Pharmaceuticals
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2021
·Vol. 14
·期 5
·452
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IF 5.863
Jiaxiong Ming,Qianqian Xu,Limin Gao,Yanfang Deng,Jie Yin,Qun Zhou,Qingyi Tong,Yonghui Zhang
Cholestasis is an important predisposing factor of liver diseases, such as hepatocyte necrosis, liver fibrosis and primary biliary cirrhosis. In this study, we aimed to investigate the effects of Kinsenoside (KD), a natural active ingredient ofAnoectochilus roxburghii, on estrogen-induced cholestatic liver injury in Sprague-Dawley rats and the underlying mechanism. The rats were randomly divided into six groups: control group, model group, low-dose KD group (50 mg/kg body weight, KD-L), medium-dose KD group (100 mg/kg body weight, KD-M), high-dose KD group (200 mg/kg body weight, KD-H) and ursodeoxycholic acid group (40 mg/kg body weight, UDCA). 17α-Ethinylestradiol (EE) was used to establish an experimental animal model of estrogen-induced cholestasis (EIC). The results demonstrated that KD alleviated liver pathologic damage, serum biochemical status and inhibited hepatocellular microstructure disorder and bile duct hyperplasia in EE-induced cholestatic rats. Mechanically, KD alleviated EE-induced cholestatic liver injury by inhibiting inflammatory responses and regulating bile acid homeostasis. Concretely, KD reduced the expression of IL-1β and IL-6 by inhibiting NF-κB p65 to suppress EE-mediated inflammation in rat liver. KD enhanced the expression of FXR and inhibited EE-mediated reduction of FXR in vitro and in vivo. It was the potential mechanism that KD mitigates cholestasis by increasing efflux and inhibiting uptake of bile acids via FXR-mediated induction of bile salt export pump (BSEP) and reduction of Na+-dependent taurocholate cotransport peptide (NTCP) to maintain bile acid homeostasis. Moreover, KD repressed the bile acid synthesis through reducing the expression of synthetic enzyme (CYP7A1), thereby normalizing the expression of metabolic enzyme (SULT2A1) of bile acid. In conclusion, our results revealed that KD may be an effective drug candidate for the treatment of cholestasis.Keywords:kinsenoside;17α-ethinylestradiol;inflammation;cholestasis
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Environmental Chemical Engineering
·
2023
·
IF 7.7
Yanting Li,Shu Zhu,Hua Zhao,Yan Xiong,Tao Gong,Yanru Tao,Jin Li,Jiangling Hu,Hongmei Wang,Xinhui Jiang
Recently, the endocrine interference of endocrine disruptors on the environment and aquatic organisms has been a hot topic. Ethinyl estradiol (EE2) is an estrogen endocrine disruptor and one of the most widely used ingredients in oral contraceptives, resulting in high emissions and environmental pollution . Therefore, it is urgent to construct a non-enzymic, simple and low-cost sensor to detect EE2 in environmental and biological samples. We successfully prepared cobalt ferric oxide with anti-spinel structure and reduced graphene oxide composite (CoFe 2 O 4 /RGO) using hydrothermal synthesis, which decorated on the glass carbon electrode (GCE) to detect EE2. The morphological structure of CoFe 2 O 4 /RGO composites was studied by FESEM, HRTEM, EDX, FT-IR, XRD, and XPS techniques. Additionally, the experimental conditions were optimized and the oxidation mechanism of EE2 was explained theoretically and EE2 was detected by CV, EIS, and SWV, which displayed a fantastic current response of EE2. The electrochemical results illustrated that the prepared sensor has good selectivity , high sensitivity, a wide linear range of 0.05–100 μM, and a lower detection limit of 42 nM. Finally, the practicability of the sensor to detect EE2 in real samples was also studied and obtained a satisfactory recovery.
研究领域:
环境科学
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分析化学
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产品关联
DOI
高影响因子
eLife
·
2022
·
IF 8.713
Gang Zhai,Tingting Shu,Guangqing Yu,Haipei Tang,Chuang Shi,Jingyi Jia,Qiyong Lou,Xiangyan Dai,Xia Jin,Jiangyan He,Wuhan Xiao,Xiaochun Liu,Zhan Yin
Disruption of androgen signaling is known to cause testicular malformation and defective spermatogenesis in zebrafish. However, knockout of cyp17a1, a key enzyme responsible for the androgen synthesis, in ar-/- male zebrafish paradoxically causes testicular hypertrophy and enhanced spermatogenesis. Because Cyp17a1 plays key roles in hydroxylation of pregnenolone and progesterone (P4), and converts 17α-hydroxypregnenolone to dehydroepiandrosterone and 17α-hydroxyprogesterone to androstenedione, we hypothesize that the unexpected phenotype in cyp17a1-/-;androgen receptor (ar)-/- zebrafish may be mediated through an augmentation of progestin/nuclear progestin receptor (nPgr) signaling. In support of this hypothesis, we show that knockout of cyp17a1 leads to accumulation of 17α,20β-dihydroxy-4-pregnen-3-one (DHP) and P4. Further, administration of progestin, a synthetic DHP mimetic, is sufficient to rescue testicular development and spermatogenesis in ar-/- zebrafish, whereas knockout of npgr abolishes the rescue effect of cyp17a1-/- in the cyp17a1-/-;ar-/- double mutant. Analyses of the transcriptomes among the mutants with defective testicular organization and spermatogenesis (ar-/-, ar-/-;npgr-/- and cyp17a-/-;ar-/-;npgr-/-), those with normal phenotype (control and cyp17a1-/-), and rescued phenotype (cyp17a1-/-;ar-/-) reveal a common link between a downregulated expression of insl3 and its related downstream genes in cyp17a-/-;ar-/-;npgr-/- zebrafish. Taken together, our data suggest that genetic or pharmacological augmentation of the progestin/nPgr pathway is sufficient to restore testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling.
研究领域:
生物学
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生殖生物学
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内分泌学
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遗传学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Junxian Zhu,Yongchang Wang,Luo Lei,Chen Chen,Liqin Ji,Jiansong Li,Congcong Wu,Wenjun Yu,Laifu Luo,Weiqin Chen,Pan Liu,Xiaoyou Hong,Xiaoli Liu,Haigang Chen,Chengqing Wei,Xinping Zhu,Wei Li
A feature of the Chinese soft-shelled turtle ( Pelodiscus sinensis ) is seasonal spermatogenesis ; however, the underlying molecular mechanism is not well clarified. Here, we firstly cloned and characterized P. sinensis DKKL1 , and then performed comparative genomic studies, expression analysis, and functional validation. P. sinensis DKKL1 had 2 putative N-glycosylation sites and 16 phosphorylation sites. DKKL1 also had classic transmembrane structures that were extracellularly localized. DKKL1 's genetic distance was close to turtles, followed by amphibians and mammals, but its genetic distance was far from fishes. DKKL1 genes from different species shared distinct genomic characteristics. Meanwhile, they were also relatively conserved among themselves, at least from the perspective of classes. Notably, the transcription factors associated with spermatogenesis were also identified, containing CTCF , EWSR1 , and FOXL2 . DKKL1 exhibited sexually dimorphic expression only in adult gonads, which was significantly higher than that in other somatic tissues ( P < 0.001), and was barely expressed in embryonic gonads. DKKL1 transcripts showed a strong signal in sperm, while faint signals were detected in other male germ cells. DKKL1 in adult testes progressively increased per month ( P < 0.05), displaying a seasonal expression trait. DKKL1 was significantly downregulated in testes cells after the sex hormones (17β-estradiol and 17α-methyltestosterone) and Wnt/β-catenin inhibitor treatment ( P < 0.05). Likewise, the Wnt/β-catenin inhibitor treatment dramatically repressed CTCF, EWSR1, and FOXL2 expression. Conversely, they were markedly upregulated after the 17β-estradiol and 17α-methyltestosterone treatment, suggesting that the three transcription factors might bind to different promoter regions, thereby negatively regulating DKKL1 transcription in response to the changes in the estrogen and androgen pathways, and positively controlling DKKL1 transcription in answer to the alterations in the Wnt/β-catenin pathway. Knockdown of DKKL1 significantly reduced the relative expression of HMGB2 and SPATS1 ( P < 0.01), suggesting that it may be involved in seasonal spermatogenesis of P. sinensis through a positive regulatory interaction with these two genes. Overall, our findings provide novel insights into the genome evolution and potential functions of seasonal spermatogenesis of P. sinensis DKKL1 .
研究领域:
基因组学
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生殖生物学
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分子生物学
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比较基因组学
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产品关联
DOI
PubMed
高影响因子
ACS Synthetic Biology
·
2023
·
IF 4.7
Ruosi Zhang,Mingdong Yao,Haidi Ma,Wenhai Xiao,Ying Wang,Yingjin Yuan
Substrate competition within a metabolic network constitutes a common challenge in microbial biosynthesis system engineering, especially if indispensable enzymes can produce multiple intermediates from a single substrate. Androstenedione (4AD) is a central intermediate in the production of a series of steroidal pharmaceuticals; however, its yield via the coexpression of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17α-hydroxylase/17,20-lyase (CYP17A1) in a microbial chassis affords a nonlinear pathway in which these enzymes compete for substrates and produce structurally similar unwanted intermediates, thereby reducing 4AD yields. To avoid substrate competition, we split the competing 3β-HSD and CYP17A1 pathway components into two separate Yarrowia lipolytica strains to linearize the pathway. This spatial segregation increased substrate availability for 3β-HSD in the upstream strain, consequently decreasing the accumulation of the unwanted intermediate 17-hydroxypregnenolone (17OHP5) from 94.8 ± 4.4% in single-chassis monocultures to 24.8 ± 12.6% in cocultures of strains expressing 3β-HSD and CYP17A1 separately. Orthologue screening to increase CYP17A1 catalytic efficiency and the preferential production of desired intermediates increased the biotransformation capacity in the downstream pathway, further decreasing 17OHP5 accumulation to 3.9%. Furthermore, nitrogen limitation induced early 4AD accumulation (final titer, 7.71 mg/L). This study provides a framework for reducing intrapathway competition between essential enzymes during natural product biosynthesis as well as a proof-of-concept platform for linear steroid production.
研究领域:
代谢工程
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生物技术
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药学
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微生物生物技术
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产品关联
DOI
PubMed
高影响因子
Journal of Environmental Chemical Engineering
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2023
·
IF 7.7
Huan He,Qingsong Yue,Qicheng Ma,Xiaoxia Yang,Juhong Zhan,Feng Liu,Zhicheng Liao,Ziwei Guo,Bin Huang,Xuejun Pan
The reuse of reclaimed water has been limited by the ecological and human health risks of the residual trace organic pollutants , antibiotic-resistant bacteria and antibiotic resistance genes it often contains. The emerging photoelectrocatalytic technology may be able to break through this bottleneck. Nevertheless, the detailed information about such technology in the reclaiming water treatment has not been fully addressed. A laboratory-scale photoelectrocatalytic purification system was constructed using TiO 2 nanotube arrays doped with BiFeO 3 nanoparticles as the anode and carbon/polytetra-fluoroethylene as the cathode. The anode was stable with excellent optical and electrochemical properties. About 5.6 log of antibiotic-resistant bacteria were inactivated within 30 min, and 60% of free antibiotic resistance genes were removed within 60 min. The effective removal was mainly due to mutual promotion between photoelectrocatalysis and Fenton reactions which produced abundant active radicals. Low concentrations of effluent organic matter promoted the inactivation. The process was demonstrated in a bench-scale reactor treating 17α-ethinylestradiol and antibiotic-resistant bacteria with high removal rates. The designed photoelectrocatalytic reactor can provide efficient technology for the reuse of reclaiming water.
研究领域:
环境工程
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水处理
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光电催化
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废水回用
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产品关联
DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2020
·
IF 4.872
Wenhao Huang,Weiming Ai,Weiwei Lin,Fang Fang,Xuedong Wang,Haishan Huang,Randy A. Dahlgren,Huili Wang
Herein, eight common endocrine disrupting chemicals (EDCs) were exposed to zebrafish ( Danio rerio ) to investigate the relationship between different EDCs and their activated estrogen receptors. Under acute exposure, we identified five major malformation types whose incidence and deformity modes differed among EDCs. Luciferase analysis divided the EDC receptors into four categories: (i) triclosan (TCS), 17ß-estradiol (E2) and estriol (E3) mainly activated GPER expression; (ii) bisphenol A (BPA), p -(tert-octyl) phenol (POP), 17α-ethynylestradiol (EE2), E2 and E3 activated ERβ expression; (iii) E2 and E3 acted on both GPER and ERβ; and (iv) estrone (E1) and 9,9-bis(4-hydroxyphenyl)fluorene (BHPF) had little effect on the two receptors. In vivo immunofluorescence experiments on 96-hpf larvae provided evidence that TCS and POP acted on GPER and ERβ, respectively, while E2 acted on the two receptors simultaneously. Luciferase activities in the promoter regions of gper (−986 to −488) and erβ (−1998 to −1496) were higher than those in other regions, identifying these key regions as targets for transcription activity. TCS promoted GPER expression by acting on the JUND transcription factor, while POP promoted ERβ expression by activating the Foxl1 transcription factor. In contrast, E2 mainly regulated transcription of GPER and ERβ by Arid3a. These findings provide compelling evidence that different EDCs possess varying estrogen receptors, leading to differential regulatory pathways and abnormality symptoms. These results offer an experimental strategy and fundamental information to assess the molecular mechanisms of EDC-induced estrogen effects.
研究领域:
毒理学
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环境科学
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分子生物学
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发育生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEMBRANE SCIENCE
·
2023
·
IF 9.5
Haojie Zeng,Feiyun Sun,Jianjun Zhang,Ying Wang,Songwen Yang,Dingyu Xing
Polyvinyl alcohol (PVA) has been employed and crosslinked as the selective layer of NF membranes with enhanced hydrophilicity. However, the influences of different crosslinking methods and agents on the reaction mechanism and membrane performance still need to be comprehensively studied. In this study, NF membranes were prepared by coating crosslinking (CC-membrane) and gradient crosslinking (GC-membrane) methods. Compared with CC-membrane, the GC-membrane possessed a 65% higher flux with Na 2 SO 4 rejection around 90%, under the optimal preparation conditions with PVA content of 0.10%, curing at 80 °C for 10 min. Crosslinking agents including 1,3,5-benzenetricarboxylic acid (TMA), 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA) and pyromellitic dianhydride (PMDA) with different spatial structure were used to optimize the GC-membrane. As confirmed by SEM, XPS, FTIR and contact angle tests, the 6FDA-GC membrane showed a thinner, smoother and more hydrophilic selective layer, and kept an excellent balance between the water flux (88.6 L/m 2 h) and Na 2 SO 4 rejection (88.7%). This is because the 6FDA with a large molecule and flexible spatial structure could form a more integrated crosslinking structure compared to PMDA. Meanwhile, the 6FDA-GC membrane showed rejections of over 80% towards the endocrine-disrupting compound 17α-Ethinylestradiol and exhibited stable antifouling ability and durability. Overall, this work studied systematically the influences of various crosslinking agents on the GC-membrane, and verified the potential of hydrophilic PVA membranes for nanofiltration.
研究领域:
材料科学
·
化学工程
·
环境科学
·
膜技术
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）