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The biological role of D-glucaric acid and its derivatives: Potential use in medicine
Abstract
D-glucaric acid is a natural non-toxic compound produced in small amounts by mammals, including humans. In mammals, D-glucaric acid and D-glucaro-l,4-lactone are end-products of the D-glucuronic acid pathway. The enzyme D-glucuronolactone dehydrogenase has been found to be responsible for the oxidation of the lactone of D-glucuronic acid to D-glucaro-l,4;6,3-dilactone. This dilactone hydrolyzes spontaneously in aqueous solution to D-glucaro-l,4-lactone, a potent beta-glucuronidase inhibitor. D-glucaric acid is also found in many fruits and vegetables, with the highest concentrations found in grapefruits, apples, oranges, and cruciferous vegetables. b-glucuronidase is present in the circulation and probably all vertebrate tissues and is capable of hydrolyzing glucuronide conjugates. This enzyme is also produced by colonic microflora. Elevated b-glucuronidase activity is associated with an increased risk for various cancers, particularly hormone-dependent cancers such as breast and prostate cancer. D-glucaro-l,4-lactone increases detoxification of carcinogens and tumor promoters by inhibiting b-glucuronidase and preventing the hydrolysis of their glucuronides. D-glucaro-l,4-lactone was found to be formed from supplemented D-glucarate salt in the stomach and it is absorbed from the intestinal track, transported with the blood to different internal organs, and excreted in urine and, to a lesser extent, in bile. D-glucaro-l,4-lactone and its precursors exert their anticancer action in part through alterations in steroidogenesis accompanied by changes in the hormonal environment and proliferative status of the target organs. D-glucarates not only suppress cell proliferation and inflammation, but also induce apoptosis. By supplementing D-glucarates, one can favor the body's natural defense mechanism for eliminating carcinogens and tumor promoters and their effects.
... D-glucarates not only suppress cell proliferation and inflammation, but also induce apoptosis. By supplementing D-glucarates, one can enhance the body's natural defense mechanism for eliminating carcinogens, tumor promoters and their effects (39)(40)(41). ...
In this study, it was aimed to demonstrate the short-term effect of breast cancer surgery and tumor removal on the metabolomic profiles of patients with early-stage breast cancer. This cohort consisted of 18 early-stage breast carcinoma patients who had breast cancer surgery to remove tumor and surrounding tissues. The blood samples obtained preoperatively and 24 h after surgery were used in this investigation. Gas chromatography-mass spectrometry (GC-MS) based metabolomic analysis was performed to determine the metabolites. The GC-MS-based metabolomics profile enabled the identification of 162 metabolites in the plasma samples. Postoperatively, glyceric acid, phosphoric acid, O-phosphocolamine, 2-hydroxyethyliminodiacetic acid, N-acetyl-D-mannosamine, N-acetyl-5-hydroxytryptamine, methyl stearate, methyl oleate, iminodiacetic acid, glycerol 1-phosphate, β-glycerol phosphate and aspartic acid were found to be significantly increased (P < 0.05 for all), whereas saccharic acid, leucrose, gluconic acid, citramalic acid and acetol were significantly decreased (P < 0.05 for all). Breast cancer surgery and tumor removal has an impact on the metabolomic profiles of patients with early-stage breast cancer. These findings can be used for understanding the pathogenesis of breast cancer biology and screening the success of the surgery.
... The synthesis of glucaric acid in particular has been widely acknowledged for its high value. With applications in many industries, glucaric acid has being listed as one of the most valueadded chemicals by the US Department of Energy [45][46][47]. However, conventional methods for glucaric acid production often require intense pressures, temperatures and harsh chemicals [48]. ...
Humanity’s overreliance on fossil fuels for chemical and energy production has resulted in uncontrollable carbon emissions that have warranted widespread concern regarding global warming. To address this issue, there is a growing body of research on renewable resources such as biomass, of which cellulose is the most abundant type. In particular, the electrochemical reforming of biomass is especially promising, as it allows greater control over valorization processes and requires milder conditions. Driven by renewable electricity, electroreforming of biomass can be green and sustainable. Moreover, green hydrogen generation can be coupled to anodic biomass electroforming, which has attracted ever-increasing attention. The following review is a summary of recent developments related to electroreforming cellulose and its derivatives (glucose, hydroxymethylfurfural, levulinic acid). The electroreforming of biomass can be achieved on the anode of an electrochemical cell through electrooxidation, as well as on the cathode through electroreduction. Recent advances in the anodic electroreforming of cellulose and cellulose-derived glucose and 5-hydrooxylmethoylfurural (5-HMF) are first summarized. Then, the key achievements in the cathodic electroreforming of cellulose and cellulose-derived 5-HMF and levulinic acid are discussed. Afterward, the emerging research focusing on coupling hydrogen evolution with anodic biomass reforming for the cogeneration of green hydrogen fuel and value-added chemicals is reviewed. The final chapter of this paper provides our perspective on the challenges and future research directions of biomass electroreforming.
... D-Saccharic acid, also known as glucaric acid was also found to be present in AELE on LC-MS. This compound previously demonstrated chemopreventive and anticancer abilities by decreasing β-glucuronidase activity, an enzyme linked to high cancer risk, especially breast and prostate cancer [73]. D-(-)-Salicin, the precursor of aspirin was also reported to possess antioxidant and antiangiogenic and anticancer properties. ...
Annonaceae family has broad uses in herbal medicine for treatment of several diseases, whether through seeds' or leaves' extracts. The present study investigates the antiproliferative and antitumor activity of Annona cher-imola aqueous leaf (AAL) extract/infusion in acute myeloid leukemia (AML) cell lines in vitro. High-resolution LC-MS was first used to analyze the composition of the aqueous extract. Cell proliferation assay, Annexin V staining, cell cycle analysis, dual Annexin V/PI staining, cell death quantification by ELISA, ROS level detection and Western Blotting were then performed to elucidate the therapeutic effects of AAL extract. The results obtained revealed a potent antioxidant activity of AAL extract. Moreover, the extract exhibited dose-and time-dependent antiproliferative effects on AML cell lines by decreasing cell viability with an IC 50 of 5.03% (v/v) at 24 h of treatment of KG-1 cells. This decrease in viability was accompanied with a significant increase in apoptotic cell death with cell cycle arrest and flipping of the phosphatidylserine from the inner to the outer leaflet of the cell membrane. The respective overexpression and downregulation of proapoptotic proteins like cleaved caspase-8, cleaved PARP-1 and Bax and antiapoptotic proteins like Bcl-2 further validated the apoptotic pathway induced by AAL on AML cells. Finally, LC-MS revealed the presence of several compounds like fatty acids, terpenes, phenolics, cinnamic acids and flavonoids that could contribute to the antioxidant and anti-cancer effects of this herbal infusion. In addition to the generally known nutritional effects of the Annona cherimola fruit and leaves, the presented data validates the antioxidant and anti-cancerous effects of the leaf infusion on AML cell lines, proposing its potential therapeutic use against acute myeloid leukemia with future in vivo and clinical trials.
... Introduction Glucarate (Fig. 1), a physiologic end-product of the Dglucuronic acid pathway in mammals, is a six-carbon dicarboxylic acid that has been widely used in food, pharmaceutical, and chemical industries [1][2][3][4]. Initially, it was used as a transchelator of Tc-99m for radiolabeling antibody fragments [5][6][7]. ...
Glucarate, a physiologic end-product of the D-glucuronic acid pathway in mammals, is a six-carbon dicarboxylic acid with a wide range of uses. Glucarate-based molecular imaging probes including [99mTc]glucarate and [18F]glucarate have been developed and demonstrated to have infarct/necrosis-avid and/or tumor-seeking properties, showing potential applications in early detection of myocardial infarction, evaluation of tissue viability, monitoring of therapeutic effectiveness, and noninvasive imaging of certain tumors including drug-resistant ones. The mechanism by which [99mTc]glucarate localizes in acute necrotic tissues has been demonstrated to be largely attributable to its binding to the positively charged histones, which become accessible after the disruption of the cell and nuclear membranes as a result of irreversible damage, while the tumor-seeking mechanism of [99mTc]glucarate has been found to be closely related to glucose transporter 5 expression. Moreover, the recently developed [18F]glucarate provides a new alternative probe for positron emission tomography imaging and may have potential advantages over [99mTc]glucarate. In this review, we present the untiring pursuit for glucarate-based molecular imaging probes as infarct/necrosis-avid agent and/or tumor-seeking agent. Moreover, the limitations and the prospects for future research of glucarate-based molecular probes are also discussed.
Access to a wide range of plastic materials has been rationalized by the increased demand from growing populations and the development of high-throughput production systems. Plastic materials at low costs with reliable properties have been utilized in many everyday products. Multibillion-dollar companies are established around these plastic materials, and each polymer takes years to optimize, secure intellectual property, comply with the regulatory bodies such as the Registration, Evaluation, Authorisation and Restriction of Chemicals and the Environmental Protection Agency and develop consumer confidence. Therefore, developing a fully sustainable new plastic material with even a slightly different chemical structure is a costly and long process. Hence, the production of the common plastic materials with exactly the same chemical structures that does not require any new registration processes better reflects the reality of how to address the critical future of sustainable plastics. In this review, we have highlighted the very recent examples on the synthesis of common monomers using chemicals from sustainable feedstocks that can be used as a like-for-like substitute to prepare conventional petrochemical-free thermoplastics.
Objectives
: The aim of this study was to evaluate the relationship between β-glucuronidase and androgen levels in overweight and obese women with polycystic ovary syndrome PCOS. The connection between β-glucuronidase, the abundance of selected gut bacteria, carbohydrate metabolism, and diet quality was also determined.
Methods
: This cross-sectional study was conducted on 56 women with mean age of 29.14 ± 5.11 years and a mean body mass index (BMI) of 34.15 ± 5.72 kg/m². Anthropometrical parameters, fecal β-glucosidase activity, and selected food frequency intake were measured.
Results
: Women with better quality diets, apart from lower BMI and better carbohydrate metabolism parameters, had more abundant F. prausnitzii and A. muciniphila. 2 hours oral glucose tolerance test (OGTT-2hrs-glu (mg/dL)) was the main predictor of β-glucuronidase activity and there was no relationship between β-glucuronidase activity and androgen levels. Non-Healthy Diet Index-14 (nHDI-14) was the main predictor for A. muciniphila, B.longum, and F. prausnitzii abundance. QUICKI was a significant predictor of A. muciniphila abundance and OGTT-2hrs-glu was a significant predictor of F. prausnitzii abundance.
Conclusion
: There was no relationship between β-glucuronidase activity and androgen levels in overweight and obese women with PCOS, but β-glucuronidase activity may be an important factor in carbohydrate metabolism. Modulation of the abundances of F. prausnitzii, A. muciniphila, and B. longum using special diets should thus be considered a promising intervention.
Petrochemical based non-sustainable resources are being utilized for the production of energy and various platform chemicals. However, the fuel-based technology results in hazardous outputs, and hence, sustainable green routes are essential to save our resources and compensate energy requisites. Alternative sustainable green synthesis approach shifts the dependence from fossil fuels to the bio-based feedstock. Lignocellulose (cellulose and hemicellulose), wood, and crop residue, namely sugar cane, herbs and wheat straw, are frequently utilized to generate value-added platform molecules. The chapter portrays the bioprivileged molecules recognized by the US Department of Energy, their contribution to a drop-in replacement, the green route(s) for their preparation and the global market potential.
Glucose electrooxidation to glucaric acid, a highly valuable platform chemical, has been conducted, for the first time, in two consecutive steps employing a bare gold electrode in a batch reactor. The first step, at low potential, enabled the effective formation of the intermediate, gluconic acid, promoted by the oxidation of the aldehyde group on C1. For this reaction step, except for the reaction time, all the operational parameters had a strong impact on the selectivity. At the optimal conditions of pH 11.3, 5°C and 0.04 M initial glucose, a maximum selectivity of 97.6% was obtained, the highest reported to date for the electrochemical process, with a conversion of 25%. At higher potential, gluconic acid was further converted to glucaric acid by the oxidation of the hydroxymethyl group on C6. For this oxidation step, the variation of the operational parameters (pH, gluconic acid initial concentration, reaction temperature and time) had no conspicuous effect on the selectivity, while the applied potential had a major role: at 1.1 VRHE, a maximum selectivity of 89.5% to glucaric acid was obtained, which is one of the highest values reported in literature so far. In all experiments, irrespective of conditions and reaction time, a maximum concentration of ca 1.2 mM of glucaric acid was achieved, and a drastic decrease of the current density was observed in the first hours of electrolysis. Additional control experiments revealed a poisoning process caused by glucaric acid that, once formed, remains strongly bonded to the catalyst's active sites, thus deactivating it.
The aim of the present study was to determine the composition, antiradical and antimicrobial activity of fruits, leaves and roots of an underestimated species of barberry-Berberis iliensis-growing in Kazakhstan. Particular attention was paid to the determination of the composition of its extracts by high-performance liquid chromatography coupled with mass spectrometry (HPLC-ESI-Q-TOF-MS) analysis. As a result of the chromatographic and spectrometric study 33 secondary metabolites from the groups of phenolic acids and their esters, flavonoids, alkaloids and organic acids were identified and 15 of them-quantified. The isomers of caffeoyl-glucaric acid, caffeic acid derivatives, isoquercetin, berberine and jatrorrhizine were the most abundant components of the tested extracts. The antiradical activity tests were performed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and Folin-Ciocalteu assays on four types of extracts (water, ethanol, ethanol-water 7:3 v/v, ethanol-water 1:1 v/v) from the three organs of the plant. The highest antiradical potential (IC50 = 80 ± 6.36 µg/mL) and phenolic content (440 ± 17.1 mg gallic acid equivalents/L) was calculated for ethanol-water (1:1 v/v) extracts from the leaves and could be influenced by the abundant presence of simple phenolic acids, flavonoids and glucaric acid esters. Among reference microorganisms, M. luteus, S. epidermidis, some S. aureus and B. cereus belonging to Gram-positive bacteria and yeasts from Candida species were the most sensitive to roots extract that was found the most active among the studied samples. The results of the study classify Berberis iliensis as a strong antioxidant agent and as a plant with an antimicrobial potential.
The conformations of d-glucaric acid (1), d-glucaro-1,4-lactone (2), d-glucaro-6,3-lactone (3), and d-glucaro-1,4:6,3-dilactone (4) in solution were investigated by 1H-n.m.r. and 13C-p.F.t., n.m.r. spectroscopy. The solvents used were deuterium oxide, methanol-d4, and dimethyl sulfoxide-d6, and praseodymium chloride was employed as a lanthanide shift-reagent. For 2, it was found that the conformational equilibrium 3E(d) E3(d) exists in solution, and that the OH-5 group tends to occupy the position over the lactone ring in the favored E3(d),gg conformation. The n.m.r. data for 3 indicated that the conformational equilibrium is shifted in favor of the 4E(d) E4(d),gt conformation in solution. The dienvelope conformation 3E:E4(d) was found to be the favored conformation of 4. For 1, a conformational equilibrium between one planar, zigzag form and two sickle forms was indicated by the n.m.r. data observed. 13C-N.m.r. spectroscopy proved to be a convenient method for monitoring the lactonization of 1, and the hydrolysis of its lactones. Lactones other than 2–4 were not found in solutions prepared from 1–4, either during their mutarotation or after equilibration at 30°.
This experiment was designed to test the hypothesis that orally administered D-glucaro-1,4-lactone might be excreted in the bile and thus suppress the activity of biliary beta-glucuronidase, which is believed to play a key role in the development of pigment gallstones. D-Glucaro-1,4-lactone, 50 to 2,600 mu moles, was fed to adult Sprague-Dawley rats which had a bile fistula and were kept in metabolic cages for bile and urine collection. A total of 21 feeding experiments were carried out. Quantitation of D-glucaro-1,4-lactone and total D-glucaric acid as the sum of D-glucaric acid and its lactones in the bile and urine involved extraction of bile with tetrahexylammonium chloride, adjustment of pH, boiling and determination of percentage inhibition of beta-glucuronidase activity. The maximal velocity of beta-glucuronidase in the bile was also determined by the enzyme kinetic method. The results showed that 11% of administered D-glucaro-1,4-lactone was excreted in the urine and only 0.2% in the bile, with D-glucaro-1,4-lactone accounting for 20% of the total excreted D-glucaric acid. The concentration and excretory rate of total D-glucaric acid and D-glucaro-1,4-lactone in the urine, but not in the bile, were proportional to the amount of D-glucaro-1,4-lactone fed. The mean concentration of D-glucaro-1,4-lactone in the bile after feeding was 0.06 mM, which was capable of suppression of 75% of beta-glucuronidase activity. Oral administration of D-glucaro-1,4-lactone decreased biliary beta-glucuronidase concentration, slowed bile flow rate and hence decreased biliary beta-glucuronidase secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
A single oral dose of 1.5 g/kg of glucuronolactone to rats significantly prolonged for 6 days the whole blood clotting times. Since the anticoagulant action is pronounced in siliconized glass tubes, clotting is inhibited at stage(s) after the contact activation. Administration of 1,4-saccharolactone (a metabolite of D-glucuronolactone) at 1.5 g/kg also exhibited similar anticoagulant properties. Animals receiving glucuronolactone or 1,4-saccharolactone showed no toxic effects viz. loss of body weight or changes in the appearance of the internal organs.
Free radicals, such as superoxide, hydroxyl and nitric oxide, and other reactive species, such as hydrogen peroxide, hypochlorous acid and peroxynitrite, are formed in vivo. Some of these molecules, e.g. superoxide and nitric oxide, can be physiologically useful, but they can also cause damage under certain circumstances. Excess production of reactive oxygen or nitrogen species (ROS, RNS), their production in inappropriate relative amounts (especially superoxide and NO ) or deficiencies in antioxidant defences may result in pathological stress to cells and tissues. This oxidative stress can have multiple effects. It can induce defence systems, and render tissues more resistant to subsequent insult. If oxidative stress is excessive or if defence and repair responses are inadequate, cell injury can be caused by such mechanisms as oxidative damage to essential proteins, lipid peroxidation, DNA strand breakage and base modification, and rises in the concentration of intracellular free Ca2+. Considerable evidence supports the view that oxidative damage involving both ROS and RNS is an important contributor to the development of atherosclerosis. Peroxynitrite (derived by reaction of superoxide with nitric oxide) and transition metal ions (perhaps released by injury to the vessel wall) may contribute to lipid peroxidation in atherosclerotic lesions.
The beneficial properties of different vitamins, minerals, and other micronutrients have been studied for quite some time. But only recently has the potential usefulness of d-glucaric acid and its derivatives in disease prevention been demonstrated. d-Glucaric acid is an end product of the d-glucuronic acid pathway in mammals. Its dietary sources include different fruits and vegetables. In the present study, d-glucaric acid content in various fruits and vegetables was found to range from about 0.1 g/kg in grapes and lettuce to about 3.5 g/kg in apples and broccoli. It was also shown that purified diets containing calcium d-glucarate or potassium hydrogen d-glucarate markedly lowered serum levels of cholesterol in female Sprague-Dawley rats. The d-glucarates reduced total serum cholesterol in rats by up to 14% (P<0.05) and lowered LDL-cholesterol by up to 35% (P<0.05), but had no effect on HDL cholesterol. These results provide a starting point for further studies of the mechanism by which d-glucaric acid salts lower serum cholesterol.