PLANTA MEDICA
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2018
·Vol. 85
·期 03
·225-230
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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
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2015
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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
Frontiers in Pharmacology
·
2018
·
IF 3.831
Yong Tianqiao,Chen Shaodan,Xie Yizhen,Chen Diling,Su Jiyan,Shuai Ou,Jiao Chunwei,Zuo Dan
Ganoderma applanatum (G. applanatum) dispels wind to eliminate dampness and exhibited nephron- and liver-protective effects as noted in Chinese herbal classic literature; it might also affect hyperuricemia. Therefore, we examined the hypouricemia effects and mechanisms underlying G. applanatum on chemical-induced hyperuricemia in mice. Ethanol (GAE) and water (GAW) extracts were prepared by extracting G. applanatum in ethanol (GAE), followed by bathing the remains in water to yield GAW. GAE and GAW were administered orally at different doses to hyperuricemia mice, while allopurinol and benzbromarone served as positive controls. Both GAE and GAW showed remarkable hypouricemia activities, rendering a substantial decline in the SUA (serum uric acid) level in hyperuricemia control (P < 0.01). Moreover, the urine uric acid (UUA) levels were enhanced by GAE and GAW. In contrast to the evident renal toxicity of allopurinol, GAE and GAW did not show a distinct renal toxicity. Almost no suppressing effect was observed on the XOD activities. However, compared to the hyperuricemia control, OAT1 was elevated remarkably in mice drugged with GAE and GAW, while GLUT9 was significantly decreased. Similar to benzbromarone, GAE decreased the URAT1 protein levels significantly (P < 0.01), while GAW did not display a similar effect. GAE and GAW downregulated the level of CNT2 proteins in the gastrointestinal tract of hyperuricemia mice. Thus, G. applanatum produced outstanding hypouricemic effects, mediated by renal OAT1, GLUT9, and URAT1 and gastrointestinal CNT2 that might elevate urine uric secretions and decline in the absorption of purine in the gastrointestinal tracts. G. applanatum showed little negative influence on inner organs. By docking screening, four top-ranked compounds were identified that necessitated further investigation.Compounds: potassium oxonate, hypoxanthine, allopurinol, benzbromarone.
研究领域:
药理学
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医学
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分子生物学
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DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
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2018
·Vol. 46
·期 03
·585-599
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IF 3.12
Tianqiao Yong,Shaodan Chen,Yizhen Xie,Diling Chen,Jiyan Su,Ou Shuai,Huiping Hu,Dan Zuo,Danling Liang
Ethanol and water extracts of Armillaria mellea were prepared by directly soaking A. mellea in ethanol (AME) at 65 ∘ C, followed by decocting the remains in water (AMW) at 85 ∘ C. Significantly, AME and AMW at 30, 60 and 120 mg/kg exhibited excellent hypouricemic actions, causing remarkable declines from hyperuricemic control (351 μ mol/L, P < 0 . 0 1 ) to 136, 130 and 115 μ mol/L and 250, 188 and 152 μ mol/L in serum uric acid, correspondingly. In contrast to the evident renal toxicity of allopurinol, these preparations showed little impacts. Moreover, they showed some inhibitory effect on XOD (xanthine oxidase) activity. Compared with hyperuricemic control, protein expressions of OAT1 (organic anion transporter 1) were significantly elevated in AME- and AMW-treated mice. The levels of GLUT9 (glucose transporter 9) expression were significantly decreased by AMW. CNT2 (concentrative nucleoside transporter 2), a key target for purine absorption in gastrointestinal tract was involved in this study, and was verified for its innovative role. Both AME and AMW down-regulated CNT2 proteins in the gastrointestinal tract in hyperuricemic mice. As they exhibited considerable inhibitory effects on XOD, we selected XOD as the target for virtual screening by using molecular docking, and four compounds were hit with high ranks. From the analysis, we concluded that hydrogen bond, Pi–Pi and Pi-sigma interactions might play important roles for their orientations and locations in XOD inhibition.
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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医学
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PubMed
高影响因子
Scientific Reports
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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
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微生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
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IF 5.195
Jinxia Hou,Lanping Zhong,Jianming Liu,Fanglan Liu,Chunhua Xia
Ethnopharmacological relevance Shengmai formula (SMF) is a classical traditional Chinese medicine prescription, which is widely used in the treatment of cardiovascular and cerebrovascular diseases . Our previous studies have demonstrated that some components in SMF can interact with each other through breast cancer resistance protein , sodium taurocholate co-transporting polypeptide , organic anion transporting polypeptide 1B1 and 1B3. Organic anion transporter 1 (OAT1) is highly expressed in kidney, mediating the elimination of many endogenous and exogenous substances. However, the interaction between the main active components in SMF and OAT1 is not clear. Aim of the study This study aimed to investigate the interactions of the major bioactive components in SMF mediated by OAT1. Materials and methods Four main fractions, namely, ginseng total saponins (GTS), ophiopogon total saponins (OTS), ophiopogon total flavonoids (OTF), fructus schisandrae total lignans (STL), and 12 active components, namely, ginsenoside Rg1, Re, Rd and Rb1, ophiopogonin D and Dˊ, methylophiopogonanone A and B, schizandrol A and B, schizandrin A and B, were selected to explore the interactions of SMF with OAT1 using cell and rat models. Results The above four main fractions in SMF all exhibited inhibitory effects on the uptake of 6-carboxyfluorescein (6-CF), a classic substrate of OAT1. Among the 12 main effective components, only ginsenoside Re , Rd, and methylophiopogonanone A showed inhibition of 6-CF uptake. Additionally, we found that schizandrin B was transported by HEK293-OAT1 cells, and schizandrin B uptake was markedly inhibited by GTS, OTS, OTF, ginsenoside Re, Rd, and methylophiopogonanone A. In rats, ginsenoside Re, Rd, and methylophiopogonanone A jointly increased the AUC (0-t) , AUC (0-∞) , and C max of schizandrin B, but they decreased its clearance in plasma and excretion in urine. Conclusions Ginsenoside Re, Rd, and methylophiopogonanone A were the potential inhibitors of OAT1, and may interact with some drugs serving as OAT1 substrates clinically. Schizandrin B was a potential OAT1 substrate, and its OAT1-mediated transport was inhibited by ginsenoside Re, Rd, and methylophiopogonanone A. OAT1-mediated interactions of the main active components in SMF can be regarded as one of the important compatibility mechanisms of traditional Chinese medicine preparations.
研究领域:
药理学
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中药学
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分子生物学
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药物代谢
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2017
·Vol. 161
·期 2
·321-334
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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
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毒理学
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药物化学
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分子生物学
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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
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
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2016
·Vol. 60
·期 10
·
IF 4.415
Xi Yang,Zhiyuan Ma,Sisi Zhou,Yayun Weng,Hongmei Lei,Su Zeng,Liping Li,Huidi Jiang
Entecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption.
研究领域:
药理学
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肾脏生理学
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分子生物学
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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
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化学
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分子生物学
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DOI
PubMed
高影响因子
Pharmacological Reports
·
2017
·
IF 2.587
Ting Wu,Haixin Li,Jiasheng Chen,Ying Cao,Weimin Fu,Pingzheng Zhou,Jianxin Pang
Background Apigenin is a flavonoid compound, widely distributed in natural plants. Various studies have suggested that apigenin has inhibitory effects towards several drug transporters, such as the organic anion transporting (OAT) polypeptides , 1B1 and 1B3 (OATP1B1 and OATP1B3). However, the mechanism by which apigenin interacts with OAT1 has not been well studied. Methods MDCK cells stably-expressing OAT1 were used to examine the inhibitory effects of apigenin on OAT1. UPLC–MS/MS was used to evaluate the in vitro and in vivo effects of apigenin on the uptake of acyclovir by OAT1. Cytotoxicity was determined by the cell viability , MTT assays . Results Apigenin effectively inhibited the activity of OAT1 in a dose-dependent manner with an IC50 value of 0.737 μM. Pre-incubation of cells with apigenin caused a time-dependent inhibition (TDI) of OAT1. Additionally, we examined the interactions between apigenin and acyclovir or adefovir . Data showed that apigenin (1 μM) significantly blocked the uptake of acyclovir by OAT1 in vitro with an inhibition rate of 55%. In vivo , apigenin could increase the concentration of acyclovir in plasma when co-administered with acyclovir. Importantly, the MTT assays showed that, at a dose of 50 μM, apigenin significantly reduced the cytotoxicity of adefovir and substantially increased cell viability from 50.6% to 112.62%. Conclusion Our results demonstrate that apigenin regulates OAT1, and can cause TDI or herb-drug interaction (HDI) when used in combination with acyclovir or adefovir. Therefore, apigenin could be used as a nephroprotective agent when used in combination with the substrates of OAT1.
研究领域:
药理学
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分子生物学
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PubMed
高影响因子
Journal of Functional Foods
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2019
·
IF 3.197
Yin Wan,Fen Wang,Bin Zou,Yuefeng Shen,Yizhen Li,Axi Zhang,Guiming Fu
The mechanism underlying the reduction in uric acid levels in hyperuricemia rats by caffeic acid was investigated in this study. Different doses of caffeic acid (25, 50, and 100 mg/kg) were administered to hyperuricemia rats induced by the intraperitoneal injection of potassium oxonate. In vivo study showed that caffeic acid can down-regulate the transcription levels of URAT1 and GLUT9 mRNA and up-regulate the transcription levels of OAT1, UAT, and ABCG2 mRNA. In vitro study indicated caffeic acid competitively binds with xanthine oxidase to inhibit its activity, and the IC 50 value was 53.45 µM. It was concluded that caffeic acid decreases serum uric acid levels in hyperuricemia rats by binding with xanthine oxidase and inhibiting its catalytic activity and by regulating the mRNA transcription of the renal uric acid transporters.
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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高影响因子
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