Showing papers in "Biofactors in 2012"
TL;DR: Those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin‐based therapies and noting the growing interest in the discovery of small molecules modifying their activities.
Abstract: Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD(+) for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex(®) , SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.
298 citations
TL;DR: Evidence is presented that Alzheimer's disease has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years, which leads to the conclusion that something in the developed environment is a major risk factor for AD.
Abstract: In this special issue about biofactors causing cognitive impairment, we present evidence for and discuss two such biofactors. One is excess copper, causing neuronal toxicity. The other is zinc deficiency, causing neuronal damage. We present evidence that Alzheimer's disease (AD) has become an epidemic in developed, but not undeveloped, countries and that the epidemic is a new disease phenomenon, beginning in the early 1900s and exploding in the last 50 years. This leads to the conclusion that something in the developed environment is a major risk factor for AD. We hypothesize that the factor is inorganic copper, leached from the copper plumbing, the use of which coincides with the AD epidemic. We present a web of evidence supporting this hypothesis. Regarding zinc, we have shown that patients with AD are zinc deficient when compared with age-matched controls. Zinc has critical functions in the brain, and lack of zinc can cause neuronal death. A nonblinded study about 20 years ago showed considerable improvement in AD with zinc therapy, and a mouse AD model study also showed significant cognitive benefit from zinc supplementation. In a small blinded study we carried out, post hoc analysis revealed that 6 months of zinc therapy resulted in significant benefit relative to placebo controls in two cognitive measuring systems. These two factors may be linked in that zinc therapy significantly reduced free copper levels. Thus, zinc may act by lowering copper toxicity or by direct benefit on neuronal health, or both.
146 citations
TL;DR: The trace metal zinc is a biofactor that plays essential roles in the central nervous system across the lifespan from early neonatal brain development through the maintenance of brain function in adults and is implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure.
Abstract: The trace metal zinc is a biofactor that plays essential roles in the central nervous system across the lifespan from early neonatal brain development through the maintenance of brain function in adults. At the molecular level, zinc regulates gene expression through transcription factor activity and is responsible for the activity of dozens of key enzymes in neuronal metabolism. At the cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Given these key roles, it is not surprising that alterations in brain zinc status have been implicated in a wide array of neurological disorders including impaired brain development, neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression. Zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.
141 citations
TL;DR: The pathogenetic role of AGEs in the development, progression and instability of atherosclerosis, and the potential targets of this biological system for the prevention and treatment of cardiovascular disease are reviewed.
Abstract: Advanced glycation endproducts (AGEs) are a group of modified molecular species formed by nonenzymatic reactions between the aldehydic group of reducing sugars with proteins, lipids, or nucleic acids. Formation and accumulation of AGEs are related to the aging process and are accelerated in diabetes. AGEs are generated in hyperglycemia, but their production also occurs in settings characterized by oxidative stress and inflammation. These species promote vascular damage and acceleration of atherosclerotic plaque progression mainly through two mechanisms: directly, altering the functional properties of vessel wall extracellular matrix molecules, or indirectly, through activation of cell receptor-dependent signaling. Interaction between AGEs and the key receptor for AGEs (RAGE), a transmembrane signaling receptor which is present in all cells relevant to atherosclerosis, alters cellular function, promotes gene expression, and enhances the release of proinflammatory molecules. The importance of the AGE-RAGE interaction and downstream pathways, leading to vessel wall injury and plaque development, has been amply established in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. Blocking the vicious cycle of AGE-RAGE axis signaling may be essential in controlling and preventing cardiovascular complications. In this article, we review the pathogenetic role of AGEs in the development, progression and instability of atherosclerosis, and the potential targets of this biological system for the prevention and treatment of cardiovascular disease.
116 citations
TL;DR: Development of S1P receptor agonists and antagonists with improved receptor subtype‐selectivity, inhibitors, or modulators of sphingolipid‐metabolizing enzymes, and their optimal drug delivery system provide novel therapeutic tactics.
Abstract: Sphingosine-1-phosphate (S1P), which acts as both the extracellular and intracellular messenger, exerts pleiotropic biological activities including regulation of formation of the vasculature, vascular barrier integrity, and lymphocyte trafficking. Many of these S1P actions are mediated by five members of the G protein-coupled S1P receptors (S1P(1) -S1P(5) ) with overlapping but distinct coupling to heterotrimeric G proteins. The biological activities of S1P are based largely on the cellular actions of S1P on migration, adhesion, and proliferation. Notably, S1P often exhibits receptor subtype-specific, bimodal effects in these cellular actions. For example, S1P(1) mediates cell migration toward S1P, that is, chemotaxis, via G(i) /Rac pathway whereas S1P(2) mediates inhibition of migration toward a chemoattractant, that is, chemorepulsion, via G(12/13) /Rho pathway, which induces Rac inhibition. In addition, S1P(1) mediates stimulation of cell proliferation through the G(i) -mediated signaling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and ERK whereas S1P(2) mediates inhibition of cell proliferation through mechanisms involving G(12/13) /Rho/Rho kinase/PTEN-dependent Akt inhibition. These differential effects of S1P receptor subtypes on migration and proliferation lead to bimodal regulation of various biological responses. An observed biological response is likely determined by an integrated outcome of the counteracting signals input by S1P receptor subtypes. More recent studies identified the new intracellular targets of S1P including the inflammatory signaling molecule TRAF2 and histone deacetylases HDAC1 and HDAC2. These interactions of S1P regulate NF-κB activity and gene expression, respectively. Development of S1P receptor agonists and antagonists with improved receptor subtype-selectivity, inhibitors, or modulators of sphingolipid-metabolizing enzymes, and their optimal drug delivery system provide novel therapeutic tactics.
107 citations
TL;DR: The inflammatory response has been implicated in the pathogenesis of many chronic diseases and the modulation of the inflammatory response by the consumption of bioactive food compounds, such as procyanidins, is a powerful tool to promote health.
Abstract: The inflammatory response has been implicated in the pathogenesis of many chronic diseases. Thus, the modulation of the inflammatory response by the consumption of bioactive food compounds, such as procyanidins, is a powerful tool to promote health. Procyanidin-mediated anti-inflammatory molecular mechanisms include, among others, the modulation of the arachidonic acid pathway, the inhibition of the gene transcription, protein expression and enzymatic activity of eicosanoid generating enzymes, the production and secretion of inflammatory mediators (such as cytokines and nitric oxide), the inhibition of mitogen-activated protein kinase (MAPK) pathway activation, and the modulation of the nuclear factor-κB (NF-κB) pathway. The NF-κB pathway can be regulated by procyanidins at several levels. During early events in NF-κB signaling, procyanidins modulate Iκκ activity, and the cytoplasmic retention of p65:p50 NF-κB by the inhibition of IκB phosphorylation and proteasomal degradation, while at late stages, they affect the nuclear translocation of pro/anti-inflammatory NF-κB homo/hetero dimers and their subsequent binding to the promoter regions of target genes. To identify and understand the value of procyanidins in the modulation of the inflammatory response, the molecular mechanisms underlying the anti-inflammatory activities and prohomeostatic effects of procyanidins need to be investigated further.
98 citations
TL;DR: An overview of what is known of the role of vitamin K in brain function is presented and data to suggest that vitamin K has the potential to influence psychomotor behavior and cognition are suggested.
Abstract: Historically discovered for its role in blood coagulation, there is now convincing evidence that vitamin K has important actions in the nervous system. As a unique cofactor to the γ-glutamyl carboxylase enzyme, vitamin K contributes to the biological activation of proteins Gas6 and protein S, ligands for the receptor tyrosine kinases of the TAM family (Tyro3, Axl, and Mer). Functionally, Gas6 has been involved in a wide range of cellular processes that include cell growth, survival, and apoptosis. In brain, vitamin K also participates in the synthesis of sphingolipids, an important class of lipids present in high concentrations in brain cell membranes. In addition to their structural role, sphingolipids are now known to partake in important cellular events such as proliferation, differentiation, senescence and cell-cell interactions. In recent years, studies have linked alterations in sphingolipid metabolism to age-related cognitive decline and neurodegenerative diseases such as Alzheimer's disease (AD). Emerging data also point to unique actions of the K vitamer menaquinone-4 (MK-4) against oxidative stress and inflammation. Finally, there is now data to suggest that vitamin K has the potential to influence psychomotor behavior and cognition. This review presents an overview of what is known of the role of vitamin K in brain function.
82 citations
TL;DR: EPC alterations will be examined in the context of macrovascular and microvascular complications of diabetes, highlighting their roles and functions in the progression of the disease.
Abstract: Diabetes mellitus is associated with an increased risk of cardiovascular disease due to its negative impact on the vascular endothelium. The damaged endothelium is repaired by resident cells also through the contribution of a population of circulating cells derived from bone marrow. These cells, termed endothelial progenitor cells (EPCs) are involved in maintaining endothelial homeostasis and contributes to the formation of new blood vessels with a process called postnatal vasculogenesis. The mechanisms whereby these cells allow for protection of the cardiovascular system are still unclear; nevertheless, consistent evidences have shown that impairment and reduction of EPCs are hallmark features of type 1 and type 2 diabetes. Therefore, EPC alterations might have a pathogenic role in diabetic complications, thus becoming a potential therapeutic target. In this review, EPC alterations will be examined in the context of macrovascular and microvascular complications of diabetes, highlighting their roles and functions in the progression of the disease.
82 citations
TL;DR: It is suggested that HA may modulate proinflammatory cytokines via its different degree of polymerization and inflammatory action may be modulated as a result of the interaction between HA and TLR-4.
Abstract: Hyaluronic acid (HA) may exert different action depending on its degree of polymerization. Small HA fragments induce proinflammatory responses, while highly polymerized HA exerts a protective effect in inflammatory pathologies such as rheumatoid arthritis. In both cases the toll-like receptor 4 (TLR-4) seems to be involved in the modulation of the inflammation process. The aim of this study was to investigate the influence of short HA oligosaccharides (HA 4-mers) and high molecular weight HA (HMWHA) in the inflammatory response in normal mouse chondrocytes. Messenger RNA and related protein levels were measured for TLR-4, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-18 (IL-18) in cells with and without the addition of HA. NF-kB activation was also evaluated. 4-mer HA treatment produced a significant up-regulation of all parameters considered while HMWHA did not exert any activity in untreated cells although it was able to reduce the effects of 4- mers HA significantly. Specific TLR-4 small interference RNA (siRNA) was used to confirm TLR-4 as the target of HA action. This study suggests that HA may modulate proinflammatory cytokines via its different degree of polymerization and inflammatory action may be modulated as a result of the interaction between HA and TLR-4.
77 citations
TL;DR: This article will consider the existing literature regarding the biological properties of vitamin E and the potential therapeutic and/or preventative roles that this natural dietary factor plays in brain aging, cognition, and Alzheimer's dementia.
Abstract: Since its discovery, vitamin E has been extensively researched by a large number of investigators in an attempt to fully understand its role in a variety of pathophysiological contexts. The vast majority of published work has focused on vitamin E's antioxidant properties, which is why it is well known as a lipophilic antioxidant that protects membranes from being oxidatively damaged by free radicals. However, several lines of investigation have recently revealed that vitamin E has biological roles unrelated to its antioxidant properties. Among these roles, vitamin E has been described as: a regulator of signal transduction, gene expression, and redox sensor. In parallel with the discovery of novels cellular functions of vitamin E, the introduction of the free radical theory of brain aging has propelled a renewed interest in this vitamin. Most of the resulting work has been based on the postulate that, by preventing and/or minimizing the oxidative stress-dependent brain damage, vitamin E could be used as therapeutic approach. In this article, we will consider the existing literature regarding the biological properties of vitamin E and the potential therapeutic and/or preventative roles that this natural dietary factor plays in brain aging, cognition, and Alzheimer's dementia.
77 citations
TL;DR: The role of iron is discussed in the progression of AD, which is associated with accumulation of numerous markers of oxidative stress and has been shown to precede hallmark neuropathological lesions early in the disease process.
Abstract: Iron is both essential for maintaining a spectrum of metabolic processes in the central nervous system and elsewhere, and potent source of reactive oxygen species. Redox balance with respect to iron, therefore, may be critical to human neurodegenerative disease but is also in need of better understanding. Alzheimer disease (AD) in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.
TL;DR: The enzyme cyclooxygenase‐2, responsible for the first committed step in the synthesis of several important mediators which are involved in both initiation and resolution of inflammation, and the subsequent generation of prostaglandins upon activation has been shown to participate in the neurodegenerative processes of a variety of diseases.
Abstract: The enzyme cyclooxygenase-2 (COX-2), responsible for the first committed step in the synthesis of several important mediators which are involved in both initiation and resolution of inflammation, and the subsequent generation of prostaglandins (PGs) upon activation has been shown to participate in the neurodegenerative processes of a variety of diseases. This review looks particular at the role of COX-2 in the pathogenesis of Parkinson's disease, involving the generation of PGs and the role of the two different parts of the cyclooxygenase-cyclooxygenase and peroxidase activity.
TL;DR: This review focuses on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context.
Abstract: The postsynaptic density protein-95/disks large/zonula occludens-1 (PDZ) protein domain family is one of the most common protein-protein interaction modules in mammalian cells, with paralogs present in several hundred human proteins. PDZ domains are found in most cell types, but neuronal proteins, for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context.
TL;DR: Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the proline degradative pathway, plays a special role in tumorigenesis and tumor development and can be understood considering the temporal and spatial context of the tumor.
Abstract: Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the proline degradative pathway, plays a special role in tumorigenesis and tumor development. Proline metabolism catalyzed by PRODH/POX is closely linked with the tricarboxylic acid (TCA) cycle and urea cycle. The proline cycle formed by the interconversion of proline and Δ(1) -pyrroline-5-carboxylate (P5C) between mitochondria and cytosol interlocks with pentose phosphate pathway. Importantly, by catalyzing proline to P5C, PRODH/POX donates electrons into the electron transport chain to generate ROS or ATP. In earlier studies, we found that PRODH/POX functions as a tumor suppressor to initiate apoptosis, inhibit tumor growth, and block the cell cycle, all by ROS signaling. It also suppresses hypoxia inducible factor signaling by increasing α-ketoglutarate. During tumor progression, PRODH/POX is under the control of various tumor-associated factors, such as tumor suppressor p53, inflammatory factor peroxisome proliferator-activated receptor gamma (PPARγ), onco-miRNA miR-23b*, and oncogenic transcription factor c-MYC. Recent studies revealed the two-sided features of PRODH/POX-mediated regulation. Under metabolic stress such as oxygen and glucose deprivation, PRODH/POX can be induced to serve as a tumor survival factor through ATP production or ROS-induced autophagy. The paradoxical roles of PRODH/POX can be understood considering the temporal and spatial context of the tumor. Further studies will provide additional insights into this protein and on its metabolic effects in tumors, which may lead to new therapeutic strategies.
TL;DR: Observations strongly suggest that adipokines, by alternatively interfering with placental development, may affect pregnancy outcome and fetal growth.
Abstract: Latter half of pregnancy is characterized by a "physiological diabetogenic state" since changes in insulin-sensitivity have been well documented. These changes ensure continuous supply of nutrients to the growing fetus. In the last years the role of adipocyte-derived signaling molecules, collectively known as adipokines has been object of different in vitro and in vivo studies. Of interest, adipokines and/or their receptors are expressed in the placental tissue which, therefore, can contribute to development of maternal insulin-resistance and, as a consequence, fetal growth. Leptin, adiponectin, and resistin represent the most well studied adipokines and, with the exception of adiponectin, their serum and placental levels increase as pregnancy progresses. High levels of adipokines have also been detected in umbilical plasma hence suggesting a possible role on fetal development and metabolism; however, it remains still unclear if such adipokines can directly stimulate fetal tissues development acting as growth factors. In addition to their well known metabolic effects, we also reported studies describing the role of adipokines in promoting proliferation and invasiveness of trophoblast cells and affecting local angiogenic processes. These observations strongly suggest that adipokines, by alternatively interfering with placental development, may affect pregnancy outcome and fetal growth. However, further studies are needed to better understand the local regulation of their expression. © 2012 International Union of Biochemistry and Molecular Biology, Inc.
TL;DR: A research framework for how nutrition affects brain aging is proposed with emphasis on AA intake, status, metabolism, and transport into brain tissue.
Abstract: This narrative review appraises the human and animal studies implicating ascorbic acid (AA) in normal cognitive function and Alzheimer's disease. A research framework for how nutrition affects brain aging is proposed with emphasis on AA intake, status, metabolism, and transport into brain tissue. A final synopsis highlights areas for future research regarding AA nourishment and healthy brain aging.
TL;DR: It is suggested that equol has the potential to be used topically for the treatment and prevention of skin aging, by enhancing ECM components in human skin.
Abstract: The purpose of this study was to investigate the effects of equol, a plant and intestinal flora derived isoflavonoid molecule on the expression of skin genes and proteins using human dermal models. As equol has been shown to mimic 17β-estradiol and bind specifically to 5α-dihydrotestostone (5α-DHT), these agents were used (in addition to equol) to determine whether equol may play important and beneficial roles in the extracellular matrix (ECM). Equol at 0.3 or 1.2% in qPCR experiments using a human skin barrier model examined ECM gene expression. Equol, 5α-DHT, and 17β-estradiol at 10 nM were studied in human monolayer fibroblasts cultures (hMFC) for ECM protein expression. Human fibroblast three-dimensional organotypic cultures revealed equol's influence (@ 10 nM) on ECM proteins via fluorescent-activated cell sorting (FACS) analysis. In qPCR experiments, equol significantly increased collagen, elastin (ELN), and tissue inhibitor of metalloprotease and decreased metalloproteinases (MMPs) gene expression and caused significant positive changes in skin antioxidant and antiaging genes. In hMFC, equol significantly increased collagen type I (COL1A1), whereas, 5α-DHT significantly decreased cell viability that was blocked by equol. FACS analysis showed equol and 17β-estradiol significantly stimulated COL1A1, collagen type III (COL3A1), and ELN while MMPs were significantly decreased compared with control values. Finally, tamoxifen blocked the positive influences of equol on ECM proteins via FACS analysis. These findings suggest that equol has the potential to be used topically for the treatment and prevention of skin aging, by enhancing ECM components in human skin.
TL;DR: The concept of mitochondrial electron‐carrier bypass is presented as a potential result of mild‐redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging, which may prevent/delay mitochondria‐driven disorders.
Abstract: Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential (-0.1 V; 0.1 V) improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. This is different from redox agents with strong negative (-0.4 V; -0.2 V) or positive (0.2 V; 0.4 V) redox potentials who alter the redox status of redox-centers (i.e., become permanently reduced or oxidized). This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB, redox potential ≅10 mV) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders.
TL;DR: Results obtained in the frame of a longitudinal study on Se and cognitive impairment are consistent with the hypothesis that low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors.
Abstract: Preventing cognitive impairment and dementia in the elderly is a major public health challenge for our century and all hypotheses should be explored. Selenium (Se) is one of the factors that may affect the risk of cognitive decline. Its importance in the health and aging process has been documented. Because of the potential of selenoproteins to protect against oxidative stress, Se raises significant expectations for the prevention of chronic diseases including cancer, cardiovascular disease, and type 2 diabetes conditions commonly associated with oxidative stress. Thus, the relationships between Se and cognitive impairment or dementia can be examined through vascular risk factors for dementia, with particular interest in diabetes and dyslipidemia. In addition, in cases of Se deficiency, the brain is the organ that remains Se replete the longest suggesting that Se plays an important role in brain functions. This article presents results obtained in the frame of a longitudinal study on Se and cognitive impairment. They are consistent with the hypothesis that low Se status is a risk factor for cognitive decline even after taking into account vascular risk factors. The concomitant evolution between plasma Se decrease over a 9-year period and cognitive decline suggested that optimal Se status is potentially important to maintain neuropsychological functions in aging people. However, as our understanding of Se biology is incomplete, epidemiological studies are needed to define the groups of population that could benefit from Se supplementation.
TL;DR: The fact that inflammatory processes are essential steps in the course of the disease offers future therapeutic targets for the interruption of the atherogenic process or for the management of acute events.
Abstract: Coronary artery disease (CAD) is one of the most common manifestations of atherosclerosis. Inflammation is considered one of the major processes that contribute to atherogenesis. Inflammation plays an important role not only on the initiation and progression of atherosclerosis but also on plaque rupture, an event that leads to acute vascular events. Various biomarkers express different pathways and pathophysiologic mechanisms of cardiovascular disease, and inflammatory biomarkers express different parts of the atherogenic process, regarding the initiation and progression of atherosclerosis or the destabilization of the atherosclerotic plaque. Therefore, inflammatory biomarkers may prove to be useful in the detection, staging, and prognosis of patients with CAD. Furthermore, the fact that inflammatory processes are essential steps in the course of the disease offers future therapeutic targets for the interruption of the atherogenic process or for the management of acute events.
TL;DR: Although high CO concentrations inhibit generally heme‐protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogen‐activated protein kinases.
Abstract: CO is a colorless and odorless gas produced by the incomplete combustion of hydrocarbons, both of natural and anthropogenic origin. Several microorganisms, including aerobic and anaerobic bacteria and anaerobic archaea, use exogenous CO as a source of carbon and energy for growth. On the other hand, eukaryotic organisms use endogenous CO, produced during heme degradation, as a neurotransmitter and as a signal molecule. CO sensors act as signal transducers by coupling a "regulatory" heme-binding domain to a "functional" signal transmitter. Although high CO concentrations inhibit generally heme-protein actions, low CO levels can influence several signaling pathways, including those regulated by soluble guanylate cyclase and/or mitogen-activated protein kinases. This review summarizes recent insights into CO metabolism, sensing, and signaling.
TL;DR: This review focuses on recent advances in the field of huntingtin disease, with a particular emphasis on the identified target proteins and the role that their oxidation has or might have in the pathophysiology of HD.
Abstract: Huntington disease (HD) is an inherited neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene, affecting initially the striatum and progressively the cortex Oxidative stress, and consequent protein oxidation, has been described as important to disease progression This review focuses on recent advances in the field, with a particular emphasis on the identified target proteins and the role that their oxidation has or might have in the pathophysiology of HD Oxidation and the resulting inactivation and/or degradation of important proteins can explain the impairment of several metabolic pathways in HD Oxidation of enzymes involved in ATP synthesis can account for the energy deficiency observed Impairment of protein folding and degradation can be due to oxidation of several heat shock proteins and Valosin-containing protein Oxidation of two enzymes involved in the vitamin B6 metabolism could result in decreased availability of pyridoxal phosphate, which is a necessary cofactor in transaminations, the kynurenine pathway and the synthesis of glutathione, GABA, dopamine and serotonin, all of which have a key role in HD pathology In addition, protein oxidation often contributes to oxidative stress, aggravating the molecular damage inside the cell
TL;DR: The suggestion that the supplementation of ubiquinol in subjects with type 2 diabetes, in addition to conventional antihyperglycemic medications, improves glycemic control by improving insulin secretion without any adverse effects is consistent with the suggestion.
Abstract: Coenzyme Q10 (CoQ10) provides the energy for vital cellular functions and is known to act as an antioxidant. We conducted an open label study to examine the clinical effects of supplementation of the reduced form of CoQ10, ubiquinol, in addition to conventional glucose-lowering agents in patients with type 2 diabetes. Nine subjects (3 males and 6 females) with type 2 diabetes and receiving conventional medication were recruited. The subjects were assigned to receive an oral dose of 200 mg ubiquinol daily for 12 weeks. The effect of ubiquinol on blood pressure, lipid profile, glycemic control, oxidative stress, and inflammation were examined before and after ubiquinol supplementation. In addition, five healthy volunteers were also assigned to receive an oral dose of 200 mg ubiquinol daily for 4 weeks to examine the effects of ubiquinol on insulin secretion. In patients with diabetes, there were no differences with respect to blood pressure, lipid profile, oxidative stress marker, and inflammatory markers. However, there were significant improvements in glycosylated hemoglobin (53.0 ± 4.3 to 50.5 ± 3.7 mmol/mol, P = 0.01) (7.1 ± 0.4 to 6.8 ± 0.4%, P = 0.03). In healthy volunteers, the insulinogenic index (0.65 ± 0.29 to 1.23 ± 0.56, P = 0.02) and the ratio of proinsulin to insulin were significantly improved (3.4 ± 1.8 to 2.1 ± 0.6, P = 0.03). The results of our study are consistent with the suggestion that the supplementation of ubiquinol in subjects with type 2 diabetes, in addition to conventional antihyperglycemic medications, improves glycemic control by improving insulin secretion without any adverse effects
TL;DR: It is concluded that AD is a multifactorial disorder kindled by vascular risk factors that generate chronic brain hypoperfusion (CBH) during advanced aging and a proactive lifestyle consisting of a healthy diet coupled to physical and mental activity should be applied as part of any therapeutic intervention.
Abstract: Despite an archive of over 73,000 research papers published in the last two decades on the subject of Alzheimer's disease (AD), little clinical progress has been made relative to how people get sporadic AD and what can be done to help them avoid it. This review spotlights strategic steps that could be a turning point in the dramatic lowering of Alzheimer prevalence. The main strategy includes application of four pillars of prevention: 1) early identification of AD vascular risk factors; 2) early detection of AD vascular risk factors; 3) early intervention of AD vascular risk factors based on evidence-based medical decisions; 4) patient follow-up to assess and modify interventions as needed. Tandem to these four pillars of prevention, a proactive lifestyle consisting of a healthy diet coupled to physical and mental activity should be applied as part of any therapeutic intervention. We are persuaded by mounting and compelling evidence that AD is a multifactorial disorder kindled by vascular risk factors that generate chronic brain hypoperfusion (CBH) during advanced aging. A pathobiological cascade of biochemical events in the presence of CBH that leads to oxidative stress and neurodegeneration appears to involve multiple biofactors including micronutrients, trace metals, lipids, and pro-oxidants, as reviewed in this special issue of BioFactors. Modulation of these biofactors may help prevent or control incipient AD. © 2012 International Union of Biochemistry and Molecular Biology, Inc.
TL;DR: The data suggests that chromium supplementation as CrP is beneficial in correcting hyperglycemia, implying that the modulation of the glucose metabolism by chromium may be therapeutically beneficial in the treatment of diabetes.
Abstract: Chromium has been recognized as an essential trace element that plays an important role in carbohydrate metabolism. However, the molecular mechanisms involved in its action are not clear. This study was undertaken to understand the mechanism of chromium action in experimental diabetes. Streptozotocin-induced diabetic animals were administered chromium as chromium picolinate (CrP) at a daily dose of 1 mg/kg body weight for a period of 4 weeks. It was observed that chromium complexed with picolinate was effective in lowering plasma glucose levels as well as was able to alleviate polyphagia, polydipsia, and weight loss in diabetic animals. Administration of chromium was also found to normalize glycogen content in liver of diabetic animals to near control levels. The reduction in plasma glucose levels by chromium was accompanied by increase in activity of glycolytic enzymes (e.g., glucokinase, phosphofructokinase, and pyruvate kinase) and by suppression in activity of gluconeogenic enzymes (e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) in liver. Hepatic glucose uptake was found to be increased by chromium supplementation as demonstrated by decrease in Km and increase in Vmax values in diabetic animals. Chromium levels were lower in the liver of diabetic rats when compared with that of control rats. A negative correlation was observed between plasma glucose and chromium concentration in patients with diabetes. The data suggests that chromium supplementation as CrP is beneficial in correcting hyperglycemia, implying that the modulation of the glucose metabolism by chromium may be therapeutically beneficial in the treatment of diabetes. © 2012 International Union of Biochemistry and Molecular Biology, Inc.
TL;DR: Despite some encouraging trials showing benefit of B‐vitamins for slowing brain atrophy and cognitive decline, the majority of these studies have not demonstrated that B‐ vitamin supplementation has protective or therapeutic cognitive benefit.
Abstract: A compelling and extensive epidemiological literature documents the strong association of inadequate status of folate, vitamin B₁₂, and to a lesser degree vitamin B6, with increased risk of neurodegenerative and cerebrovascular disease. Mildly elevated plasma total homocysteine, which is biochemically related to low status of these B-vitamins, is similarly associated with increased risk for these conditions. This, together with experimental data showing that experimental B-vitamin deficiency and/or hyperhomocysteinemia can cause a variety of neurological and vascular deficits in animals, has provided the evidence base and motivation for a growing number of large randomized, double-blind clinical trials aimed at determining the efficacy and safety of B-vitamin supplementation for preserving cognitive function in older adults. Despite some encouraging trials showing benefit of B-vitamins for slowing brain atrophy and cognitive decline, the majority of these studies have not demonstrated that B-vitamin supplementation has protective or therapeutic cognitive benefit. There are many possible explanations for the inconsistency between the clinical trials and for the discrepancy between their findings and the predictions of the epidemiological evidence. Among these are the possibility of inadequate hypotheses guiding the trials, design limitations of the individual trials, and inherent limitations of nutritional randomized clinical trials. Resolving these issues will be crucial for designing definitive trials and ultimately for guiding nutritional interventions for cognitive protection.
TL;DR: Clinical studies involving in cognitively impaired older adults with Alzheimer's disease are beginning with a variety of retinoids, and hope for demonstrating efficacy in translating these basic mechanisms to treatment of a widespread dementing illness is held.
Abstract: Retinoids are Vitamin A derivatives involved in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. Retinoids may also influence Amyloid beta processing upregulation of alpha secretase via ADAM10. Vitamin A and other retinoids also directly inhibit formation of Amyloid fibrils in vivo. These properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis. Retinoids are already used in treatment of acne vulgaris, psoriasis, neuroblastoma and acute promyelocytic leukemia. Clinical studies involving in cognitively impaired older adults with Alzheimer's disease are beginning with a variety of retinoids. These studies need to address safety issues of retinoids in older populations, and hold hope for demonstrating efficacy in translating these basic mechanisms to treatment of a widespread dementing illness.
TL;DR: The results suggest that BF% correlates with risk factors for cardiovascular disease and metabolic syndrome for both men and women, and thatBF% may be a useful predictor of risk, particularly in metabolically obese, normal weight individuals.
Abstract: Body mass index (BMI) is an important diagnostic tool for determining obesity; however, while BMI reflects the influence of body height over body weight, it does not reveal body fat percentage (BF%). We explored whether BF% correlated with risk factors for cardiovascular disease and metabolic syndrome and whether metabolically obese, normal weight people were at risk for these diseases. A total of 2,867 healthy volunteers participated in this study. Blood pressure, height, weight, waist circumference, BMI, BF%, lipid profile, fasting glucose, uric acid, and lifestyle factors were collected from healthy subjects during their annual health examinations. In both males and females, BF% correlated positively with BMI and waist circumference. Participants were divided into three groups according to BF% and data were compared between groups. The results suggest that BF% correlates with risk factors for cardiovascular disease and metabolic syndrome for both men and women, and that BF% may be a useful predictor of risk, particularly in metabolically obese, normal weight individuals.
TL;DR: It is proposed that the stimulatory effect of αT on angiogenesis and vasculogenesis is potentiated by phosphorylation to αTP, which may act as a cofactor or active lipid mediator increasing VEGF expression.
Abstract: Vitamin E was originally discovered as a dietary factor essential for reproduction in rats. Since then, vitamin E has revealed many important molecular properties such as the scavenging of reactive oxygen and nitrogen species or the modulation of signal transduction and gene expression in antioxidant and nonantioxidant manners. A congenital disease, ataxia with vitamin E deficiency, which is characterized by impaired enrichment of α-tocopherol (αT) in plasma due to mutations in the α-tocopherol transfer protein gene, has been discovered. An effect of vitamin E on angiogenesis and vasculogenesis has been observed in several studies, and recently, it has been demonstrated in the placenta of pregnant ewes, possibly involving the stimulation of vascular endothelial growth factor (VEGF) expression. We recently observed that the phosphorylated form of αT, α-tocopheryl phosphate (αTP), increases the expression of VEGF. We propose that the stimulatory effect of αT on angiogenesis and vasculogenesis is potentiated by phosphorylation to αTP, which may act as a cofactor or active lipid mediator increasing VEGF expression. Increased VEGF expression and consequent enhanced angiogenesis and vasculogenesis induced by αTP may explain not only the essential roles of vitamin E on reproduction, but also its beneficial effects against pre-eclampsia, ischemia/reperfusion injury, and during wound healing. It may also serve as a survival factor for brain and muscle cells. The finding that αTP may regulate vasculogenesis may indicate potential, important pathophysiological implications.
TL;DR: The results demonstrate that phloretin has a strong chemopreventive effect against AFB1 through its inhibitory effect on CYP1A2, CYP3A4, and its inductive effect on GST activity.
Abstract: Typically, chemopreventive agents involve either induction of phase II detoxifying enzymes and/or inhibition of cytochrome P450 enzymes (CYPs) that are required for the activation of procarcinogens. In this study, we investigated the protective effects of phloretin against aflatoxin B1 (AFB1) activation to the ultimate carcinogenic intermediate, AFB(1)-8, 9-epoxide (AFBO), and its subsequent detoxification. Phloretin markedly inhibited formation of the epoxide with human liver microsomes in a dose-dependent manner. Phloretin also inhibited the activities of nifedipine oxidation and ethoxyresorufin O-deethylase (EROD) in human liver microsomes. These data show that phloretin strongly inhibits CYP1A2 and CYP3A4 activities, which are involved in the activation of AFB1. Phloretin increased glutathione S-transferase (GST) activity of alpha mouse liver 12 (AML 12) cells in a dose-dependent manner. GST activity toward AFBO in cell lysates treated with 20 μM phloretin was 23-fold that of untreated control cell lysates. The expression of GSTA3, GSTA4, GSTM1, GSTP1 and GSTT1 was induced by phloretin in a dose-dependent manner in AML 12 cells. GSTP1, GSTM1, and GSTT1 were able to significantly increase the conjugation of AFBO with glutathione. Concurrently, induction of the GST isozyme genes was partially associated with the Nrf2/ARE pathway. Taken together, the results demonstrate that phloretin has a strong chemopreventive effect against AFB1 through its inhibitory effect on CYP1A2, CYP3A4, and its inductive effect on GST activity.