Cytosolic β-glucosidase inhibition and renal blood flow suppression are leading causes for the enhanced systemic exposure of salidroside in hypoxic rats

Qi, Te; Ge, Beikang; Zhao, Lifeng; Ma, Yi; Li, Xiaorong; Xu, Ping; Xue, Ming

doi:10.1039/c7ra13295f

Cited by 11 publications

(3 citation statements)

References 40 publications

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“…Studies have shown that RC may synergistically inhibit myocardial apoptosis and improve MI-reperfusion injury through the anti-inflammatory regulation of energy metabolism and oxidative stress, which may be related to the HIF-1/VEGF/PI3K-Akt signaling pathway [32]. Further research found that the systemic exposure to salidroside in hypoxia increased significantly, which may be related to the weakening of liver metabolism under the disease state [33]. This conclusion is consistent with our results.…”

Section: Discussionsupporting

confidence: 91%

Pharmacokinetic–Pharmacodynamic Correlation Analysis of Rhodiola crenulata in Rats with Myocardial Ischemia

Jia,

Zou,

Xie

et al. 2024

Pharmaceuticals

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The pharmacokinetics (PK) of Rhodiola crenulata in rats were studied, and pharmacokinetic–pharmacodynamic (PK-PD) correlation analysis was performed to elucidate their time–concentration–effect relationship. The myocardial ischemia model was made with pituitrin. Rats were divided into sham operation, sham operation administration, model, and model administration groups (SG, SDG, MG, and MDG, respectively; n = 6). Blood was collected from the fundus venous plexus at different time points after oral administration. The HPLC-QQQ-MS/MS method was established for the quantification of five components of Rhodiola crenulata. CK, HBDH, SOD, LDH, and AST at different time points were detected via an automatic biochemical analyzer. DAS software was used to analyze PK parameters and PK-PD correlation. The myocardial ischemia model was established successfully. There were significant differences in the PK parameters (AUC0–, AUC0–∞, Cmax) in MDG when compared with SDG. Two PD indicators, CK and HBDH, conforming to the sigmoid-Emax model, had high correlation with the five components, which indicated a delay in the pharmacological effect relative to the drug concentration in plasma. The difference in the PK parameters between modeled and normal rats was studied, and the time–concentration–effect of composition and effect indicators were investigated. This study can provide reference for the rational clinical application of Rhodiola crenulata and for related studies of other anti-myocardial ischemia drugs.

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Section: Discussionsupporting

confidence: 91%

Pharmacokinetic–Pharmacodynamic Correlation Analysis of Rhodiola crenulata in Rats with Myocardial Ischemia

Jia,

Zou,

Xie

et al. 2024

Pharmaceuticals

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“…We believe that salidroside directly reaches the lesion site when interfering with colitis by gavage. Moreover, DSS‐induced intestinal barrier breakdown may result in higher plasma concentration (Chang, Yao, Hsieh, Lu, & Yeh, 2007; Qi et al, 2018). Combined with the dual effect of salidroside on the intestinal flora, a small dose may achieve a suitable therapeutic effect on gastrointestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis‐associated Th17/Treg imbalance

Liu

Zhou

Luo

et al. 2022

Phytotherapy Research

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by flora disequilibrium and mucosal immunity disorder. Here, we report that salidroside effectively restricts experimental colitis from two aspects of intestinal macrophage pyroptosis and dysbacteriosis‐derived colonic Th17/Treg imbalance. In innate immunity, the upregulated TREM1 and pyroptosis‐related proteins in inflamed colons were inhibited by salidroside administration and further experiments in vitro showed that salidroside suppressed LPS/ATP‐induced bone marrow‐derived macrophages (BMDMs) pyroptosis evident by the decline of LDH and IL‐1β release as well as the protein level of NLRP3, caspase‐1, and GSDMD p30. Moreover, the TREM1 inhibitor weakened the effect of salidroside on BMDMs pyroptosis, whereas salidroside still could downregulate TREM1 when NLRP3 was inhibited. In adaptive immunity, salidroside improved the gut microflora diversity and Th17/Treg ratio in DSS‐induced mice, especially promoting the abundance of Firmicutes. Clearance of the gut flora blocked the benefit of salidroside on colonic inflammation and Th17/Treg adaptive immunity, but transplanting salidroside‐treated foecal bacterium into flora‐depleted wild mice reproduced the resistance of salidroside to gut inflammation. Taken together, our data demonstrated that salidroside protected experimental colitis via skewing macrophage pyroptosis and Th17/Treg balance, indicating its potential effect on UC and other immune disorders.

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“…Mouse intestinal S9 was prepared, according to the method reported. , The incubation system was composed of intestinal S9 (2.0 mg protein/mL), MgCl 2 (3.2 mM), MLT (100 μM), and GCL (20 mM) or TCA (1.0 mM) , in 100 μL of phosphate-buffered saline (PBS, 0.1 M, pH 7.4) fortified with capture agents GSH (200 μM) or NAC (2.0 mM). Control incubation groups lacked GCL or TCA.…”

Section: Experimental Proceduresmentioning

confidence: 99%

Metabolic Activation of Militarine In Vitro and In Vivo

Zou

Wang

et al. 2022

Chem. Res. Toxicol.

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Bletilla striata is consumed as food and herbal medicine. Militarine (MLT) is a major ingredient in B. striata. Previous studies demonstrated that MLT showed teratogenic toxicity to zebrafish embryos. The present study aimed to identify reactive metabolites possibly involved in the cytotoxicity of MLT and determine the metabolic pathways involved. MLT was found to be hydrolyzed to p-hydroxybenzyl alcohol (HBA) by β-glucosidase and esterases. The resulting HBA further underwent spontaneous dehydration to form quinone methide. HBA was also metabolized to the corresponding sulfate, followed by departure of the sulfate to generate a quinone methide. The resultant quinone methide reacted with hepatic glutathione (GSH) and protein to form the corresponding GSH conjugate and protein adduction. Additionally, inhibition of sulfotransferases (SULTs) attenuated the susceptibility of hepatocytes to the toxicity of MLT. This study provides that the hydrolytic enzymes β-glucosidase, esterases, and SULTs participate in the metabolic activation of MLT.

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Cytosolic β-glucosidase inhibition and renal blood flow suppression are leading causes for the enhanced systemic exposure of salidroside in hypoxic rats

Abstract: CBG inhibition and renal blood flow suppression are leading causes for the enhanced systemic exposure of SAL in hypoxic rats.

Cited by 11 publications

References 40 publications

Pharmacokinetic–Pharmacodynamic Correlation Analysis of Rhodiola crenulata in Rats with Myocardial Ischemia

Pharmacokinetic–Pharmacodynamic Correlation Analysis of Rhodiola crenulata in Rats with Myocardial Ischemia

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis‐associated Th17/Treg imbalance

Metabolic Activation of Militarine In Vitro and In Vivo

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