JOURNAL OF ETHNOPHARMACOLOGY
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2019
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IF 3.414
Peter Yaro,Jing Nie,Mingcheng Xu,Kui Zeng,Houhong He,Jianbiao Yao,Ruwei Wang,Su Zeng
Ethnopharmacological relevance The major terpene lactones of ginkgo biloba extract (GBE) include ginkgolide A , B, C and bilobalide are used for the protection of cardiovascular, cerebrovascular and neurodegenerative diseases. Terpene lactones are orally bioavailable and predominantly eliminated via the renal pathway. However, information on the transporters involved in the pharmacokinetics (PK) and renal excretion of terpene lactones is limited. Aim of the study The objective of this study is to assess the role of OAT1/3 which are important transporters in the human kidney in the PK and renal excretion ginkgolide A, B, C and bilobalide. Materials and methods Uptake of ginkgolide A, B, C and bilobalide in Madin-Darby Canine Kidney (MDCK) and human embryonic kidney 293 (HEK293) cells overexpressing OAT1 or OAT3, respectively were studied. To verify the result from in vitro cell models, the studies on PK, kidney accumulation and urinary excretion of ginkgolide A, B, C and bilobalide were carried out in rats. Results The result showed that ginkgolide A, B, C and bilobalide are low-affinity substrates of OAT1/3. Following co-administration with probenecid , a typical inhibitor of OAT1/3, the rat plasma concentrations of ginkgolide A, B, C and bilobalide increased significantly. AUC showed a significant increase in the probenecid-treated rats compared to control rats (893.48 vs. 1123.85, 314.91 vs. 505.74, and 2724.97 vs. 3096.40 μg/L*h for ginkgolide A, B and bilobalide, respectively), while the clearance of these compounds significantly decreased. The accumulation of ginkgolide A, B and bilobalide in the kidney of the probenecid-treated rats was reduced by 1.8, 2.4, and 1.5-fold, respectively; further reducing the cumulative urinary recovery of these compounds. Conclusion The findings indicated that ginkgolide A, B and bilobalide are excreted via OAT1/3-mediated transport in the kidney and OAT1/3 inhibitor significantly influence the PK ginkgolides and bilobalide.
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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).
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
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2017
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IF 3.756
Yixian Liu,Bingjie Liu,Yan Zhang,Youmei Peng,Chenzheng Huang,Ning Wang,Jinhua Jiang,Qingduan Wang,Junbiao Chang
2′-Deoxy-2′-β-fluoro-4′-azidocytidine (FNC), a cytidine analog, has attracted great interest because of its potent activity against wild-type and multidrug-resistant HIV. The purpose of current study was to investigate the absorption mechanisms of FNC in the small intestine, as well as the interactions between FNC and P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). The experiments were performed using Caco-2 cells and the rat small intestine. The uptake experiment indicated that FNC concentration, extracellular pH and the incubated temperature could influence the uptake of FNC in Caco-2 cells. NaN 3 , verapamil , probenecid , MK571 and GF120918 could significantly increase the FNC uptake in Caco-2 cells. The transport experiment showed that both the absorption and secretion of FNC were concentration dependent. The secretion of FNC was approximately 2-fold greater than the absorption. In the presence of verapamil, probenecid, MK571 or GF120918, the efflux ratio decreased by > 50%. In everted rat intestine, the absorption of FNC also depended on its concentration and was not significantly different in the different segments of the small intestine. Real-time RT-PCR results indicated that the gene expressions of P-gp, MRP2 and BCRP were up-regulated after exposure to FNC. The reduction in accumulation of rhodamine 123 after treatment with FNC revealed its ability to up-regulate P-gp activity. In conclusion, FNC was completely absorbed by passive diffusion and active transport mechanisms. P-gp, MRP2 and BCRP could influence the absorption of FNC in the small intestine. FNC could modulate the gene expressions of P-gp, MRP2 and BCRP, and increase the activity of P-gp.
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BIOORGANIC CHEMISTRY
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2024
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IF 4.5
Hongming Tang,Tao Hou,Han Zhou,Han Liao,Fangfang Xu,Xiaomin Xie,Wenjie Yuan,Zhixin Guo,Yanfang Liu,Jixia Wang,Weijia Zhou,Xinmiao Liang
Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream G i and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC 50 value of 11.68 ± 1.30 μM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists.
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Neuropsychiatric Disease and Treatment
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2024
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IF 2.5
Yueyuan Wang,Bo Lv,Kai Fan,Cunjin Su,Delai Xu,Jie Pan
Purpose Parkinson’s disease (PD) is a common neurodegenerative disease that severely affects patients’ daily lives and places a significant burden on the global economy. There are currently no specific biomarkers for distinguishing between the different stages of PD.Methods We divided 78 mice into six equal groups, including five model PD groups (W1–W5; based on the PD stage induced by length of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/propofol induction time) and a control group. Then, we used metabolomics technology to detect the serum small-molecule metabolites present in each group. Ultimately, we screened for potential biomarkers using the variable importance in the projection of the orthogonal partial least squares discriminant analysis and the coefficient value of LASSO ordinal logistic regression.Results We identified 12 potential biomarkers, including dehydroepiandrosterone sulfate, pipecolic acid, N-acetylleucine, 2-aminoadipic acid, L-tyrosine, uric acid, and 5-hydroxyindoleacetaldehyde. Pathway analysis revealed their involvement in amino acid metabolism, caffeine metabolism, steroid hormone biosynthesis, and purine metabolism. Additionally, the receiver operating characteristic curve indicated that a biomarker panel comprising the 12 biomarkers could differentiate between the different PD stages.Conclusion Different PD stages are characterized by different metabolites. The biomarkers identified in this study are helpful to understand the PD process.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Qianyi Zhang,Hongjun Zhuang,Xiaofei Wen,Yonghui Su,Jiamian Wang,Hao Qin,Jiaqian Wang,Zhaoshui Shangguan,Yiqun Ma,Jian Dong,Bo Tian,Xilei Li
Cancer neuroscience has revealed the pivotal role of neural pathways in tumor progression and cancer-associated pain, particularly in bone metastases. To address both tumor growth and pain, we developed a novel nanomedicine strategy that targets mitochondrial dysfunction in cancer cells. The engineered H-MnCa/3MA-ALD nanoparticle system combines hollow mesoporous manganese-calcium (H-MnCa) nanoparticles functionalized with alendronate (ALD) for bone targeting, and loaded with 3-Methyladenine (3MA) to inhibit autophagy. This system disrupts mitochondrial ATP production, exploiting the inherent vulnerability of mitochondria to oxidative stress, and enhances reactive oxygen species (ROS) generation. The elevated ROS selectively induces cancer cell death while also reducing the secretion of nerve growth factor (NGF). This dual-action mechanism not only inhibits tumor growth and metastasis but also alleviates cancer-induced bone pain by downregulating neuro-pain mediators such as p-STAT-3 and NGF. This approach overcomes traditional chemodynamic therapy (CDT) limitations, ensuring targeted mitochondrial damage and apoptosis while preventing protective mitophagy. In vivo studies further confirm that H-MnCa/3MA-ALD provides effective tumor eradication and pain relief, offering a comprehensive solution for both cancer progression and pain management.
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Science Advances
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2024
·Vol. 10
·期 16
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IF 11.7
Zherui Zhang,Yuhao Luo,Yuanhong Ma,Yaofeng Zhou,Dingcheng Zhu,Wanhua Shen,Junqiu Liu
The in situ generation of H2O2 in cells in response to external stimulation has exceptional advantages in modulating intracellular Ca2+ dynamics, including high controllability and biological safety, but has been rarely explored. Here, we develop photocatalyst-based metal-organic frameworks (DCSA-MOFs) to modulate Ca2+ responses in cells, multicellular spheroids, and organs. By virtue of the efficient photocatalytic oxygen reduction to H2O2 without sacrificial agents, photoexcited DCSA-MOFs can rapidly trigger Ca2+ outflow from the endoplasmic reticulum with single-cell precision in a repeatable and controllable manner, enabling the propagation of intercellular Ca2+ waves (ICW) over long distances in two-dimensional and three-dimensional cell cultures. After photoexcitation, ICWs induced by DCSA-MOFs can activate neural activities in the optical tectum of tadpoles and thighs of spinal frogs, eliciting the corresponding motor behaviors. Our study offers a versatile optical nongenetic modulation technique that enables remote, repeatable, and controlled manipulation of cellular and animal behaviors.
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Journal of Advanced Research
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2024
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IF 11.4
Sijia Lu,Quanxin Jiang,Peihui Zhou,Limin Yin,Ning Wang,Junting Xu,Qiqi Qian,Mijia Tao,Hanrui Yin,Liu Han,Yunqing Gu,Fei Gao,Junli Liu,Suzhen Chen
Introduction Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. Objectives The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. Methods To assess the anti-obesity efficacy of orally administered HPF in vivo , Dlat heterozygous knockout (Dlat +/- ) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro . Results Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca 2+ ) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3-AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat +/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. Conclusion In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.
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JOURNAL OF SEPARATION SCIENCE
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2025
·Vol. 48
·期 12
·e70326
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IF 2.8
Meichen Liu,Yingxia Guo,Jinhe Liu,Zihan Tang,Yufeng Guo,Xintao Liu,Deshan Zhou,Lei Yin,Meiyun Shi
An ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous determination of fipronil and its three metabolites (fipronil sulfone, fipronil sulfide, and fipronil desulfinyl) in zebrafish tissues. Protein precipitation was employed for sample preparation, followed by chromatographic separation on a C 18 column. The method demonstrated excellent linearity ( r 2 > 0.99) across a range of 0.1–10 ng/mL, with a lower limit of quantification (LLOQ) of 0.1 ng/mL for all analytes. Validation results confirmed acceptable accuracy (−5.0% to 8.9%), precision (0.6%–13.2%), recoveries (86.3%–113.6%), and minimal matrix effects (86.0%–110.6%). When applied to zebrafish exposed to 50 µg/L fipronil for 12 h, the method revealed preferential accumulation of fipronil and fipronil sulfone in liver tissues, while lower levels were detected in muscle tissues. Fipronil sulfide was rarely detected, and fipronil desulfinyl concentrations were below the LLOQ (0.1 ng/mL) in all tested samples. This reliable and sensitive method is well-suited for environmental toxicology studies, pesticide residue monitoring, and ecological risk assessment.
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2025
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IF 2.8
Meichen Liu,Yingxia Guo,Ziyi Niu,Yufeng Guo,Shuang Feng,Xiaoyan Zhang,Jiansong You,Lei Yin,Hongyu Xue,Meiyun Shi
A sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry cubed (UPLC-MS 3 ) assay was established for detection of fipronil in zebrafish tissue samples. Following protein precipitation pretreatment, the concentrations of fipronil in various zebrafish tissue samples were quantified by the developed UPLC-MS 3 assay. Fipronil was monitored by MS 3 transition ( m/z 435.0 → 398.9 → 330.0) with a ± 1.0 Da isolation window for secondary product ions. Chromatographic separation was achieved with 0.1 % formic acid-water ( v /v) as the aqueous phase and acetonitrile as the organic phase. Gradient elution with C 18 column was employed for separation of fipronil and probenecid (internal standard, IS). Method validation demonstrated excellent linearity over the range of 0.1–10 ng/mL (r 2 > 0.995), with the accuracies ranging from −10.33 % to 3.17 % and precisions between 3.25 % and 11.34 %. Consistent extraction recoveries (89.92–113.49 %) and acceptable matrix effects (92.54–110.27 %) were observed across all tested matrices. The implementation of MS 3 scanning significantly enhanced specificity by eliminating endogenous interference compared to conventional MRM detection. The successful application of this method in zebrafish tissue distribution studies confirmed its reliability for environmental toxicology research. This MS 3 -based approach provides a robust analytical platform for investigating biodistribution of fipronil in aquatic models.
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American Journal of Translational Research
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2025
·Vol. 17
·期 11
·8712
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IF 1.6
Yaoyong Wang,Yifan Li,Zihan Chen,Yongchen Zhao
Objective: To explore the association between Parkinson’s disease (PD) and the expression of ubiquitin-related proteins, and to elucidate its potential significance. Methods: Differential expression analyses were performed using the GSE20141 , GSE7621 , and GSE20164 datasets to identify and intersect differentially expressed genes (DEGs). Functional enrichment analyses were conducted to further explore the biological significance of these DEGs. C57BL/6J mice were randomly divided into either a PD model group or a control group. Behavioral performance on the balance beam test and the expression levels of PSMC1, α-syn, UCH-1, and Parkin in the substantia nigra were compared between groups. Results: Gene overlap analysis across the three datasets identified 25 core DEGs, among which PSMC1 was the only ubiquitin-proteasome system (UPS)-related gene. Compared with the controls, the number of paw slips from balance beam in the model group significantly increased after 3, 6, and 10 modeling sessions (P<0.05). The mRNA expression levels of PSMC1, UCH-1, and Parkin in the substantia nigra of the model group mice significantly decreased (P<0.05), whereas the mRNA expression of α-syn significantly increased (P<0.05). Conclusions: Integrating bioinformatics with experimental verification, this study confirms that dysregulation of key UPS genes-particularly PSMC1-is closely related to the pathological process of PD.
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