FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Longyan Yang,Ruili Yin,Ziyu Shan,Anqi Feng,Kun Li,Yan Wang,Ke Yu,Yongsong Xu,Lin Mao,Jianan Lang,Baoyu Zhang,Dong Zhao
Aims Overweight and obesity are closely associated with hyperuricemia (HUA). However, the effect of obesity-induced adipokine on the level of serum uric acid (UA) has not been fully elucidated. This study aimed to determine the role of adipokine in the pathogenesis of HUA. Methods Omental adipose tissues from HUA patients with obesity were collected for data- independent acquisition (DIA) proteomics analysis, and the secreted protein angiopoietin-like protein (ANGPTL2) was identified and further validated via Western blot and ELISA. Angptl2 knockout (ko) and adipocyte-specific ANGPTL2 overexpression mice were generated to establish HUA models. HK2 cells and primary renal tubule epithelial cells (RTECs) were applied to induce HUA cell model and treated with recombinant human ANGPTL2 or supernatants derived from C3H10 cells differentiated into adipocytes. Result ANGPTL2 levels were significantly elevated in the omental adipose tissue from HUA with obesity patients compared to control participants. Circulating ANGPTL2 levels were also increased, and positively correlated with serum UA levels, especially in male participants. Plasma UA levels were significantly decreased in Angptl2 ko mice, coinciding with up-regulated expression of ATP binding cassette subfamily G member 2 (ABCG2) and down-regulated glucose transporter 9 (GLUT9) in renal tissue. However, plasma UA levels were significantly increased, accompanied by decreased ABCG2 expression and enhanced GLUT9 expression after adipocyte-specific ANGPTL2 overexpression. Furthermore, adipocyte- derived ANGPTL2 increased UA level in cell supernatants through the inhibition of protein kinase B (AKT)/ABCG2 signaling in RTECs and HK2 cells. Conclusion Adipokine ANGPTL2 levels were significantly elevated in HUA patients with obesity. Circulating ANGPTL2 concentrations were independently associated with serum UA levels, particularly in obese males. Adipocyte-secreted ANGPTL2 promoted the level of UA through AKT/ABCG2 signaling in renal tubular cells. These findings establish ANGPTL2 as a critical adipokine linking obesity to hyperuricemia and suggest its potential as a novel therapeutic target for HUA.
研究领域:
内分泌学
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代谢研究
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分子生物学
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PubMed
高影响因子
Journal of Cancer
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2020
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IF 3.565
Hao Hu,Shao-Ju Luo,Zhi-rui Cao,Yingzi Wu,Zhuomao Mo,Yongdan Wang,Ling Yu,Yan Chen,Liang Xu,Shi-Jun Zhang
Depressive disorder (DD) is the leading cause of disability worldwide and is the most prevalent mood disorder. Accumulative evidence from epidemiological studies has shown that DD is a risk factor for cancer. However, the role and molecular mechanism of DD in hepatocellular carcinoma (HCC) are still unknown. In this study, 30 mice were randomly divided into two groups: the HCC group and the HCC-DD group. The DD mouse model of HCC was established by induction with reserpine every other day and with monthly doses of diethylnitrosamine (DEN). All of the molecular studies were based on primary cell culture, and the effects of DD on HCC cell proliferation and migration and cancer stem cell (CSC) self-renewal were determined by colony formation, wound healing, and sphere culture assays. We found that the CSC markers ABCG2 and CD133 were upregulated in HCC-DD primary cells compared with HCC primary cells. Moreover, HCC-DD primary cells were more aggressive in terms of metastasis and self-renewal than HCC primary cells. Further study revealed that DD promoted tumor growth and metastasis by activating the AKT signaling pathway followed by an increased ABCG2 expression. Taken together, our novel findings indicate that DD promotes proliferation, self-renewal, and metastasis by upregulating ABCG2 in the AKT pathway.
研究领域:
肿瘤学
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分子生物学
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神经科学
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PubMed
高影响因子
Genes
·
2020
·Vol. 11
·期 2
·186
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IF 3.759
Yujuan Zhang,Jinhu Huang,Xiangxiu Li,Ci Fang,Liping Wang
Breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) half transporter encoded by theAbcg2gene, is reported to influence the pharmacokinetics of substrate drugs during clinical therapy. The aim of this study was to clarify the mechanisms that regulate the transcription of the chickenAbcg2gene through cloning and characterization of its promoter region. Results showed that theAbcg2gene is transcribed by a TATA-less promoter with several putative Sp1 sites upstream from two putative CpG islands. A luciferase reporter assay conducted both in chicken leghorn male hepatoma (LMH) cells and chicken primary hepatocytes mapped a basal promoter to nucleotides −110 to +30, which is responsible for the constitutive expression ofAbcg2. The 5′-region upstream of the basal promoter was characterized by both positive and negative regulatory domains. Further, using the cell-based reporter gene assay combined with RT-PCR and drug accumulation analysis, we found that four xenobiotics, daidzein, clotrimazole, ivermectin, and lipopolysaccharide (LPS), influence the expression and function of BCRP through significant regulation of theAbcg2gene promoter. Interaction sites with theAbcg2gene promoter of these four selected regulators were clarified by progressive deletions and mutation assays. This study shed some light on the regulatory mechanisms involved in chickenAbcg2gene expression and the results may have far-reaching significance regarding the usage and development of veterinary drugs.Keywords:chickenAbcg2;promoter;regulators;LMH;primary hepatocytes
研究领域:
分子生物学
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药理学
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遗传学
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PubMed
高影响因子
PLOS BIOLOGY
·
2023
·Vol. 21
·期 9
·e3002256
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IF 9.8
Jiaojiao Hao,Jinsheng Huang,Chunyu Hua,Yan Zuo,Wendan Yu,Xiaojun Wu,Liren Li,Guoqing Xue,Xinyu Wan,Liyuan Ru,Ziyue Guo,Shilong Han,Wuguo Deng,Fei Lin,Wei Guo
The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem–like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up–regulated in CRC CSCs (cCSCs) expansion and chemo–resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to −261 to −141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri–methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem–like traits and chemoresistance to CRC by co–regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo–resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3–WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem–like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2–deregulated tumors.
研究领域:
肿瘤学
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分子生物学
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癌症干细胞
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转录调控
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表观遗传学
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PubMed
高影响因子
Foods
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2025
·Vol. 14
·期 16
·2765
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IF 5.1
Furong Xue,Renqin Zhu,Jiaxing Li,Zheng Liu,Lidan Niu,Wei Chen,Chengtao Wang,Jie Zheng
The increasing global prevalence of hyperuricemia (HUA), particularly among younger populations, underscores the urgent need for safe and effective dietary interventions.Monascusfungi, long utilized in East Asian food culture, ferment rice to produce red yeast rice (RYR), a functional food rich in monacolin K and Monascus pigments. Among these,Monascusyellow pigments (MYPs)—natural azaphilone compounds used as food additives and colorants—have shown antioxidant, anti-inflammatory, and metabolic regulatory activities. However, their potential to alleviate hyperuricemia remains unexplored. This study investigates the urate-lowering and organ-protective effects of MYPs through a combination of in vitro, in vivo, and gut microbiota analyses. MYPs exhibited significant xanthine oxidase (XOD) inhibitory activity, and molecular docking confirmed that monascin (MS) and ankaflavin (AK) competitively bind to the XOD active site. In a murine HUA model, MYPs significantly reduced serum uric acid (SUA) levels without causing hepatic or renal toxicity. Mechanistically, MYPs downregulated renal UA reabsorption transporters (URAT1, GLUT9) and upregulated the excretory transporter ABCG2, enhancing uric acid (UA) excretion. These findings highlight MYPs as promising food-derived bioactives with dual XOD inhibition and uricosuric effects, offering a novel nutraceutical strategy for hyperuricemia prevention and management.
研究领域:
食品科学
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生物化学
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药理学
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营养学
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分子生物学
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微生物学
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PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2018
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IF 3.296
Shishi Li,Jinjin Xu,Zhihong Yao,Liufang Hu,Zifei Qin,Hao Gao,Kristopher W. Krausz,Frank J. Gonzalez,Xinsheng Yao
Cycloicaritin is a bioactive natural phenolic compound from Epimedium species. However, the glucuronidation and excretion which would influence oral bioavailability and pharmacokinetics of cycloicaritin still remain unknown. Here we aimed to establish UGT1A1 stably transfected HeLa cells, and to determine the contributions of BCRP and MRPs transporters to excretion of cycloicaritin-3- O -glucuronide. First, β-estradiol was used to validate the expression of active UGT1A1 protein in engineered HeLa1A1 cells. Furthermore, Ko143 (5 and 20 μM) led to a significant decrease (42.4%–63.8%, p < 0.01) in CICT-3-G excretion and obvious accumulation (19.7%–54.2%, p < 0.05) of intracellular CICT-3-G, while MK571 (5 and 20 μM) caused a significant reduction (46.8%–64.8%, p < 0.05) in the excretion and obvious elevation (50.7%–85.2%, p < 0.01) of intracellular level of CICT-3-G. Furthermore, BCRP knocked-down brought marked reduction in excretion rates of CICT-3-G (26.0%–42.2%, p < 0.01), whereas MRP1 and MRP4-mediated silencing led to significant decrease in the excretion of CICT-3-G (23.8%–35.4%, p < 0.05 for MRP1 and 11.9%–16.0%, p < 0.05 for MRP4). By contrast, neither CICT-3-G excretion nor CICT-3-G accumulation altered in MRP3 knocked-down cells as compared to scramble cells. Taken together, BCRP, MRP1 and MRP4 were identified as the most important contributors for CICT-3-G excretion. Meanwhile, the UGT1A1 modified HeLa cells were a simple and practical tool to study UGT1A1-mediated glucuronidation and to characterize BCRP and MRPs-mediated glucuronide transport at a cellular level.
研究领域:
药理学
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分子生物学
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药物代谢
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2020
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IF 3.263
Qiurui Li,Hua Lin,Yanfen Niu,Yan Liu,Zhenyu Wang,Liudong Song,Lihui Gao,Ling Li
Increasing evidence shows that the intestinal tract plays an important role in maintaining urate homeostasis and might be a potential therapeutic target for hyperuricaemia . However, uric acid-lowering drugs available in the clinic do not target intestinal excretion as a therapeutic strategy. We previously reported that mangiferin had potent hypouricaemic effects in hyperuricaemic animals. However, the underlying mechanisms are not completely clear. Here, we investigated the effects of mangiferin on the intestinal excretion of urate and its underlying mechanisms. The data revealed that mangiferin concentration-dependently promoted the intestinal secretion of endogenous urate in in situ intestinal closed loops in normal and hyperuricaemic mice, as well as inhibited the absorption of exogenous uric acid perfused into the intestinal loops in rats. Administration of mangiferin not only decreased the serum urate levels in the hyperuricaemic mice but also increased the protein expression of ATP-binding cassette transporter, subfamily G, member 2 (ABCG2) and inhibited the protein expression of glucose transporter 9 (GLUT 9) in the intestine. These findings suggested that intestinal ABCG2 and GLUT9 might be pivotal and possible action sites for the observed hypouricaemic effects. Moreover, no significant changes in intestinal xanthine oxidoreductase activities were observed, suggesting that mangiferin did not affect intestinal uric acid generation in the hyperuricaemic mice. Overall, promoting intestinal elimination of urate by upregulating ABCG2 expression and downregulating GLUT9 expression might be an important mechanism underlying mangiferin lowering serum uric acid levels. Mangiferin supplementation might be beneficial for the prevention and treatment of hyperuricaemia.
研究领域:
药理学
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生物化学
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医学
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PubMed
高影响因子
Cell Host & Microbe
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2024
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IF 20.6
Ying-Xi Xu,Lu-Di Liu,Jiang-Yuan Zhu,Shan-Shan Zhu,Bing-Qi Ye,Jia-Lu Yang,Jing-Yi Huang,Zhi-Hao Huang,Yi You,Wen-Kang Li,Jia-Lin He,Min Xia,Yan Liu
Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.
研究领域:
微生物学
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代谢组学
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药理学
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胃肠病学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Hongxuan Yang,Yun Liang,Yue’e Chen,Lin Liu,Yingfang Wang,Qiting Dou,Jinmei Gong,Zijing Liao,Junqiu Dong,Xuguang Hu
Ethnopharmacological relevance Lonicera japonica Thunb (honeysuckle), a traditional Chinese medicine, has been historically used to clear heat, detoxify, and dispel wind-heat. Modern research has identified various bioactive constituents from honeysuckle, supporting its potential in managing inflammatory and metabolic disorders. However, the anti-hyperuricemic activity and mechanism of its peptide components remain unexplored. Aim of the study: This study aimed to investigate the anti-hyperuricemic effect of honeysuckle-derived peptides and the underlying mechanisms, with a focus on uric acid production, excretion, and gut microbiota modulation. Materials and methods Nine novel peptides were identified from honeysuckle by HPLC-MS/MS and screened through molecular docking against xanthine oxidase (XOD). In vitro XOD inhibition and antioxidant assays were performed. A hyperuricemic mouse model was induced by potassium oxonate and hypoxanthine. Mice were treated with honeysuckle peptides at low, medium, and high doses. Serum biomarkers, renal and ileal histopathology, protein and mRNA expression of PGC-1α/PPARγ/ABCG2 pathway components, and gut microbiota composition (16S rRNA sequencing) were analyzed. Results Molecular docking confirmed strong binding between the peptides and XOD. In vitro , honeysuckle peptides significantly inhibited XOD activity and exhibited potent antioxidant capacity. In vivo , peptide treatment effectively reduced serum uric acid, XOD, creatinine, and blood urea nitrogen levels, alleviated renal and intestinal tissue damage, and suppressed inflammatory cytokines. The treatment also significantly upregulated the renal PGC-1α/PPARγ/ABCG2 pathway at both protein and mRNA levels. Furthermore, the peptides restored gut microbial diversity and corrected the Firmicutes/Bacteroidota ratio. Conclusion Honeysuckle peptides ameliorate hyperuricemia through a dual mechanism: inhibiting uric acid production by suppressing XOD activity and promoting its renal excretion by activating the PGC-1α/PPARγ/ABCG2 pathway, coupled with restoring gut microbiota homeostasis. This study provides a pharmacological basis for the traditional use of honeysuckle and highlights its peptides as promising candidates for managing hyperuricemia.
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高影响因子
ONCOLOGY REPORTS
·
2020
·Vol. 44
·期 3
·927-938
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IF 3.417
Songhui Zhou,Ruicheng Wang,Hong Xiao
The resistance of cancer cells to carboplatin restricts their efficacy in the clinical setting, and a solution to reverse the resistance is urgently required for the treatment of ovarian cancer. An increasing number of studies have found associations between obesity and the incidence, and mortality rates of female cancer. However, the association between adipocytes and the resistance of ovarian cancer has rarely been reported. Based on this, the present study first revealed the inductive effect of adipocytes on the resistance of ovarian cancer to carboplatin using in vivo and in vitro experiments. Subsequently, it was identified that the angiopoietin‑like 4 (ANGPTL4) secreted by adipocytes played a vital role in the resistance of ovarian cancer using bioinformatics analysis, cellular and molecular biological experiments, as well as forward and backward validation. The glycosylated ANGPTL4 protein could bind with integrin α5β1 on the surface of ovarian cancer cells; following which, it could activate the c‑myc/NF‑κB pathway and stimulate the expression of the antiapoptotic protein Bcl‑xL, as well as the ABC transporter family members ABCB1, ABCC1 and ABCG2. Thus, inducing the resistance of ovarian cancer to carboplatin. In conclusion, targeting the adipocyte‑derived ANGPTL4 combined with the application of carboplatin contributes to the clinical treatment for ovarian cancer.
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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PubMed
高影响因子
Journal of Functional Foods
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2019
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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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产品关联
DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2026
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IF 5.9
Ying He,Nengbin Wan,Hongwu Deng,Yi Zhang,Qiang Liu,Li Li,Hao Liu,Xiao He,Qing Zhu
Triple-negative breast cancer (TNBC) is an aggressive malignancy often characterized by chemoresistance, partly due to the overexpression of drug efflux transporters like ABCG2. To address this challenge, this study developed and evaluated a cRGD-modified, pH-sensitive liposomal system for the targeted co-delivery of docetaxel (DTX) and siRNA against ABCG2 (si-ABCG2). The synthesized nanoparticles (DTX/siRNA/cRGD-PLPs) exhibited optimal physicochemical properties, including a mean particle size of approximately 241.7 nm, efficient co-loading of DTX and siRNA, and pH-responsive cargo release, while protecting the siRNA from degradation in serum. Also, DTX/siRNA/cRGD-PLPs maintained homogeneous size distributions over the storage period and induced minimal hemoglobin release, with hemolysis rates remaining below safety threshold. These liposomes demonstrated enhanced, time-dependent uptake into TNBC cell lines HCC1937 and MDA-MB-231. In vitro , the DTX/siRNA/cRGD-PLPs formulation was significantly more effective at inhibiting cell viability, proliferation, migration, and invasion, and at inducing apoptosis, compared to the free drug combinations and other controls. Moreover, the dual-payload co-delivery liposomes (DTX/siRNA/cRGD-PLPs) exerted superior anti-tumor effects relative to single-agent formulations. In an MDA-MB-231 xenograft mouse model, the liposomal treatment was well-tolerated and resulted in marked tumor growth inhibition, which was associated with reduced cell proliferation (Ki67) and increased apoptosis (Caspase-3) within the tumor tissue. This targeted co-delivery system shows significant potential for improving TNBC treatment by synergistically enhancing therapeutic efficacy and overcoming chemoresistance.
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高影响因子
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