BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
Huan Wu,Yichun Ning,Zhaoxing Sun,Ji Ji,Min Lu,Xiaoyan Jiao,Xiaoliang Xu,Xiaoqiang Ding,Xin Cheng,Xiaofang Yu
Background Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2. Methods The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin. Results Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells. Conclusion Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.
研究领域:
药理学
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肾脏病学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Lulu Huang,Yun Xiao,Xiaoyu Han,Yang Yu,Chao Zheng,Xiangdong Fang,Qing Li,Fanglan Liu,Chunhua Xia,Yongjie Zhang,Jiake He
Objective: The objective of the study was to investigate whether bupropion (BUP) or its circulation metabolites could decrease plasma level of asymmetric dimethylarginine (ADMA) and ameliorate renal injury by modulation of Ddah1, Oatp4c1, Oct2, and Mate1 in rats with adenine-induced chronic renal injury.Methods: The study initially determined the effect of BUP and its metabolites on cell viability and apoptosis in HK2 cells in the presence and absence of ADMA. Secondly, the study explored whether long-term administration of BUP could reduce the plasma level of ADMA and mitigate renal damage. Thirdly, the expression and activity of Oct2, Ddah1, Mate1 and Oatp4c1 was determined by Western blot and UPLC-MS/MS.Results: With 0.5 μmol/L ADMA, hydroxybupropion (HBUP, 100 nmol/L), threo-hydrobupropion (TBUP, 10 nmol/L and 1 μmol/L) reduced N-Acetyl-β-D-glucosidase (NAG) level. At 5 μmol/L ADMA, BUP (1 nmol/L-1 μmol/L), HBUP (1–100 nmol/L), and BUP cocktail enhanced survival. At 50 μmol/L ADMA, HBUP (10 nmol/L and 1 μmol/L), TBUP/erythro-hydrobupropion (EBUP) (10–100 nmol/L), and BUP cocktail stimulated survival. EBUP (1 and 100 nmol/L) lowered LDH. BUP (100 nmol/L) and TBUP (1 μmol/L) decreased NAG. TBUP (10 nmol/L, 1 μmol/L) and EBUP (100 nmol/L) inhibited apoptosis. In adenine-induced chronic renal injury rats, long-term administration of BUP significantly decreased the serum concentration of ADMA and creatinine by 12.78% and 38.85%, respectively, ameliorated interstitial lesions and fibrosis and upregulated Ddah1, Oatp4c1, Oct2, Mate1. BUP increased metformin renal clearance without affecting digoxin disposition.Conclusion: Bupropion moderately decreases plasma levels of ADMA and ameliorates renal injury by modulation of Ddah1, Oatp4c1, Oct2, and Mate1.
研究领域:
药理学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2016
·Vol. 60
·期 10
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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
BIOPHARMACEUTICS & DRUG DISPOSITION
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2017
·Vol. 38
·期 9
·526-534
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IF 2.091
Liping Li,Yayun Weng,Wei Wang,Mengru Bai,Hongmei Lei,Hui Zhou,Huidi Jiang
Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2-K (hMATE2-K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK-hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK-hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells ( m PRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2-K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.
研究领域:
药理学
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肾病学
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药物代谢
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产品关联
DOI
PubMed
高影响因子
Theranostics
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2020
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IF 8.579
Lu Chen,Zeyang Wang,Qingwen Xu,Yuxi Liu,Le Chen,Suhang Guo,Hua Wang,Kui Zeng,Junqing Liu,Su Zeng,Lushan Yu
Background: Human organic cation transporter 2 (OCT2) is the most abundant and important uptake transporter involved in the renal excretion of cationic drugs. Abnormal hypermethylation- mediated silencing of OCT2 results in oxaliplatin resistance in renal cell carcinoma (RCC). The epigenetic activation of OCT2 by decitabine (DAC) reversed this resistance in normoxic conditions. Given the hypoxic characteristic of RCC, it is still unclear whether hypoxia promotes DAC resistance and is involved in the regulation of OCT2. Methods: The mRNA and protein expression of OCT2 was determined by qRT-PCR and Western blotting. MSRE-qPCR and BSP were used to examine methylation modifications at the OCT2 promoter. The ChIP-qPCR analysis was performed to detect the abundance of histone modification and HIF-1α. The accumulation of DAC and 5-mC were detected using LC-MS, and the amount of 5-hmC was determined by dot blot analysis. To understand the role of hypoxia in the regulation of equilibrative nucleoside transporter 1 (ENT1) expression, the HIF-1α KO cell model was constructed. The re-emulsion method was used for the construction of H-NPs, an oxygen nanocarrier based on hemoglobin, to alleviate the drug resistance of DAC under hypoxia. Results: DAC was unable to upregulate OCT2 expression in hypoxic conditions because of the hypermethylation and low H3K4me3 modification in its promoter region. Hypoxia-mediated repression of human ENT1, which was markedly suppressed in RCC, resulted in a decrease in the cellular accumulation of DAC. Besides, hypoxia-induced upregulation of histone deacetylase HDAC9, which impaired the enrichment of H3K27ac modification in the OCT2 promoter, led to the transcriptional repression of OCT2. H-NPs could attenuate the hypoxia-induced loss of DAC activity and sensitize RCC cells to the sequential combination therapy of DAC and oxaliplatin. Conclusions: Hypoxia-mediated repression of ENT1 led to the inability of DAC to upregulate the expression of OCT2 under hypoxia. H-NPs could alleviate resistance to oxaliplatin and DAC in RCC cells under hypoxia and may have potential clinical applications.
研究领域:
肿瘤学
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分子生物学
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药理学
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纳米技术
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表观遗传学
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DOI
PubMed
高影响因子
XENOBIOTICA
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2019
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IF 1.902
Siyuan Sun,Sisi Zhou,Shaowei Lei,Shujie Zhu,Kai Wang,Huidi Jiang,Hui Zhou
1. Jatrorrhizine is an active ingredient found in various traditional Chinese medicinal plants. Based on our previous finding that jatrorrhizine was a potent inhibitor of OCT2 and OCT3, the aim of the present study was to explore whether jatrorrhizine has an antidepressant-like action action via inhibition of uptake-2 transporters.2. In vitro uptake tests showed that jatrorrhizine strongly inhibited PMAT-mediated MPP+ uptake with an IC50 value of 1.05 μM and reduced 5-HT and NE uptake mediated by hOCT2, hOCT3 and hPMAT with IC50 values of 0.1–1 μM (for OCT2 and OCT3) and 1–10 μM (for PMAT).3. In mouse synaptosomes, jatrorrhizine suppressed 5-HT and NE uptake in a concentration dependently manner, where the role of uptake-2 inhibition is significant.4. The antidepressant-like action of jatrorrhizine was evaluated by mouse tail suspension test (TST). The TST showed that one week of jatrorrhizine (5, 10 and 20 mg/kg, i.p.) or venlafaxine (20 mg/kg, i.g.) can significantly reduce the duration of immobility when compared with vehicle control group.5. The concentration of jatrorrhizine shows a dose-dependent increase in brain tissues.6. Our study suggested that jatrorrhizine might be used as an antidepressant agent via inhibition of uptake-2 transporters.
研究领域:
药理学
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神经科学
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中医药学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2021
·
IF 4.221
Yaodong Yi,Liping Li,Feifeng Song,Ping Li,Mingyang Chen,Shixin Ni,Hengbin Zhang,Hui Zhou,Su Zeng,Huidi Jiang
Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo . Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1−100 μM) reduced OXA (40 μM) induced cytotoxicity in MDCK-hOCT2 (Madin–Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5–20 mg/kg for mice, 10–40 mg/kg for rats; twice a week, iv or ig ) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv ) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1−100 μM for cells; 10–20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 μM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.
研究领域:
药理学
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神经毒理学
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癌症研究
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药物递送系统
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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