PeerJ
·
2017
·
IF 2.177
Hang Lu,Zhiqiang Lu,Xue Li,Gentao Li,Yilin Qiao,Robert P. Borris,Youcai Zhang
Background Herb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities. Methods HEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 µg/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract of Juncus effusus , a well-known traditional Chinese medicine, was assessed for its effect on the in vivo pharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3. Results More than 30% of the plant extracts at the concentration of 5 µg/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC 50 values being <5 µg/ml. Juncus effusus showed a strong inhibition to OAT3 in vitro , and markedly altered the in vivo pharmacokinetic parameters of furosemide in rats. Conclusion The present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs.
研究领域:
药理学
·
毒理学
·
植物科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2021
·
IF 3.269
Xia Zhao,Jing Wang,Liying Tang,Pei Li,Jing Ru,Yuzhi Bai
The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. In vitro study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.
研究领域:
药理学
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 11
·2307
·
IF 6.525
Xueyan Gou,Fenglin Ran,Jinru Yang,Yanrong Ma,Xin’an Wu
Background: Organic anion transporter 1 (OAT1) and OAT3 have an overlapping spectrum of substrates such that one can exert a compensatory effect when the other is dysfunctional. As a result, the knockout of either OAT1 or OAT3 is not reflected in a change in the excretion of organic anionic substrates. To date, only the mOAT1 and mOAT3 individual knockout mouse models have been available. Methods: In this study, we successfully generated aSlc22a6/Slc22a8double-knockout (KO) rat model using CRISPR/Cas9 technology and evaluated its biological properties. Results: The double-knockout rat model did not expressionmRNAfor rOAT1 or rOAT3 in the kidneys. Consistently, the renal excretion ofp-aminohippuric acid (PAH), the classical substrate of OAT1/OAT3, was substantially decreased in theSlc22a6/Slc22a8double-knockout rats. The relativemRNAlevel ofSlco4c1was up-regulated in KO rats. No renal pathological phenotype was evident. The renal elimination of the organic anionic drug furosemide was nearly abolished in theSlc22a6/Slc22a8knockout rats, but elimination of the organic cationic drug metformin was hardly affected. Conclusions: These results demonstrate that this rat model is a useful tool for investigating the functions of OAT1/OAT3 in metabolic diseases, drug metabolism and pharmacokinetics, and OATs-mediated drug interactions.Keywords:OAT1/OAT3;CRISPR/Cas9;gene knockout;pharmacokinetic
研究领域:
药理学
·
分子生物学
·
遗传学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF FOOD BIOCHEMISTRY
·
2022
·Vol. 46
·期 7
·e14140
·
IF 3.654
Dongyin Yuan,Ling Lin,Yingqi Peng,Yang Zhou,Li Li,Wenjun Xiao,Zhihua Gong
Black tea, a traditional drink, can induce urination and quench thirst. Black brick tea with fungal growth, prepared by steaming, pressing, inducing fungal growth, and drying the black tea, is a new type of black tea with different sensory qualities and is suitable for storage. However, the effects of black brick tea with fungal growth on lowering uric acid are still unexplored. Therefore, the potassium oxonate was administered for 7 consecutive days to establish the hyperuricemic mice. Then allopurinol, black tea, and black brick tea with fungal growth were orally administered with hyperuricemic mice for 14 days. Serum uric acid levels, liver xanthine oxidase (XOD) and adenosine deaminase (ADA) activities, and expression of renal urate transporters and inflammatory response were detected. Compared to the model group, both types of black tea lowered serum uric acid by decreasing the uric acid production with inhibiting the activities of XOD and ADA, and increasing uric acid excretion because of downregulating urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expressions, and upregulating organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) expressions. They could also improve renal injury by suppressing the activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, and nuclear factor-κB (NF-κB) signaling, thereby reducing renal proinflammatory cytokine levels. Compared with black tea, black brick tea with fungal growth with a higher content of theabrownins had a better effect on lowering serum uric acid. Practical applications Black tea accounts for approximately 78% of the total consumed tea in the world. Black brick tea with fungal growth is a new kind of black tea product with different sensory qualities and is suitable for storage. The study found that black brick tea with fungal growth is superior to black tea in reducing serum uric acid levels, which make a significant contribution to promote people’s health and stimulate the production and consumption of black brick tea with fungal growth. In addition, it provides a clue for future research to identify the effective components of black brick tea with fungal growth lowering uric acid.
研究领域:
药理学
·
生物化学
·
营养学
·
动物科学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）