Mechanisms of Lung Cancer Chemoprevention by d-Glucarate

Wałaszek, Zbigniew; Hanausek, Margaret; Naróg, Maciej; Raich, Peter C.; Slaga, Thomas J.

doi:10.1378/chest.125.5_suppl.149s

Cited by 4 publications

(3 citation statements)

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“…Daily supplementation of D-glucarate has some key beneficial effects (i.e., detoxification of noxious substances and anticancer regimens). [41][42][43] The primary mechanisms of action of D-glucarate may be through its ability to enhance detoxification of toxins and carcinogens as well as its antioxidative potential, 44,45 which may be linked to the inhibition of MIOX. In addition, a derivative of D-glucaric acid, D-saccharic acid 1, 4-lactone, has been recently reported to be protective in both diabetes and its renovascular complications in rats.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

241

251

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Diabetic kidney disease (DKD) is associated with oxidative stress and mitochondrial injury. Myo-inositol oxygenase (MIOX), a tubular-specific enzyme, modulates redox imbalance and apoptosis in tubular cells in diabetes, but these mechanisms remain unclear. We investigated the role of MIOX in perturbation of mitochondrial quality control, including mitochondrial dynamics and autophagy/mitophagy, under highglucose (HG) ambience or a diabetic state. HK-2 or LLC-PK1 cells subjected to HG exhibited an upregulation of MIOX accompanied by mitochondrial fragmentation and depolarization, inhibition of autophagy/ mitophagy, and altered expression of mitochondrial dynamic and mitophagic proteins. Furthermore, dysfunctional mitochondria accumulated in the cytoplasm, which coincided with increased reactive oxygen species generation, Bax activation, cytochrome C release, and apoptosis. Overexpression of MIOX in LLC-PK1 cells enhanced the effects of HG, whereas MIOX siRNA or D-glucarate, an inhibitor of MIOX, partially reversed these perturbations. Moreover, decreasing the expression of MIOX under HG ambience increased PTEN-induced putative kinase 1 expression and the dependent mitofusin-2-Parkin interaction. In tubules of diabetic mice, increased MIOX expression and mitochondrial fragmentation and defective autophagy were observed. Dietary supplementation of D-glucarate in diabetic mice decreased MIOX expression, attenuated tubular damage, and improved renal functions. Notably, D-glucarate administration also partially attenuated mitochondrial fragmentation, oxidative stress, and apoptosis and restored autophagy/mitophagy in the tubular cells of these mice. These results suggest a novel mechanism linking MIOX to impaired mitochondrial quality control during tubular injury in the pathogenesis of DKD and suggest D-glucarate as a potential therapeutic agent for the amelioration of DKD.

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Section: Discussionmentioning

confidence: 99%

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Zhan

Usman

Sun

et al. 2015

Journal of the American Society of Nephrology

241

251

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“…Strengths of this investigation include: 1) controlled diets in which the plant foods were dosed according to body weight to minimize confounding by weight; 2) inherent adjustment for confounding and between-person differences as each person acted as his/her own control; and 3) high participant adherence to experimental diets. Lower β-glucuronidase activity (reviewed in (3)) has been associated with higher D-glucaric acid (4, 11), caloric restriction (14), silymarin (milk thistle extract) (15), Ganoderma lucidum (16), and the calcium modulating xenobiotics A23187 (17) and thapsigargin (17). Conversely, increased β-glucuronidase activity (reviewed in (3)) has been associated with male sex (9, 18), higher BMI (18), older age (3, 18), pathological conditions (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Plant food constituents, such as D-glucaric acid, may act as nontoxic β-glucuronidase inhibitors in humans (4) and thus, lower cancer risk. D-glucaric acid is converted into D-glucaro-1,4-lactone which competitively inhibits β-glucuronidase and has been shown to reduce chemical carcinogen-mediated mammary, liver, and skin tumors in animals (5-7).…”

Section: Introductionmentioning

confidence: 99%

Serum β-Glucuronidase Activity in Response to Fruit and Vegetable Supplementation: A Controlled Feeding Study

Maruti

Chang²,

Prunty

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Fruit and vegetable (F&V) intake may lower the risk of some cancers. One hypothesized, but understudied, chemopreventive mechanism is that plant food constituents inhibit B-glucuronidase, an acid hydrolase that deconjugates glucuronides. Methods: We conducted a crossover feeding trial in 63 healthy women and men ages 20 to 40 years to examine the effect of diet on serum B-glucuronidase activity. Participants were randomized to two 2-week experimental diets with an intervening washout period: a diet high in selected citrus fruit, crucifers, and soy (F&V) and a diet devoid of fruits, vegetables, and soy (basal). Serum B-glucuronidase activity was measured during the preintervention, F&V, and basal periods. Linear mixed models were used to obtain effect estimates and 95% confidence intervals (95% CI).

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Production of Glucaric Acid from Hemicellulose Substrate by Rosettasome Enzyme Assemblies

et al. 2016

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Hemicellulose biomass is a complex polymer with many different chemical constituents that can be utilized as industrial feedstocks. These molecules can be released from the polymer and transformed into value-added chemicals through multistep enzymatic pathways. Some bacteria produce cellulosomes which are assemblies composed of lignocellulolytic enzymes tethered to a large protein scaffold. Rosettasomes are artificial engineered ring scaffolds designed to mimic the bacterial cellulosome. Both cellulosomes and rosettasomes have been shown to facilitate much higher rates of biomass hydrolysis compared to the same enzymes free in solution. We investigated whether tethering enzymes involved in both biomass hydrolysis and oxidative transformation to glucaric acid onto a rosettasome scaffold would result in an analogous production enhancement in a combined hydrolysis and bioconversion metabolic pathway. Three different enzymes were used to hydrolyze birchwood hemicellulose and convert the substituents to glucaric acid, a top-12 DOE value added chemical feedstock derived from biomass. It was demonstrated that colocalizing the three different enzymes to the synthetic scaffold resulted in up to 40 % higher levels of product compared to uncomplexed enzymes.

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Mechanisms of Lung Cancer Chemoprevention by d-Glucarate

Cited by 4 publications

References 0 publications

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

Serum β-Glucuronidase Activity in Response to Fruit and Vegetable Supplementation: A Controlled Feeding Study

Production of Glucaric Acid from Hemicellulose Substrate by Rosettasome Enzyme Assemblies

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