PLANTA MEDICA
·
2018
·Vol. 85
·期 03
·225-230
·
IF 2.494
Xinhui Wang,Dujuan Wang,Xue Wang,Manana Khutsishvili,Kamilla Tamanyan,George Fayvush,Daniel Atha,Youcai Zhang,Robert P. Borris
Phytochemical investigation of Camphorosma lessingii has resulted in the isolation of four previously unreported isoflavones (1–4) and eight known compounds (5–12). Nine of these compounds (1–6, 8–10) are reported for the first time from members of the family Amaranthaceae. The structures of all isolated compounds were determined by spectroscopic methods, primarily one-dimensional and two-dimensional nuclear magnetic resonance and mass spectrometry. The absolute configuration of 6 was confirmed by circular dichroism. Inhibition of the organic anion transporters, OAT1 and OAT3, by the isolated compounds was evaluated. Among them, 7, 2′-dihydroxy- 6,8-dimethoxyisoflavone (1), 2′-hydroxy-6,7,8-trimethoxyisoflavone (2), 6,2′-dihydroxy-7,8-dimethoxyisoflavone (3), and 7-methoxyflavone (5) showed a significant inhibitory effect on 6-carboxyfluorescein uptake mediated by OAT1 and OAT3.
研究领域:
药理学
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生物化学
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植物科学
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DOI
PubMed
高影响因子
Biomed Research International
·
2015
·
IF 1.579
Wen-Hao Yu,Na Zhang,Jin-Feng Qi,Chen Sun,Yong-Hui Wang,Mei Lin
Toxic heavy metals, including mercury (Hg) and arsenic (As), accumulate preferentially in kidneys and always cause acute renal failure. The aim of this study was to investigate whether these samples affect organic anion transporters, Oat1 and Oat3, in vivo in mice kidney. Mice () were orally treated with investigational samples. After last administration, all mice were i.v. p-aminohippuric acid (PAH), and the blood and kidneys samples were collected. The concentrations of PAH were quantified by spectrophotometry. mRNA expressions of Oat1 and Oat3 were assayed by real-time PCR. In comparison with corresponding control, major pharmacokinetic parameters of PAH in sera were significantly changed by investigational samples (), PAH accumulations in the kidney tissues were significantly higher (), PAH uptake by renal slices was greatly reduced, Oat1 and Oat3 mRNA expression were significantly inhibited in investigational sample groups. Arsenic and mercury containing traditional Chinese medicine (Realgar and Cinnabar) probably induce kidney damage through inhibiting several members of the organic anion transporters (such as OAT1 and OAT3).
研究领域:
药理学
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毒理学
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肾脏病学
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DOI
PubMed
高影响因子
Scientific Reports
·
2019
·Vol. 9
·期 1
·1-9
·
IF 4.011
Li Xue,Wang Xue,Li Caiyu,Khutsishvili Manana,Fayvush George,Atha Daniel,Zhang Youcai,Borris Robert P.
A bioactivity guided program exploring the interaction of phytochemicals in the entire plant Primula macrocalyx with the organic anion transporters (OAT1 and OAT3) and microorganisms led to the elucidation of ten known flavones ( 1 – 4 , 6 – 10 , 12 ) and two previously undescribed flavones ( 5 , 11 ). The structures of the compounds were determined by extensive analysis of spectroscopic data, as well as by comparison with data from previous reports. Two known flavones ( 9 , 12 ) are reported for the first time from the family Primulaceae. All compounds were evaluated for inhibition of OAT1 and OAT3. Six flavones ( 2 , 3 , 6 – 8 , 12 ) showed potent inhibitory activity on OAT1, while seven flavones ( 2 , 3 , 6 – 9 , 12 ) showed marked inhibitory activity on OAT3, with IC 50 ≤ 10.0 µ M. Antimicrobial activities of crude fractions against sixteen microorganisms were tested to give a target yeast strain Candida rugosa for further evaluation of MICs on the isolates. Three flavones ( 7 , 8 , 12 ) showed marked antifungal activity with MIC < 2.0 µ M. To our knowledge, this study is the first to evaluate these flavones as inhibitors of the OAT1 and OAT3, and as antifungal agents.
研究领域:
药理学
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生物化学
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植物科学
·
微生物学
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DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2017
·Vol. 161
·期 2
·321-334
·
IF 4.081
Wang Xue,Han Lifeng,Li Gentao,Peng Wei,Gao Xiumei,Klaassen Curtis D,Fan Guanwei,Zhang Youcai
Mercury accumulates in kidneys and produces acute kidney injury. Semen cassiae (SC), a widely consumed tea and herbal medicine in Eastern Asia, has been reported to have protective effects on kidneys. In this study, SC extract was shown to almost abolish the histological alterations induced by mercuric chloride in rat kidneys. A total of 22 compounds were isolated from SC, and 1,7,8-methoxyl-2-hydroxyl-3-methyl-anthraquinone was detected in SC for the first time. Among the eight compounds identified in the blood of rats after SC treatment, six were strong inhibitors of human organic anion transporter 1 and 3 (OAT1 and OAT3). Inhibitory studies revealed that OAT1 and OAT3 were inhibited by SC constituents, in both a competitive and noncompetitive manner. Both OAT1- and OAT3-overexpressing cells were susceptible to the cytotoxicity of the cysteine–mercury conjugate, but only OAT1-overexpressing cells could be protected by 200 μM probenecid or 10 μM of the eight inhibitors in SC, suggesting that OAT1 is the major determinant in the cellular uptake of mercury. To facilitate the identification of inhibitors of OAT1 and OAT3, models of OAT1 and OAT3 were constructed using recently determined protein templates. By combining in silico and in vitro methods, inhibitors of OAT1 and OAT3 were predicted and validated from SC constituents. Collectively, the present study suggests that additional inhibitors of OAT1 and OAT3 can be predicted and validated from natural products by combining docking and in vitro screening, and could be a source of pharmaceutical compounds for developing treatments for mercury-induced kidney injury.
研究领域:
药理学
·
毒理学
·
药物化学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NATURAL PRODUCTS
·
2019
·
IF 4.257
Xue Li,Yilin Qiao,Xue Wang,Ruicong Ma,Tianxiang Li,Youcai Zhang,Robert P. Borris
Organic anion transporters 1 (OAT1) and 3 (OAT3) play important roles in the renal elimination of a range of substrate molecules. Little is known about natural products that can modulate OAT1 and OAT3 activities. The medullae of Juncus effusus is often used for the treatment of dysuria in traditional Chinese medicine. To study the interactions of phytochemicals in J. effusus with human OAT1 and OAT3, a bioactivity guided phytochemical investigation led to seven new phenanthrenoids along with nine known compounds, including eight phenanthrenoids and a benzophenone from the dichloromethane soluble fraction of a methanol extract of the medullae of J. effusus. The structures were established by physical data analysis, including high-resolution electrospray ionization mass spectrometry and 1D and 2D NMR. The compounds were evaluated for inhibition of OAT1 and OAT3 in vitro. Compounds 10 and 16 were inhibitors for OAT1, and compounds 1–3, 10, and 16 were inhibitors for OAT3 with IC50 values less than 5.0 μM. Dihydrophenanthrene 1 markedly altered the pharmacokinetic parameters of the diuretic drug furosemide, a known substrate of both OAT1 and OAT3, in vivo.
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 4.384
Wenyan Li,Zheng Jiao,Yanhui Liu,Jiacheng Yao,Guodong Li,Jing Dong
Biapenem is a carbapenem antibiotic. It is excreted predominantly through the kidney as unchanged forms. However, the molecular mechanism of renal excretion of biapenem and potential drug-drug interactions (DDIs) were still unknown. In the present study, the role of organic anion transporters (OAT) 1/3 and organic cation transporters (OCT) 2 in the renal excretion of biapenem, and the potential DDIs between biapenem and six clinical commonly prescribed antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3 were evaluated in vitro . Further, the effect of probenecid on the pharmacokinetics of biapenem was explored in the rats. We observed that biapenem could not inhibit the transport activities of OAT1 or OCT2, while mildly inhibited OAT3 (IC 50 >500 μM). Among the tested antibiotics and antiviral drugs, the relatively high DDI index values (maximal unbound plasma concentration over IC 50 , I max,u /IC 50 ) were found for piperacillin, linezolid and benzylpenicillin, which were 2.84, 1.7 and 0.62, respectively. Although probenecid had the highest DDI index (27.1) in vitro , no significant impact of it on the pharmacokinetics of biapenem was observed in the rats. Our results indicated that biapenem was primarily eliminated by the glomerular filtration, while OAT3-mediated renal tubular secretion was a minor route. Biapenem is not a clinically relevant substrate or inhibitor because of its low affinity to OAT3. According to current results, it would be safe to use biapenem with other antibiotics and antiviral drugs that acted as substrates or inhibitors of OAT3.
研究领域:
药理学
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分子生物学
·
临床医学
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DOI
PubMed
高影响因子
NATURAL PRODUCT RESEARCH
·
2018
·
IF 1.928
Xu Pang,Li-Ming Wang,You-Cai Zhang,Li-Ping Kang,He-Shui Yu,Guan-Wei Fan,Li-Feng Han
A continuous phytochemical study on the seeds of Senna obtusifolia (Syn.: Cassia obtusifolia) led to the isolation of a new anthraquinone analogue, obtusifolin-2-O-β-D-(6’-O-α,β-unsaturated butyryl)-glucopyranoside (1) and a new eurotinone analogue, epi-9-dehydroxyeurotinone-β-D-glucopyranoside (2). Their structures were established mainly by NMR and MS experiments as well as the necessary chemical evidences. Their inhibitory effects on two organic anion transporters (OAT1 and OAT3) were investigated and the results showed that 1 exhibited a strongly specific inhibitory effect on OAT1 at 100 μM.
研究领域:
药理学
·
化学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Tianqiao Yong,Danling Liang,Shaodan Chen,Chun Xiao,Xiong Gao,Qingping Wu,Yizhen Xie,Longhua Huang,Huiping Hu,Xiangmin Li,Yuancao Liu,Manjun Cai
Background Hyperuricemia is characterized with high serum uric acids (SUAs) and directly causes suffering gout. Caffeic acid phenethyl ester (CAPE) is widely included in dietary plants and especially propolis of honey hives. Hypothesis/Purpose Since CAPE exerts a property resembling a redox shuttle, the hypothesis is that it may suppress xanthine oxidase (XOD) and alleviate hyperuricemia. The aim is to unveil the hypouricemic effect of CAPE and the underlying mechanisms. Methods By establishing a hyperuricemic model with potassium oxonate (PO) and hypoxanthine (HX) together, we investigated the hypouricecmic effect of CAPE. On this model, the expressions of key mRNAs and proteins, including glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), and the activity of XOD were assayed in vivo . Also, the inhibitory effect of CAPE against XOD was assayed in vitro through enzymatic activity tests and by molecular docking. Results CAPE demonstrated a remarkable hypouricemic effect, which reduced the SUAs of hyperuricemic mice (401 ± 111 µmol/l) to 209 ± 56, 204 ± 65 and 154 ± 40 µmol/l ( p < 0.01) at the doses of 15, 30 and 60 mg/kg respectively, depicting efficacies between 48 and 62% and approaching allopurinol's efficacy (52%). Serum parameters, body weights, inner organ coefficients, and H&E staining suggested that CAPE displayed no general toxicity and it alleviated the liver and kidney injuries caused by hyperuricemia. Mechanistically, CAPE decreased XOD activities significantly in vivo , presented an IC 50 at 214.57 µM in vitro and depicted a favorable binding to XOD in molecular simulation, indicating that inhibiting XOD may be an underlying mechanism of CAPE against hyperuricemia. CAPE did decreased GLUT9 protein and down-regulated URAT1 mRNA and protein. In addition, CAPE up-regulated ATP binding cassette subfamily G member 2 (ABCG2) and organic anion transporter 3 (OAT3) mRNA and proteins in comparison with that of the hyperuricemic control. All above, CAPE may alleviate hyperuricmia through inhibiting XOD, decreasing GLUT9 and URAT1 and increasing ABCG2 and OAT3. Conclusion CAPE presented potent hypouricemic effect in hyperuricemic mice through inhibiting XOD activity and up-regulating OAT3. CAPE may be a promising treatment against hyperuricemia.
研究领域:
药理学
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生物化学
·
分子生物学
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医学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Yilin Qiao,Xueling Liu,Xue Li,Xue Wang,Caiyu Li,Manana Khutsishvili,Valida Alizade,Daniel Atha,Youcai Zhang,Robert P. Borris
Organic anion transporters (OATs in humans, Oats in rodents) play an important role in the distribution and excretion of numerous endogenous metabolic products and exogenous organic anions , including a host of widely prescribed drugs. Their ligand recognition is also important for drug therapy and development. In this study, the n -butanol and dichloromethane soluble fractions of Juniperus oblonga were found to inhibit OAT3 in vitro and three biflavonoids were found to be responsible for this activity. One of these compounds, amentoflavone exhibited stronger inhibition than probenecid, a known strong inhibitor of OAT3. Biological characterization of amentoflavone in vivo also showed inhibition of Oat3. Preliminary observations of structure-activity relationships suggest that the biflavonoids are more potent inhibitors of this transporter than their corresponding monomer, and that methylation of even a single hydroxyl group results in a substantial decrease in activity. This greater potency of the biflavonoids may indicate the need for a more in-depth investigation of the distribution of biflavonoids in plants used as foodstuffs and herbal medicines, due to their potential for causing interactions with OAT3 substrate drugs.
研究领域:
药理学
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分子生物学
·
天然产物化学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 4
·1995
·
IF 4.6
Aijie Zhang,Fanlong Yang,Yang Yuan,Cai Li,Xiaokui Huo,Jing Liu,Shenzhi Zhou,Wei Li,Na Zhang,Jianfeng Liu,Shiqi Dong,Huirong Fan,Ying Peng,Jiang Zheng
Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug–drug interactions (DDIs) remain unclear. The present study aimed to determine the organic anion transporters (OATs) involved in the renal disposition of Y101 and to predict the potential DDI between Y101 and entecavir, the first-line agent against HBV and a substrate of OAT1/3. Pharmacokinetic studies and uptake assays using rat kidney slices, as well as hOAT1/3-HEK293 cells, were performed to evaluate potential DDI. The co-administration of probenecid (an inhibitor of OATs) significantly increased the plasma concentrations and area under the plasma concentration–time curves of M8 and M9 but not Y101, while reduced renal clearance and the cumulative urinary excretion of M8 were observed in rats. The time course of Y101 and M8 uptake via rat kidney slices was temperature-dependent. Moreover, the uptake of M8 was inhibited significantly by probenecid and benzylpenicillin, but not byp-aminohippurate or tetraethyl ammonium. M8 was found to be a substrate of hOAT3, but Y101 is not a substrate of either hOAT1 or hOAT3. Additionally, the entecavir inhibited the uptake of M8 in the hOAT3-transfected cells and rat kidney slices in vitro. Interestingly, no significant changes were observed in the pharmacokinetic parameters of Y101, M8 or entecavir, regardless of intravenous or oral co-administration of Y101 and entecavir in rats. In conclusion, M8 is a substrate of OAT3 in rats and humans. Furthermore, M8 also mediates the DDI between Y101 and entecavir in vitro, mediated by OAT3. We speculate that it would be safe to use Y101 with entecavir in clinical practice. Our results provide useful information with which to predict the DDIs between Y101 and other drugs that act as substrates of OAT3.Keywords:Y101;entecavir;renal excretion;organic anion transporters;drug-drug interaction
研究领域:
药理学
·
肝病学
·
分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Gao Tianshu,Xu Jin,Xiao Yuxiao,Li Jiaqi,Hu Weifeng,Su Xiaoyu,Shen Xudong,Yu Wan,Chen Zhen,Huang Baosheng,Li Honglei,Wang Xing
Objective: To observe the antioxidative effects of N-(9,10-anthraquinone-2-ylcarbonyl) xanthine oxidase inhibitors (NAY) in vitro and in vivo models of hyperuricemia and explore the mechanism.Methods: A classical experimental method of acute toxicity and a chronic toxicity test were used to compare the toxic effects of different doses of NAY in mice. The hyperuricemia mouse model was established by gavage of potassium oxonate in vivo. After treatment with different doses of NAY (low dose: 10 mg/kg, medium dose: 20 mg/kg, and high dose: 40 mg/kg) and allopurinol (positive drug, 10 mg/kg), observe the levels of uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) in urine and serum, respectively, and detect the activities of xanthine oxidase in the liver. The hyperuricemia cell model was induced by adenosine and xanthine oxidase in vitro. The cells were given different doses of NAY (50, 100, and 200 μmol/L) and allopurinol (100 μmol/L). Then the culture supernatant UA level of the medium was measured. The next step was to detect the xanthine oxidase activity in the liver and AML12 cells, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammatory factors in the kidney and serum of mice. Western blot was used to detect xanthine oxidase protein expression in mouse liver tissue and AML12 cells, ASC, Caspase-1, NLRP3, GLUT9, OAT1, and OAT3 protein expression in mouse kidney tissue and HK-2 cells. Hematoxylin–eosin staining was used to stain the liver and kidney tissues of mice and observe the tissue lesions.Results: NAY had little effect on blood routine and biochemical indexes of mice, but significantly reduced the serum UA level. NAY significantly reduced the level of UA in hyperuricemia mice and cells by inhibiting xanthine oxidase activity and reduced the levels of TNF-α, IL-6, and other inflammatory factors in serum and kidney of mice. NAY can inhibit inflammation by inhibiting the NLRP3 pathway. In addition, NAY can downregulate GLUT9 protein expression and upregulate OAT1 and OAT3 protein expression to reduce the UA level by promoting UA excretion and inhibiting UA reabsorption.Conclusion: These findings suggested that NAY produced dual hypouricemic actions. On the one hand, it can inhibit the formation of UA by inhibiting xanthine oxidase inhibitors activity, and on the other hand, it can promote the excretion of UA by regulating the UA transporter. It provides new ideas for the development of hyperuricemia drugs in the future.
研究领域:
药理学
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生物化学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2020
·Vol. 175
·期 2
·279-291
·
IF 3.703
Li Caiyu,Wang Xue,Bi Yajuan,Yu Heshui,Wei Jing,Zhang Yi,Han Lifeng,Zhang Youcai
Organic anion transporters 1 and 3 (OAT1 and OAT3) play a critical role in renal drug-drug interactions and are involved in the nephrotoxicity of many anionic xenobiotics. To date, relatively little is known about the interaction of natural compounds with OAT1 and OAT3. Of the 270 natural compounds screened in the present study, 21 compounds inhibited OAT1 and 45 compounds inhibited OAT3. Further concentration-dependent studies identified 7 OAT1 inhibitors and 10 OAT3 inhibitors with IC50 values of <10 μM, and most of them were flavonoids, the most commonly ingested polyphenolic compounds in the diet and herbal products. Computational modeling of OAT1 and OAT3 revealed the important residues for the recognition of inhibitors. The two strong OAT inhibitors, namely wedelolactone and wogonin, were evaluated for their in vivo interactions with the OAT substrate aristolochic acid I (AAI), a natural compound causing aristolochic acid-induced nephropathy (AAN) in many species. The cytotoxicity of AAI increased in two OAT-overexpressing cell lines, with more cytotoxicity in OAT1-overexpressing cells, suggesting a more important role of OAT1 than OAT3 in AAN. Both wedelolactone and wogonin markedly increased serum AAI concentrations in AAI-treated rats and ameliorated kidney injuries in AAI-treated mice. To conclude, the present findings are of significant value in understanding natural compound-drug interactions and provide a natural source for developing treatments for AAN.
研究领域:
药理学
·
毒理学
·
肾病学
·
植物化学
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产品关联
DOI
PubMed
高影响因子
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