Aβ exerts prooxidant or antioxidant effects based on the metal ion concentrations that it sequesters from the cytosol; at low metal ion concentrations, it is an antioxidant, whereas at relatively higher concentration it is a prooxidant. Thus Alzheimer disease (AD) treatment strategies based solely on the amyloid-β clearance should be re-examined in light of the vast accumulating evidence that increased oxidative stress in the human brains is the key causative factor for AD. Accumulating evidence indicates that the reduced brain glucose availability and brain hypoxia, due to the relatively lower concentration of ATP and 2,3-diphosphoglycerate, may be associated with increased concentration of endogenous ammonia, a potential neurotoxin in the AD brains. In this review, we summarize the progress in this area, and present some of our ongoing research activities with regard to brain Amyloid-β, systemic ammonia, erythrocyte energy metabolism and the role of 2,3-diphosphoglycerate in AD pathogenesis.

Amyloid-beta peptide (Abeta) is believed to be a central player in the Alzheimer disease (AD) pathogenesis. However, its mechanisms of toxicity to the central nervous system are unknown. To explore this area, investigators have recently focused on Abeta-induced cellular dysfunction. Extensive research has been conducted to investigate Abeta monomers and oligomers, and these multiple facets have provided a wealth of data from specific models. Abeta appears to be accumulated in neuronal mitochondria and mediates mitochondrial toxicity. Mitochondrial dysfunction became a hallmark of Abeta-induced neuronal toxicity. Mitochondria are currently considered as primary targets in the pathobiology of neurodegeneration. This review provides an overview of the Abeta toxicity to isolated mitochondria, mitochondria in different tissues and cells in vitro and in vivo. Full texts and abstracts from all 530 biomedical articles listed in PubMed and published before January 2014 were analysed. The mechanisms underlying the interaction between Abeta and mitochondrial membranes and resulting mitochondrial dysfunction are most disputed issues. Understanding and discussing this interaction is essential to evaluating Abeta effects on various intracellular metabolic processes.

Subject age and brain oxidative stress play pivotal roles in Alzheimer disease (AD) pathology. Erythrocytes (red blood cells: RBC) are considered as passive "reporter cells" for the oxidative status of the whole organism, not active participants in mechanisms of AD pathogenesis and are not well studied in AD. The aim of this work is to assess whether the antioxidant status and energy state of RBC from elderly people change in AD. We measured levels of key products and enzymes of oxidative metabolism in RBC from AD (n = 12) and non-Alzheimer dementia (NA, n = 13) patients, as well as in cells from age-matched controls (AC, n = 14) and younger adult controls (YC, n = 14). Parameters of the adenylate system served to evaluate the energy state of RBC. In both aging and dementia, oxidative stress in RBC increased and exhibited elevated concentrations of H₂O₂ and organic hydroperoxides, decreased the GSH/GSSG ratio and glutathione-S-transferase activity. Reductions in the ATP levels, adenine nucleotide pool size (AN) and adenylate energy charge accompanied these oxidative disturbances. The patterns of changes in these indices between groups strongly correlated with each other, Spearman rank correlation coefficients being r(s) = 1.0 or -1.0 (p < 0.01). Alterations of the RBC parameters of oxidative stress and adenylate metabolism were nonspecific and interpreted as age-related abnormalities. Decreased glutathione peroxidase activity in RBC may be considered as a new peripheral marker for AD.

Alzheimer's disease (AD) is a slowly progressive, neurodegenerative disorder of uncertain etiology. According to the amyloid cascade hypothesis, accumulation of non-soluble amyloid β peptides (Aβ) in the Central Nervous System (CNS) is the primary cause initiating a pathogenic cascade leading to the complex multilayered pathology and clinical manifestation of the disease. It is, therefore, not surprising that the search for mechanisms underlying cognitive changes observed in AD has focused exclusively on the brain and Aβ-inducing synaptic and dendritic loss, oxidative stress, and neuronal death. However, since Aβ depositions were found in normal non-demented elderly people and in many other pathological conditions, the amyloid cascade hypothesis was modified to claim that intraneuronal accumulation of soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, is the first step of a fatal cascade in AD. Since a characteristic reduction of cerebral perfusion and energy metabolism occurs in patients with AD it is suggested that capillary distortions commonly found in AD brain elicit hemodynamic changes that alter the delivery and transport of essential nutrients, particularly glucose and oxygen to neuronal and glial cells. Another important factor in tissue oxygenation is the ability of erythrocytes (red blood cells, RBC) to transport and deliver oxygen to tissues, which are first of all dependent on the RBC antioxidant and energy metabolism, which finally regulates the oxygen affinity of hemoglobin. In the present review, we consider the possibility that metabolic and antioxidant defense alterations in the circulating erythrocyte population can influence oxygen delivery to the brain, and that these changes might be a primary mechanism triggering the glucose metabolism disturbance resulting in neurobiological changes observed in the AD brain, possibly related to impaired cognitive function. We also discuss the possibility of using erythrocyte biochemical aberrations as potential tools that will help identify a risk factor for AD.

Angiotensin-converting enzyme inhibitors are effective at reducing blood pressure, whereas statins decrease plasma cholesterol, impeding atherosclerosis. The authors hypothesize that these medications may improve blood pressure by modifying the arginase-nitric oxide synthase system of erythrocytes. In this study, the effects of lisinopril alone versus lisinopril + simvastatin on erythrocyte and plasma arginase enzyme and nitric oxide metabolites are compared. Patients with atherosclerosis and hypertension are randomly assigned to receive lisinopril 10 to 20 mg/d or lisinopril 10 to 20 mg/d plus simvastatin 20 mg/d for 24 weeks. Higher arginase activity is observed in erythrocytes from 100% of patients and mainly recovered after 12 and 24 weeks of treatment with lisinopril or lisinopril + simvastatin. Plasma arginase activity is 3 orders of magnitude lower than erythrocyte arginase activity in all participants, suggesting a lack of its clinical significance. Both treatments cause the increase in plasma $$\hbox{ N }{\hbox{ O }}_{2}^{-}$$ , $$\hbox{ N }{\hbox{ O }}_{3}^{-}$$ , and $$\hbox{ N }{\hbox{ O }}_{2}^{-}$$ + $$\hbox{ N }{\hbox{ O }}_{3}^{-}$$ in 100% of patients. Erythrocyte $$\hbox{ N }{\hbox{ O }}_{2}^{-}$$ + $$\hbox{ N }{\hbox{ O }}_{3}^{-}$$ concentration is greatly decreased in hypertensive patients but recovers after monotherapy and combined therapy. The results show for the first time that lisinopril monotherapy and combined lisinopril + simvastatin therapy exhibit pronounced and equipotential normalizing effects on erythrocyte arginase and nitric oxide synthase activities.

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Alzheimer’s disease (AD) is a fatal form of dementia of unknown etiology. Although amyloid plaque accumulation in the brain has been the subject of intensive research in disease pathogenesis and anti-amyloid drug development; the continued failures of the clinical trials suggest that amyloids are not a key cause of AD and new approaches to AD investigation and treatment are needed. We propose a new hypothesis of AD development based on metabolic abnormalities in circulating red blood cells (RBCs) that slow down oxygen release from RBCs into brain tissue which in turn leads to hypoxia-induced brain energy crisis; loss of neurons; and progressive atrophy preceding cognitive dysfunction. This review summarizes current evidence for the erythrocytic hypothesis of AD development and provides new insights into the causes of neurodegeneration offering an innovative way to diagnose and treat this systemic disease.

UDC 547.972Investigations have been made of leafy shoots of four morphologically very close species of rhododendrons belonging to the subspecies Rhodorastrum (Maxim.) Drude: Rh. sichotense Pojark, Rh. mucronulatum (Turcz.) Worosc., Rh. dauricum L.,. The raw material for analysis was collected in regions of the natural area (Altai, Kharaborovskii krai, Primor'e).The total flavonoids were extracted with 80% ethanol. Purification was carried out with chloroform. The flavonoids were isolated with ethyl acetate from the concentrated aqueous alcoholic extract. After elimination of the ethyl acetate, 10 g of total flavonoids was deposited on a column (2.8 • 60 cm) of Woelm polyamide. Elution was performed with chloroform and a chloroform-methanol gradient with increasing concentrations of methanol. The eluates were monitored with the aid of thin-layer chromatography on Silufol UV-254 plates in chloroform (7:3) and by chromatography on FN-12 paper in the butan-l-ol-acetic acid-water (4:1:2.2) system. The fractions freed from accompanying substances (coumarins and phenolic acids) were combined and subjected to separation into individual components with the aid of two-dimensional paper chromatography in the butan-l-ol-acetic acid-water (4:1:2.2) (first direction) and water (second direction) systems.A mixture of substances of flavonoid nature was isolated. The four predominating components (1)-(4) were identified.Substances (1) and (2), having the nature of glycosides, were subjected to acid hydrolysis. One and the same aglycon was isolated from the products of their hydrolysis, and this was identified from physicochemical characteristics, the results of UV spectroscopy with complex-forming and ionizing reagents, and comparison with an authentic specimen as 3,3',4',5,7pentahydroxyflavone (quercetin). The sugar component of substance (1) was D-galactose and that of substance (2) was Larabinose, as was shown by paper chromatography of the hydrolysates in comparison with standard sugars.Substance (1) --C21H20012, mp 238-240~ kmax(C2H5OH ) 361, 258 nm. By comparison with an authentic specimen it was identified as 3,3',4',5,7-pentahydroxyflavone 3-O-/~-D-galactopyranoside --hyperoside.Substance (2) --C20H18Oll, mp 210-213~ ~max(C2H5OH) 360, 260 nm. By comparison with an authentic specimen it was identified as 3,3',4',5,7-pentahydroxyflavone 3-O-/3-L-arabofuranoside --avicularin. Substances (3) and (4) were free aglycons: (3) --quercetin, mp 318-320~ kmax(C2H5OH) 370, 270 nm; (4) --myricetin --mp 351-355~ )~nax(C2H5OH) 375, 255 nm.In all four of the rhododendron species studied we detected quercetin, myricetin, hyperoside, and avicularin chromatographically and preparatively, which agrees with literature reports for other species of Dahurian rhododendrons [4][5][6][7]. In view of the results of investigations of other rhododendron species [8][9][10][11], hyperoside, avicularin, and quercetin may be assigned to the constant substances of the whole Rhododendron L. genus. This is the first time that hyperoside, avicularin, quercet...