EASD consensus guidelines followed by metformin therapy. Aerobic exercise (AE) can increase insulin sensitivity by several molecular pathways including upregulation of insulin transporters in the cellular membrane of insulin-dependent cells. In addition, AE improves insulin sensitivity by amelioration of the pathophysiologic pathways involved in insulin resistance such as the reduction of adipokines, inflammatory and oxidative stress responses, and improvement of insulin signal transduction via different molecular pathways. This review details the molecular pathways by which AE induces beneficial effects on insulin resistance     

Anti-inflammatory effects of resolvins in diabetic nephropathy: Mechanistic pathways

The incidence of diabetes mellitus is growing rapidly. The exact pathophysiology of diabetes is unclear, but there is increasing evidence of the role of the inflammatory response in both developing diabetes as well as its complications. Resolvins are naturally occurring polyunsaturated fatty acids that are found in fish oil and sea food that have been shown to possess anti-inflammatory actions in several tissues including the kidneys. The pathways by which resolvins exert this anti-inflammatory effect are unclear. In this review we discuss the evidence showing that resolvins can suppress inflammatory responses via at least five molecular mechanisms through inhibition of the nucleotide-binding oligomerization domain protein 3 inflammasome, inhibition of nuclear factor κB molecular pathways, improvement of oxidative stress, modulation of nitric oxide synthesis/release and prevention of local and systemic leukocytosis. Complete understanding of these molecular pathways is important as this may lead to the development of new effective therapeutic strategies for diabetes and diabetic nephropathy.     

Omega-3 fatty acids: molecular approaches to optimal biological outcomes

PURPOSE OF REVIEW: This review discusses recent advances in delineating basic mechanisms underlying the beneficial effects of omega-3 fatty acids on health and on disease. RECENT FINDINGS: While a substantial number of studies have delineated many differences between the biological effects of saturated versus polyunsaturated fatty acids, less is known about the long-chain omega-3 fatty acids commonly present in certain fish oils. In this review, we focus on recent studies relating to basic mechanisms whereby omega-3 fatty acids modulate cellular pathways to exert beneficial effects on promoting health and decreasing risks of certain diseases. We will use, as examples, conditions of the cardiovascular, neurological, and immunological systems as well as diabetes and cancer, and then discuss basic regulatory pathways. SUMMARY: Omega-3 fatty acids are major regulators of multiple molecular pathways, altering many areas of cellular and organ function, metabolism and gene expression. Generally, these regulatory events lead to "positive" endpoints relating to health and disease.     

Defining the molecular basis of tumor metabolism: a continuing challenge since Warburg's discovery

Cancer cells are the product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of cell survival, proliferation, differentiation and death mechanisms. The role of oncogene activation and tumor suppressor inhibition in the onset of cancer is well established. Traditional antitumor therapies target specific molecules, the action/expression of which is altered in cancer cells. However, since the physiology of normal cells involves the same signaling pathways that are disturbed in cancer cells, targeted therapies have to deal with side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal metabolism displayed by cancer cells has been highlighted by many studies. Recently, the study of tumor metabolism has received much attention because metabolic transformation is a crucial cancer hallmark and a direct consequence of disturbances in the activities of oncogenes and tumor suppressors. In this review we discuss tumor metabolism from the molecular perspective of oncogenes, tumor suppressors and protein signaling pathways relevant to metabolic transformation and tumorigenesis. We also identify the principal unanswered questions surrounding this issue and the attempts to relate these to their potential for future cancer treatment. As will be made clear, tumor metabolism is still only partly understood and the metabolic aspects of transformation constitute a major challenge for science. Nevertheless, cancer metabolism can be exploited to devise novel avenues for the rational treatment of this disease.     

Effects of arrhythmogenic lipid metabolites on the L-type calcium current of diabetic vs. non-diabetic rat hearts

Accumulation of lipid metabolites, such as palmitoylcarnitine and lysophosphatidylcholine, is thought to be a major contributor to the development of cardiac arrhythmias during myocardial ischemia. This arrhythmogenicity is likely due to the effects of these metabolites on various ion channels. Diabetic hearts have been shown to accumulate much higher concentrations of these lipid metabolites during ischemia, which may be an important factor in the enhanced incidence of arrhythmias in diabetic hearts. However, it is not known whether these metabolites have similar effects on the ion channels of diabetic hearts as in non-diabetic hearts. Previous studies on myocytes from non-diabetic hearts have reported either enhancement or inhibition of L-type calcium current (I_Ca) by these lipid metabolites. Thus, it is not clear whether the effects of palmitoylcarnitine and/or lysophosphatidlycholine on I_Ca contribute to the enhanced arrhythmogenicity of diabetic hearts or protect against arrhythmias. We determined the effect of exogenous palmitoylcarnitine and lysophosphatidylcholine on the (I_Ca) in ventricular myocytes from streptozotocin-diabetic and non-diabetic rat hearts under identical conditions. We found that palmitoylcarnitine and lysophosphatidylcholine exhibited a dose-dependent inhibition of I_Ca, which was virtually identical in diabetic and non-diabetic cardiac myocytes. Thus, we conclude that these arrhythmogenic lipid metabolites have similar actions on calcium channels in diabetic and non-diabetic hearts. Therefore, the greater susceptibility of diabetic hearts to arrhythmias during myocardial ischemia is not due to an altered sensitivity of the L-type calcium channels to lipid metabolites, but may be explained, in large part, by the greater accumulation of these metabolites during ischemia.     

Cell-based therapies for the preterm infant

The severely preterm infant receives a multitude of life-saving interventions, many of which carry risks of serious side effects. Cell therapy is an important and promising arm of regenerative medicine that may address a number of these problems. Most forms of cellular therapy use stem/progenitor cells or stem-like cells, which have the capacity to migrate, engraft and exert anti-inflammatory effects. Although some of these cell-based therapies have made their way to clinical trials in adults, little headway has been made in the neonatal patient group. This review discusses the efficacy of cell therapy in preclinical studies to date and their potential applications to diseases that afflict many prematurely born infants. Specifically, we identify the major hurdles that must be overcome before cell therapies can be safely used in the neonatal intensive care unit.     

Elabela may regulate SIRT3-mediated inhibition of oxidative stress through Foxo3a deacetylation preventing diabetic-induced myocardial injury

Diabetic cardiomyopathy—pathophysiological heart remodelling and dysfunction that occurs in absence of coronary artery disease, hypertension and/or valvular heart disease—is a common diabetic complication. Elabela, a new peptide that acts via Apelin receptor, has similar functions as Apelin, providing beneficial effects on body fluid homeostasis, cardiovascular health and renal insufficiency, as well as potentially beneficial effects on metabolism and diabetes. In this study, Elabela treatment was found to have profound protective effects against diabetes-induced cardiac oxidative stress, inflammation, fibrosis and apoptosis; these protective effects may depend heavily upon SIRT3-mediated Foxo3a deacetylation. Our findings provide evidence that Elabela has cardioprotective effects for the first time in the diabetic model.     

Antiangiogenic mechanisms of diet-derived polyphenols

Accumulating evidence demonstrates that polyphenols in natural products are beneficial against human lethal diseases such as cancer and metastasis. The underlying mechanisms of anti-cancer effects are complex. Recent studies show that several polyphenols, including epigallocatechin-3-gallate (EGCG) in green tea and resveratrol in red wine, inhibit angiogenesis when administrated orally. These polyphenols have direct effects on suppression of angiogenesis in several standard animal angiogenesis models. Because angiogenesis is involved in many diseases such as cancer, diabetic retinopathy and chronic inflammations, the discovery of these polyphenols as angiogenesis inhibitors has shed light on the health beneficial mechanisms of natural products, which are rich in these molecules. At the molecular level, recent studies have provided important information on how these molecules inhibit endothelial cell growth. Perhaps the greatest therapeutic advantage of these small natural molecules over large protein compounds is that they can be administrated orally without causing severe side effects. It is anticipated that more polyphenols in natural products will be discovered as angiogenesis inhibitors and that these natural polyphenols could serve as leading structures in the discovery of more potent, synthetic angiogenesis inhibitors.