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•In Alzheimer’s disease (AD) amyloid beta (Aβ) enhances hyperphosphorylation of tau.•p-tau 181, p-tau 217, and p-tau 231 distinguish AD from healthy populations.•Arginine and ...ascorbate reduce tau phosphorylation at positions 181, 217, and 231.•Arginine and ascorbate induce release of heparan sulfate from glypican-1.
Alzheimer’s disease (AD) is characterized by accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (Tau-P) in the brain. Aβ enhances the activity of kinases involved in the formation of Tau-P. Phosphorylation at Thr 181 determines the propagation of multiple tau phosphorylations. Aβ is derived from the amyloid precursor protein (APP). Cleavage of APP by β-secretase also initiates release of heparan sulfate (HS) from the proteoglycan glypican-1 (GPC1).
In this study, we have explored possible connections between GPC1 expression, HS release, APP processing and Tau-P formation in human neural stem cells.
GPC1 formation was suppressed by using CRISPR/Cas9 and increased by using a vector encoding GPC1. HS release from GPC1 was increased by growing cells in medium containing Arg and ascorbate. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies/antisera recognizing Aβ, GPC1, HS released from GPC1, total Tau, and Tau phosphorylated at Thr-181, 217 or 231. The latter have been used as blood biomarkers for AD.
Suppression of GPC1 expression resulted in increased phosphorylation at Thr 181 and Thr 217. When GPC1 was overexpressed, phosphorylation at Thr 217 decreased. Stimulation of HS release from GPC1 diminished tau phosphorylation at all of the three Thr positions, while expression of GPC1 was unaffected. Simultaneous stimulation of HS release and APP processing by the cytokine TNF-α also suppressed tau phosphorylation.
The increased release of GPC1-derived HS may interfere with Aβ formation and/or Aβ interaction with tau.
A fluorometric turn-on assay is described for ascorbic acid (AA). It is based on the controlled release of polyallylamine-stabilized gold nanoclusters (polyallylamine-AuNCs) from MnO.sub.2 ...nanosheets. In an aqueous solution of near-neutral pH value, the positively charged capped AuNCs are adsorbed on the surface of the negatively charged MnO.sub.2 nanosheets. The adsorption leads to the quenching of the fluorescence of the AuNCs. However, in the presence of AA, MnO.sub.2 is reduced to Mn.sup.2+. This causes the destruction of the MnO.sub.2 nanosheets. As a result, the fluorescence of the polyallylamine-AuNCs at 615 nm is recovered. This method for determination of AA is inexpensive, sensitive, and selective. It works in the 0.01 to 200 muM concentration range and has a 3.2 nM detection limit (for S/N = 3).
The Pharmacokinetics of Vitamin C Lykkesfeldt, Jens; Tveden-Nyborg, Pernille
Nutrients,
10/2019, Letnik:
11, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The pharmacokinetics of vitamin C (vitC) is indeed complex. Regulated primarily by a family of saturable sodium dependent vitC transporters (SVCTs), the absorption and elimination are highly ...dose-dependent. Moreover, the tissue specific expression levels and subtypes of these SVCTs result in a compartmentalized distribution pattern with a diverse range of organ concentrations of vitC at homeostasis ranging from about 0.2 mM in the muscle and heart, and up to 10 mM in the brain and adrenal gland. The homeostasis of vitC is influenced by several factors, including genetic polymorphisms and environmental and lifestyle factors such as smoking and diet, as well as diseases. Going from physiological to pharmacological doses, vitC pharmacokinetics change from zero to first order, rendering the precise calculation of dosing regimens in, for example, cancer and sepsis treatment possible. Unfortunately, the complex pharmacokinetics of vitC has often been overlooked in the design of intervention studies, giving rise to misinterpretations and erroneous conclusions. The present review outlines the diverse aspects of vitC pharmacokinetics and examines how they affect vitC homeostasis under a variety of conditions.
Introduction Iron has a significant effect on the quantity and quality of agriculture products. Factors affecting the absorption of this element increase its efficiency. Meanwhile, the pH of the ...nutrient solution plays an important role in the absorption of iron. Iron is one of the essential elements for plant growth and plays an essential role in chloroplasts. Due to iron deficiency, the activity of several enzymes such as catalase, cytochrome and oxidase and ferroxin is significantly reduced. The amount of iron in the soil is high, but plants only absorb two-capacity of soluble soil, which is negligible compared to the total iron. Soil environmental conditions affect the amount of iron by the plant, so it is difficult to control the uptake of iron by the plant. It has the highest ability to absorb iron and manganese at pH less than 6. For this reason, acetic acid was used to stabilize the pH of the solution. Acetic Acid is a polar solvent and an organic compound. The use of inexpensive organic acid and citric acid in agriculture, despite its positive effects on calcareous soils and their reasonable price is still not common in Iran. Acetic acid has a carboxylic group and therefore has all the properties of an acid.Materials and methods This experiment was carried out in the form of double split-split plot in a completely randomized block design on a strawberry plant of diamant cultivar in the research station of Mohaghegh Ardabili University during the years 2015- 2017. Factors included Acetic Acid (0, 1, 2 and %3), iron in two levels (Sequestrin 25gr and Nano 1gr) along with two levels of agricultural soap agents (0 and % 7/5) as foliar spraying. Foliar application of pH nutrient solution from the three-leaf stage of plant (mid-April) to the end of May a total of five times 10 days apart in both years. Two weeks after the last foliar application (June of the second year) plant growth indices including, total chlorophyll, number of fruits per plant, fruit pH, total acidity, soluble solids, fruit volume, fruit fresh weight, fruit dry weight, and leaf iron content and fruit yield per plant was measured.Result The results of this study showed that the three-way interaction of foliar application of Acetic Acid with iron with agricultural Soap on the average concentration of leaf iron and number of fruits at the probability level was %5 and in total chlorophyll at the %1 probability level was significant, the best result in the mentioned traits was the combination of treatment of Acetic Acid %2 with Sequestrin iron with soap Moyan (%7/5). The interaction effect of Acetic Acid and iron type on traits of fruit pH, fruit volume, fruit fresh and dry weight at %5 probability level and in yield at %1 probability level were significant. Fruit volume, fruit fresh weight and fruit dry weight and yield showed the best results due to treatment combination of %2 Acetic Acid with Sequestrin iron fertilizer. But for fruit pH trait, the best results were related to the treatment of Acetic Acid %3 on the leave of Sequestrin iron. The Interaction of the iron and agricultural Soap was significant on the amount of soluble solids at %5 probability level and the total acidity strawberries fruit was significant at %1 probability level. In the case of soluble soild and Acidity, Sequestrin iron treatment and agricultural soap had the best results. According to the results of this study, the combination %2 Acetic Acid with of iron fertilizer Sequesterin in combination with agricultural soap Moyan (%7/5) due to the reduction in leaf area tensions improves the obsorption of iron and the quantitative and quality characteristics strawberries.Conclusion Based on the findings of this research, it can be concluded that Acetic acid %2, has better result on the absorption of iron fertilizer, along with agricultural soap (% 7/5) application than other treatments and qualitative traits of strawberry fruit. In treatment %2 Acetic acid most measured traits such as total chlorophyll, leaf iron, fresh weight, fruit dry weight and yield has shown a significant increase. Acetic acid by reducing the pH of the cell sauce and increasing the activity of the reductase enzyme increase the iron solubility and easily provides the iron to the plant. Due to the pH alkalinity of most soils in Iran, the use of Acetic acid in iron nutrient solution on the absorption of iron Sequestrin in combination with % 7/5 of agricultural soap due to having a hydrophilic head and a hydrophobic with %40 to %50 increase in effective of foliar fertilizers. As a result, with more absorption it can be an advanced approach to better absorption of iron by plant and increase the quantity and quality in the product.
Clinical studies have reported that increased epileptiform and subclinical epileptiform activity can be detected in many patients with an Alzheimer's disease (AD) diagnosis using electroencephalogram ...(EEG) and this may correlate with poorer cognition. Ascorbate may have a specific role as a neuromodulator in AD as it is released concomitantly with glutamate reuptake following excitatory neurotransmission. Insufficiency may therefore result in an exacerbated excitatory/inhibitory imbalance in neuronal signaling. Using a mouse model of AD that requires dietary ascorbate (Gulo−/-APPswe/PSEN1dE9), EEG was recorded at baseline and during 4 weeks of ascorbate depletion in young (5-month-old) and aged (20-month-old) animals. Data were scored for changes in quantity of spike trains, individual spikes, sleep-wake rhythms, sleep fragmentation, and brainwave power bands during light periods each week. We found an early increase in neuronal spike discharges with age and following ascorbate depletion in AD model mice and not controls, which did not correlate with brain amyloid load. Our data also show more sleep fragmentation with age and with ascorbate depletion. Additionally, changes in brain wave activity were observed within different vigilance states in both young and aged mice, where Gulo−/-APPswe/PSEN1dE9 mice had shifts towards higher frequency bands (alpha, beta, and gamma) and ascorbate depletion resulted in shifts towards lower frequency bands (delta and theta). Microarray data supported ascorbate insufficiency altering glutamatergic transmission through the decreased expression of glutamate related genes, however no changes in protein expression of glutamate reuptake transporters were observed. These data suggest that maintaining optimal brain ascorbate levels may support normal brain electrical activity and sleep patterns, particularly in AD patient populations where disruptions are observed.
•Decreased ascorbate causes downregulation of genes related to glutamate signaling.•Increased epileptiform activity with AD pathology and ascorbate insufficiency.•Ascorbate depletion increases sleep fragmentation with more bouts of wake time.•AD pathology causes shifts towards higher brain wave frequencies.•Ascorbate depletion causes shifts towards lower brain wave frequencies.
The efficacy of vitamin C in age-related hearing loss, i.e., presbycusis, remains debatable. On a separate note, inflammation induced by the NOD-like receptor family pyrin domain containing 3 (NLRP3) ...inflammasome is involved in the progression of presbycusis. In this study, we investigated the effect of vitamin C on male C57BL/6 mice’s presbycusis and NLRP3 inflammasome. The results showed that vitamin C treatment improved hearing, reduced the production of inflammatory factors, inhibited NLRP3 inflammasome activation, and decreased cytosolic mitochondrial DNA (mtDNA) in the C57BL/6 mouse cochlea, inferior colliculus, and auditory cortex. According to this study, vitamin C protects auditory function in male C57BL/6 presbycusis mice through reducing mtDNA release, inhibiting the NLRP3 inflammasome activation in the auditory pathway. Our study provides a theoretical basis for applying vitamin C to treat presbycusis.
The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials to investigate whether IV high-dose vitamin C improves the short-term mortality of patients ...with sepsis.
This study is a systematic review and meta-analysis of randomized controlled trials. We searched EMBASE, the Cochrane Central Register of Controlled Trials, and MEDLINE for randomized controlled trials that met inclusion criteria. The protocol was registered at the University hospital Medical Information Network Clinical Trials Registry (UMIN000040528). All analyses were presented with the use of random-effects models. The primary outcome was short-term mortality defined as 28-day, 30-day, or in-hospital mortality.
Two authors independently evaluated the following eligibility criteria: 1) randomized controlled trial, 2) patients with sepsis aged ≥18 years, and 3) received intravenous high-dose vitamin C in addition to standard of care, or standard of care alone. Then, two authors independently extracted the selected patient and study characteristics and outcomes from studies that met above eligibility criteria.
Eleven randomized controlled trials (n = 1,737 patients) were included in this meta-analysis. High-dose IV vitamin C was not associated with a significantly lower short-term mortality (risk ratio, 0.88; 95% CI, 0.73-1.06; p = 0.18; I2 = 29%) but was associated with a significantly shorter duration of vasopressor use (standardized mean difference, -0.35; 95% CI, -0.63 to -0.07; p < 0.01; I2 = 80%) and a significantly greater decline in the Sequential Organ Failure Assessment score at 72-96 hours (standardized mean difference, -0.20; 95% CI, -0.32 to -0.08; p < 0.01; I2 = 16%). One study reported significant association with hypernatremia, but adverse effects were rare, and high-dose vitamin C is deemed relatively safe.
In this meta-analysis, the use of IV high-dose vitamin C in patients with sepsis was not associated with lower short-term mortality although it was associated with significantly shorter duration of vasopressor use and greater decline in the Sequential Organ Failure Assessment score at 72-96 hours.
Background: Azithromycin (AZ) is a part of the azalide subclass of macrolides, it has a potential antiviral and anti-inflammatory effects and it has been used to treat COVID-19.Vitamin C (VIT. C); ...L-Ascorbic acid is an antioxidant that can combat free radicals in the body, thereby decreases inflammation. It is also required for collagen complex and speed wound healing. Objectives: This work aimed to study the histopathological changes in the kidney of adult albino rats induced by AZ and the possible protective role of VIT. C. Material and Methods: Forty five adult albino rats were used in this study. They were divided into equal 3 groups; group I(Control),group II (AZ) and group III(AZ + VIT. C). Drugs were administrated via intragastric route by stomach tube daily for successive two weeks. Rats were sacrificed and tissue samples were collected and processed for histopathological and immunohistochemical (IHC) examination. Results: Histological evaluation of AZ group showed abnormal structure of the renal cortex, some renal corpuscles revealed dilatation of renal spaces, cells of the proximal and distal convoluted tubules showed marked vacuolations in their cytoplasm and shrinkage of nuclei, some empty spaces, hemorrhages and mononuclear cellular infiltration. IHC examination showed significant increase in both Caspase 3 and tumor necrosis factor-α(TNF-α) immune stain. Group III showed restoration of kidney structure in H&E and IHC stained sections. Conclusion: Azithromycin induced renal adverse side effect, VIT.C can reduce this nephrotoxicity, due to its antioxidant, anti-inflammatory, and anti- fibrotic properties.
The human sodium-dependent vitamin C transporter-1 (hSVCT1) is localized at the apical membrane domain of polarized intestinal and renal epithelial cells to mediate ascorbic acid (AA) uptake. ...Currently, little is known about the array of interacting proteins that aid hSVCT1 trafficking and functional expression at the cell surface. Here we used an affinity tagging (‘One-STrEP’) and proteomic approach to identify hSVCT1 interacting proteins, which resolved secretory carrier-associated membrane protein-2 (SCAMP2) as a novel accessary protein partner. SCAMP2 was validated as an accessory protein by co-immunoprecipitation with hSVCT1. Co-expression of hSVCT1 and SCAMP2 in HEK-293 cells revealed both proteins co-localized in intracellular structures and at the plasma membrane. Functionally, over-expression of SCAMP2 potentiated 14C-AA uptake, and reciprocally silencing endogenous SCAMP2 decreased 14C-AA uptake. Finally, knockdown of endogenous hSVCT1 or SCAMP2 impaired differentiation of human-induced pluripotent stem cells (hiPSCs) toward a neuronal fate. These results establish SCAMP2 as a novel hSVCT1 accessary protein partner that regulates AA uptake in absorptive epithelia and during neurogenesis.
Throughout evolution, a number of animals including humans have lost the ability to synthesize ascorbic acid (ascorbate, vitamin C), an essential molecule in the physiology of animals and plants. In ...addition to its main role as an antioxidant and cofactor in redox reactions, recent reports have shown an important role of ascorbate in the activation of epigenetic mechanisms controlling cell differentiation, dysregulation of which can lead to the development of certain types of cancer. Although fruits and vegetables constitute the main source of ascorbate in the human diet, rising its content has not been a major breeding goal, despite the large inter- and intraspecific variation in ascorbate content in fruit crops. Nowadays, there is an increasing interest to boost ascorbate content, not only to improve fruit quality but also to generate crops with elevated stress tolerance. Several attempts to increase ascorbate in fruits have achieved fairly good results but, in some cases, detrimental effects in fruit development also occur, likely due to the interaction between the biosynthesis of ascorbate and components of the cell wall. Plants synthesize ascorbate
mainly through the Smirnoff-Wheeler pathway, the dominant pathway in photosynthetic tissues. Two intermediates of the Smirnoff-Wheeler pathway, GDP-D-mannose and GDP-L-galactose, are also precursors of the non-cellulosic components of the plant cell wall. Therefore, a better understanding of ascorbate biosynthesis and regulation is essential for generation of improved fruits without developmental side effects. This is likely to involve a yet unknown tight regulation enabling plant growth and development, without impairing the cell redox state modulated by ascorbate pool. In certain fruits and developmental conditions, an alternative pathway from D-galacturonate might be also relevant. We here review the regulation of ascorbate synthesis, its close connection with the cell wall, as well as different strategies to increase its content in plants, with a special focus on fruits.
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