Glucuronidated Flavonoids in Neurological Protection: Structural Analysis and Approaches for Chemical and Biological Synthesis

Docampo, Maite L.; Adiji, Olubu A; Wang, Xiaoqiang; Pasinetti, Giulio Maria; Dixon, Richard A.

doi:10.1021/acs.jafc.7b02633

Cited by 34 publications

(24 citation statements)

References 159 publications

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“…These results led us to hypothesize that FX cells, when under stress, are defective in glucuronidation of xenobiotics. Glucuronidated flavonoids have a reported protective role towards a range of neurological disorders(Docampo et al, 2017).…”

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confidence: 99%

Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility

Chakraborty

Jenjaroenpun

McCulley

et al. 2019

Preprint

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Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene. The protein product of FMR1, FMRP, is known as a translational repressor whose nuclear function is not understood. Here we report that FMRP is a genome maintenance protein. We show that FX cells exhibit elevated level of chromosome breaks, both spontaneous and replication stress-induced. We demonstrate that FMRP is required for abating R-loop accumulation, thereby preventing chromosome breakage. Through mapping FMRP-bound chromatin loci in normal cells and correlating with FX-specific chromosome breaks, we identified novel FXS-susceptible genes. We show that FX cells have reduced expression of the uridine diphosphoglucuronosyl transferase 1 family enzymes, suggesting defective xenobiotics glucuronidation and consequential neurotoxicity in FXS. RUNNING TITLEFMRP deficiency induces DNA breaks at R-loops.

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mentioning

confidence: 99%

Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility

Chakraborty

Jenjaroenpun

McCulley

et al. 2019

Preprint

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“…Primarily, the solubility of flavonoids is due to their sugar substitutions. Among the sugars, glucose and glucuronic acid at a single position are probably the most common substituents [32]. The importance of flavonoid glucuronides is related to their health-promoting activities such as the anti-inflammatory and neuroprotective activities of quercetin-3-O-glucuronide [33].…”

Section: Discussionmentioning

confidence: 99%

Identification of Bioactive Phytochemicals in Leaf Protein Concentrate of Jerusalem Artichoke (Helianthus tuberosus L.)

Kaszás

Alshaal

El-Ramady

et al. 2020

Plants

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Jerusalem artichoke (JA) is widely known to have inulin-rich tubers. However, its fresh aerial biomass produces significant levels of leaf protein and economic bioactive phytochemicals. We have characterized leaf protein concentrate (JAPC) isolated from green biomass of three Jerusalem artichoke clones, Alba, Fuseau, and Kalevala, and its nutritional value for the human diet or animal feeding. The JAPC yield varied from 28.6 to 31.2 g DM kg−1 green biomass with an average total protein content of 33.3% on a dry mass basis. The qualitative analysis of the phytochemical composition of JAPC was performed by ultra-high performance liquid chromatography-electrospray ionization-Orbitrap/mass spectrometry analysis (UHPLC-ESI-ORBITRAP-MS/MS). Fifty-three phytochemicals were successfully identified in JAPC. In addition to the phenolic acids (especially mono- and di-hydroxycinnamic acid esters of quinic acids) several medically important hydroxylated methoxyflavones, i.e., dimethoxy-tetrahydroxyflavone, dihydroxy-methoxyflavone, hymenoxin, and nevadensin, were detected in the JAPC for the first time. Liquiritigenin, an estrogenic-like flavanone, was measured in the JAPC as well as butein and kukulkanin B, as chalcones. The results also showed high contents of the essential amino acids and polyunsaturated fatty acids (PUFAs; 66-68%) in JAPC. Linolenic acid represented 39–43% of the total lipid content; moreover, the ratio between ω-6 and ω-3 fatty acids in the JAPC was ~0.6:1. Comparing the JA clones, no major differences in phytochemicals, fatty acid, or amino acid compositions were observed. This paper confirms the economic and nutritional value of JAPC as it is not only an alternative plant protein source but also as a good source of biological valuable phytochemicals.

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“…In natural phenolic phytochemicals, glucuronidation is linked to significant physiological properties, such as its solubility, bioactivity, bioavailability, and inter- and intracellular transport [ 15 ]. Moreover, extensive glucuronidation can be a barrier to oral bioavailability as the first-pass glucuronidation of orally administered agents usually results in poor oral bioavailability and a lack of efficacy [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of CYPs and UGTs Involved in Human Liver Microsomal Metabolism of Osthenol

et al. 2018

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Osthenol is a prenylated coumarin isolated from the root of Angelica koreana and Angelica dahurica, and is an O-demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in rat osthole studies, and 11 metabolic products were identified in rat urine. However, the metabolic pathway of osthenol in human liver microsomes (HLM) has not been reported. In this study, we elucidated the structure of generated metabolites using a high-resolution quadrupole-orbitrap mass spectrometer (HR-MS/MS) and characterized the major human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) isozymes involved in osthenol metabolism in human liver microsomes (HLMs). We identified seven metabolites (M1-M7) in HLMs after incubation in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and uridine 5′-diphosphoglucuronic acid (UDPGA). As a result, we demonstrated that osthenol is metabolized to five mono-hydroxyl metabolites (M1-M5) by CYP2D6, 1A2, and 3A4, respectively, a 7-O-glucuronide conjugate (M6) by UGT1A9, and a hydroxyl-glucuronide (M7) from M5 by UGT1A3 in HLMs. We also found that glucuronidation is the dominant metabolic pathway of osthenol in HLMs.

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Glucuronidated Flavonoids in Neurological Protection: Structural Analysis and Approaches for Chemical and Biological Synthesis

Cited by 34 publications

References 159 publications

Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility

Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility

Identification of Bioactive Phytochemicals in Leaf Protein Concentrate of Jerusalem Artichoke (Helianthus tuberosus L.)

Characterization of CYPs and UGTs Involved in Human Liver Microsomal Metabolism of Osthenol

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