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Arterial protect, Oral probiotics, Glycation, and Cognitive decline

May 2017


Mitochondrial dysfunction, proteotoxicity, and aging: causes or effects, and the possible impact of NAD+-controlled protein glycation.

Aging is frequently characterized by the accumulation of altered proteins and dysfunctional mitochondria. This review discusses possible causes of these effects, their interdependence and the impact of energy metabolism on proteostasis, especially formation and elimination of altered proteins. It is suggested NAD+ to some degree regulates formation of aberrant proteins and generation of oxygen free-radicals and reactive oxygen species (ROS), because when NAD+ is limiting, glycolytic triose phosphates spontaneously decompose into methylglyoxal (MG), a highly deleterious glycating agent and ROS inducer. That NAD+ has stimulatory effects on stress protein expression and autophagy, while mitochondria regenerate NAD+ from NADH, further integrates energy metabolism into proteostasis. It is suggested that, as altered proteins can deleteriously interact with mitochondria, changes in synthesis, or elimination, of cytosolic error-proteins will affect mitochondrial activity. It is also suggested that functional mitochondria are essentially antiaging agents, while their dysfunction or inactivity accelerate ROS formation and aging. These proposals may also help explain the oxygen paradox that while ROS may be causal to aging, increased mitochondrial activity (i.e., oxygen utilization) suppresses aging and much associated pathology. Increased synthesis of glutathione, humanin, and mitochondrial chaperone proteins are other additional consequences of increased mitogenesis and which would help ensure proteostasis.

Adv Clin Chem. 2010;50:123-50

Aging risk factors and Parkinson's disease: contrasting roles of common dietary constituents.

Aging is a Parkinson's disease (PD) risk factor. It is suggested here that certain dietary components may either contribute to or ameliorate PD risk. There is evidence, which indicates that excessive carbohydrate (glucose or fructose) catabolism is a cause of mitochondrial dysfunction in PD, one consequence is increased production of methylglyoxal (MG). However, other dietary components (carnosine and certain plant extracts) not only scavenge MG but can also influence some of the biochemical events (signal transduction, stress protein synthesis, glycation, and toxin generation) associated with PD pathology. As double blind, placebo-controlled carnosine supplementation studies have revealed beneficial outcomes in humans, it is suggested that MG scavengers such as carnosine be further explored for their therapeutic potential toward PD.

Neurobiol Aging. 2014 Jun;35(6):1469-72.

Would carnosine or a carnivorous diet help suppress aging and associated pathologies?

Carnosine (beta-alanyl-L-histidine) is found exclusively in animal tissues. Carnosine has the potential to suppress many of the biochemical changes (e.g., protein oxidation, glycation, AGE formation, and cross-linking) that accompany aging and associated pathologies. Glycation, generation of advanced glycosylation end-products (AGEs), and formation of protein carbonyl groups play important roles in aging, diabetes, its secondary complications, and neurodegenerative conditions. Due to carnosine's antiglycating activity, reactivity toward deleterious carbonyls, zinc- and copper-chelating activity and low toxicity, carnosine and related structures could be effective against age-related protein carbonyl stress. It is suggested that carnivorous diets could be beneficial because of their carnosine content, as the dipeptide has been shown to suppress some diabetic complications in mice. It is also suggested that carnosine's therapeutic potential should be explored with respect to neurodegeneration. Olfactory tissue is normally enriched in carnosine, but olfactory dysfunction is frequently associated with neurodegeneration. Olfactory administration of carnosine could provide a direct route to compromised tissue, avoiding serum carnosinases.

Ann N Y Acad Sci. 2006 May;1067:369-74

Could carnosine or related structures suppress Alzheimer's disease?

Reactive oxygen species, reactive nitrogen species, copper and zinc ions, glycating agents and reactive aldehydes, protein cross-linking and proteolytic dysfunction may all contribute to Alzheimer's disease (AD). Carnosine (beta-alanyl-L-histidine) is a naturally-occurring, pluripotent, homeostatic agent. The olfactory lobe is normally enriched in carnosine and zinc. Loss of olfactory function and oxidative damage to olfactory tissue are early symptoms of AD. Amyloid peptide aggregates in AD brain are enriched in zinc ions. Carnosine can chelate zinc ions. Protein oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloid-beta peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation. Glycated protein accumulates in the cerebrospinal fluid (CSF) of AD patients. Homocarnosine levels in human CSF dramatically decline with age. CSF composition and turnover is controlled by the choroid plexus which possesses a specific transporter for carnosine and homocarnosine. Carnosine reacts with protein carbonyls and suppress the reactivity of glycated proteins. Carbonic anhydrase (CA) activity is diminished in AD patient brains. Administration of CA activators improves learning in animals. Carnosine is a CA activator. Protein cross-links (gamma-glutamyl-epsilon-amino) are present in neurofibrillary tangles in AD brain. gamma-Glutamyl-carnosine has been isolated from biological tissue. Carnosine stimulates vimentin expression in cultured human fibroblasts. The protease oxidised-protein-hydrolase is co-expressed with vimentin. Carnosine stimulates proteolysis in cultured myocytes and senescent cultured fibroblasts. These observations suggest that carnosine and related structures should be explored for therapeutic potential towards AD and other neurodegenerative disorders.

J Alzheimers Dis. 2007 May;11(2):229-40

Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes.

OBJECTIVE: Diabetes is characterized by marked postprandial endothelial dysfunction induced by hyperglycemia, hypertriglyceridemia, advanced glycation end products (AGEs), and dicarbonyls (e.g., methylglyoxal [MG]). In vitro hyperglycemia-induced MG formation and endothelial dysfunction could be blocked by benfotiamine, but in vivo effects of benfotiamine on postprandial endothelial dysfunction and MG synthesis have not been investigated in humans until now. RESEARCH DESIGN AND METHODS: Thirteen people with type 2 diabetes were given a heat-processed test meal with a high AGE content (HAGE; 15.100 AGE kU, 580 kcal, 54 g protein, 17 g lipids, and 48 g carbohydrates) before and after a 3-day therapy with benfotiamine (1,050 mg/day). Macrovascular flow-mediated dilatation (FMD) and microvascular reactive hyperemia, along with serum markers of endothelial disfunction (E-selectin, vascular cell adhesion molecule-1, and intracellular adhesion molecule-1), oxidative stress, AGE, and MG were measured during both test meal days after an overnight fast and then at 2, 4, and 6 h postprandially. RESULTS: The HAGE induced a maximum reactive hyperemia decrease of -60.0% after 2 h and a maximum FMD impairment of -35.1% after 4 h, without affecting endothelium-independent vasodilatation. The effects of HAGE on both FMD and reactive hyperemia were completely prevented by benfotiamine. Serum markers of endothelial dysfunction and oxidative stress, as well as AGE, increased after HAGE. These effects were significantly reduced by benfotiamine. CONCLUSIONS: Our study confirms micro- and macrovascular endothelial dysfunction accompanied by increased oxidative stress following a real-life, heat-processed, AGE-rich meal in individuals with type 2 diabetes and suggests benfotiamine as a potential treatment.

Diabetes Care. 2006 Sep;29(9):2064-71

Human pericyte-endothelial cell interactions in co-culture models mimicking the diabetic retinal microvascular environment.

Pericytes regulate vascular tone, perfusion pressure and endothelial cell (EC) proliferation in capillaries. Thiamine and benfotiamine counteract high glucose-induced damage in vascular cells. We standardized two human retinal pericyte (HRP)/EC co-culture models to mimic the diabetic retinal microvascular environment. We aimed at evaluating the interactions between co-cultured HRP and EC in terms of proliferation/apoptosis and the possible protective role of thiamine and benfotiamine against high glucose-induced damage. EC and HRP were co-cultured in physiological glucose and stable or intermittent high glucose, with or without thiamine/benfotiamine. No-contact model: EC were plated on a porous membrane suspended into the medium and HRP on the bottom of the same well. Cell-to-cell contact model: EC and HRP were plated on the opposite sides of the same membrane. Proliferation (cell counts and DNA synthesis), apoptosis and tubule formation in Matrigel were assessed. In the no-contact model, stable high glucose reduced proliferation of co-cultured EC/HRP and EC alone and increased co-cultured EC/HRP apoptosis. In the contact model, both stable and intermittent high glucose reduced co-cultured EC/HRP proliferation and increased apoptosis. Stable high glucose had no effects on HRP in separate cultures. Both EC and HRP proliferated better when co-cultured. Thiamine and benfotiamine reversed high glucose-induced damage in all cases. HRP are sensitive to soluble factors released by EC when cultured in high glucose conditions, as suggested by conditioned media assays. In the Matrigel models, addition of thiamine and benfotiamine re-established the high glucose-damaged interactions between EC/HRP and stabilized microtubules.

Acta Diabetol. 2012 Dec;49 Suppl 1:S141-51

Augmentation of blood lipid glycation and lipid oxidation in diabetic patients.

Lipid oxidation plays a role in the pathophysiology of several diseases, including diabetes. Patients with type 2 diabetes show abnormally high plasma levels of phosphatidylcholine hydroperoxide (PCOOH). However, little is known about the biochemical processes that increase plasma PCOOH in diabetes. We hypothesized that "glycated lipid moieties" may form in diabetic plasma and cause oxidative stress resulting in PCOOH formation. To evaluate this hypothesis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed to analyze Amadori-glycated phosphatidylethanolamine (Amadori-PE, an early stage Maillard product), as well as the advanced glycation end products (AGE) carboxymethyl-PE (CM-PE) and carboxyethyl-PE (CE-PE). The product ion scan, neutral loss scanning, and multiple reaction monitoring provide useful structural and quantitative information about Amadori-PE, CM-PE, and CE-PE in diabetic plasma and erythrocytes. We found that plasma and erythrocyte Amadori-PE concentrations were significantly higher in diabetic patients (757±377 nM plasma, 2793±989 nM packed cells) than in normal subjects (165±66 nM plasma, 712±52 nM packed cells), and that Amadori-PE concentrations were positively correlated with PCOOH. By contrast, no significant differences were observed in blood AGE-PE concentrations between diabetic patients (CM-PE: 7.7±3.5 nM plasma, 528±83 nM packed cells; CE-PE: 2.5±1.1 nM plasma, 82±24 nM packed cells) and normal subjects (CM-PE: 6.6±3.1 nM plasma, 705±533 nM packed cells; CE-PE: 4.2±1.5 nM plasma, 68±16 nM packed cells). These results suggest that Amadori-PE is more prone to accumulation in the blood with diabetes than CM-PE or CE-PE. This review describes the involvement of blood lipid glycation and lipid oxidation in the development of diabetes.

Clin Chem Lab Med. 2014 Jan 1;52(1):47-52

Glycation of plasma lipoprotein lipid membrane and screening for lipid glycation inhibitor.

We recently reported that phosphatidylethanolamine (PE)-linked Amadori product (Amadori-PE) increased abnormally in diabetic plasma. However, the glycation mechanism of human plasma low-density lipoprotein (LDL) is still unclear. Moreover, lipid glycation inhibitors have yet to be discovered. In this study, we compared the glycation kinetics of LDL lipid and LDL protein in vitro and screened lipid glycation inhibitors. LDL-PE was converted to Amadori-PE followed by LDL protein (apoB) glycation. Pyridoxal 5'-phosphate could easily react with PE before the glucose-PE reaction, and the PE-pyridoxal 5'-phosphate adduct was detected in human red blood cells. Pyridoxal 5'-phosphate can be used in diabetes prevention.

Ann N Y Acad Sci. 2008 Apr;1126:288-90