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OleD Loki as a Catalyst for Hydroxamate Glycosylation.

ABSTRACT: Herein we describe the ability of the permissive glycosyltransferase (GT) OleD Loki to convert a diverse set of >15 histone deacetylase (HDAC) inhibitors (HDACis) into their corresponding hydroxamate glycosyl esters. Representative glycosyl esters were subsequently evaluated in assays for cancer cell line cytotoxicity, chemical and enzymatic stability, and axolotl embryo tail regeneration. Computational substrate docking models were predictive of enzyme-catalyzed turnover and suggest certain HDACis may form unproductive, potentially inhibitory, complexes with GTs.

SUBMITTER: Hughes RR

PROVIDER: S-EPMC7124993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLoki zupa (Luooukezupa) decoction, consisting of the roots of Hyssopuscuspidatus Boriss (Shenxiangcao) and Irishalophila Pall root (Yuanweigen), is commonly used in Uygur medicine to treat asthma. However, the mode of action of this material has yet to be elucidated. This study aims to investigate the effects of Loki zupa decoction on the airway inflammation of an ovalbumin (OVA)-induced asthma mouse model.MethodsMice were divided into normal control (NC), asthma (A), high, medium and low doses of Loki zupa decoction (L 14.0, L 7.0, L 3.5), water extract (LW), n-butanol extract (LN), ethyl acetate extract (LE) and dexamethasone (DEX) groups. Antiasthmatic model was induced by OVA sensitization and challenged using BALB/c mice. Airway hyperresponsiveness (AHR) toward methacholine (Mch) was assessed using Buxco equipment. Lung inflammation was measured by hematoxylin and eosin staining and bronchoalveolar lavage fluid (BALF) cell count and classification. Inflammatory cytokines in BALF and serum were analyzed by Bio-Plex assay, and mRNA levels were investigated by qPCR analysis. The roots of H. Boriss (250 g) and I. Pall (250 g) were decocted, concentrated and diluted to 14.0, 7.0 and 3.5 g crude herb/kg body weight. The LW, LN and LE of the Loki zupa decoction were prepared and diluted to a dose equivalent to 7 g of crude herb/kg body weight.ResultsLoki zupa decoction and its extracts significantly attenuated the AHR towards Mch (all P < 0.05). Treatment with Loki zupa decoction and its extracts relieved the infiltration of inflammatory cells in and around the airways, and reduced the total white blood cell (all P < 0.05), neutrophil (all P < 0.05), monocyte (all P < 0.05) and eosinophil (all P < 0.05) counts in the BALF. The BALF samples collected from the mice treated with the Loki zupa decoction and its extracts had lower levels of IL-1β (all P < 0.05), TNF-α (all P < 0.05), IL-2 (all P < 0.05), IL-4 (P = 0.047) and IL-5 (all P < 0.05). The serum samples of these mice also had lower IL-1β (all P < 0.05), TNF-α (all P < 0.05), IL-4 (all P < 0.05) and IL-5 (all P < 0.05) levels and higher levels of IFN-γ (P < 0.001) compared with the OVA-induced asthma mouse model. qPCR analysis revealed that Loki zupa decoction and its extracts inhibited mRNA expression of IL-4 (all P < 0.05), IL-5 (all P < 0.05) and IL-13 (all P < 0.05) and promoted mRNA expression of IFN-γ (all P < 0.05) in asthmatic mice.ConclusionLoki zupa decoction reduced AHR, attenuated airway inflammation, promoted Th1 and suppressed Th2 cell functions in an OVA-induced asthma mouse model.

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OleD Loki as a Catalyst for Hydroxamate Glycosylation.

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