JOURNAL OF MOLECULAR STRUCTURE
·
2023
·
IF 3.8
Yang Li,Yan Zhang,Hong Xu,Min Li,Zhen Li,Zi-yu Song,Ji-shi Chen,Yan-Jun Liu,Yong Sun,Zhao Yang
To improve the bioavailability and provide a lead compound for developing formulations of the highly water-insoluble prodrug probenecid (PRO), enhancing its solubility is a crucial challenge that needs to be addressed. Herein, we report the synthesis and solid-state characterization of a new pharmaceutical cocrystal, PRO-BPE, synthesized using trans-1,2-bis(4-pyridyl)ethylene (BPE) to improve the solubility of PRO. The PRO-BPE cocrystals were characterized using various analytical techniques, including differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, Fourier transform-infrared spectroscopy, and X-ray powder diffraction. Single-crystal X-ray diffraction was performed to determine the crystal structure of PRO-BPE. PRO-BPE crystallized in the triclinic crystal system P-1 space group and its asymmetric unit consists of half a BPE molecule and one PRO molecule. The N1 atoms located at both ends of the BPE molecule form stable hydrogen bonds with two PRO carboxyl hydrogens through N1···H4—O4 (1.777 Å, 166.78°) interactions, whereas the O3 atoms of the carboxylic groups form C1—H1···O3 (2.479 Å, 132.10°) hydrogen bonds with two pyridyl hydrogens, resulting in a stable seven-membered ring structure. Furthermore, these fragments are further assembled via C—H···O intermolecular interactions to form a two-dimensional layered structure. Interestingly, the two pyridyl rings of each BPE molecule engage in π···π interactions with the benzene rings of two other non-coplanar PRO molecules. Finally, a three-dimensional framework structure is formed through intramolecular non-covalent interactions. Comprehensive characterization analyses provided further information regarding PRO-BPE cocrystal formation. Based on the equilibrium solubility results, the water solubility of the PRO-BPE cocrystal was superior to that of pure PRO, with an increase of 2.43 times. In summary, this study provides the first evidence that cocrystals could enhance the solubility of PRO and offers valuable insights into the solid-state properties of PRO-BPE cocrystals.
研究领域:
药学
·
材料科学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2019
·
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.
研究领域:
药理学
·
民族药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGICAL SCIENCES
·
2017
·Vol. 161
·期 2
·321-334
·
IF 4.081
Wang Xue,Han Lifeng,Li Gentao,Peng Wei,Gao Xiumei,Klaassen Curtis D,Fan Guanwei,Zhang Youcai
Mercury accumulates in kidneys and produces acute kidney injury. Semen cassiae (SC), a widely consumed tea and herbal medicine in Eastern Asia, has been reported to have protective effects on kidneys. In this study, SC extract was shown to almost abolish the histological alterations induced by mercuric chloride in rat kidneys. A total of 22 compounds were isolated from SC, and 1,7,8-methoxyl-2-hydroxyl-3-methyl-anthraquinone was detected in SC for the first time. Among the eight compounds identified in the blood of rats after SC treatment, six were strong inhibitors of human organic anion transporter 1 and 3 (OAT1 and OAT3). Inhibitory studies revealed that OAT1 and OAT3 were inhibited by SC constituents, in both a competitive and noncompetitive manner. Both OAT1- and OAT3-overexpressing cells were susceptible to the cytotoxicity of the cysteine–mercury conjugate, but only OAT1-overexpressing cells could be protected by 200 μM probenecid or 10 μM of the eight inhibitors in SC, suggesting that OAT1 is the major determinant in the cellular uptake of mercury. To facilitate the identification of inhibitors of OAT1 and OAT3, models of OAT1 and OAT3 were constructed using recently determined protein templates. By combining in silico and in vitro methods, inhibitors of OAT1 and OAT3 were predicted and validated from SC constituents. Collectively, the present study suggests that additional inhibitors of OAT1 and OAT3 can be predicted and validated from natural products by combining docking and in vitro screening, and could be a source of pharmaceutical compounds for developing treatments for mercury-induced kidney injury.
研究领域:
药理学
·
毒理学
·
药物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY IN VITRO
·
2024
·
IF 2.6
Jia-hong Liang,Xiao-lei Yi,Jia-min Gong,Zuo Du
Gout is an immune-metabolic disease that frequently coexists with multiple comorbidities such as chronic kidney disease, cardiovascular disease and metabolic syndrome, therefore, it is often treated in combination with these complications. The present study aimed to evaluate the inhibitory effect of antigout drugs (allopurinol, febuxostat, topiroxostat, benzbromarone, lesinurad and probenecid) on the activity of the crucial phase I drug-metabolizing enzymes, carboxylesterases (CESs). 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were utilized as the probe reactions to determine the activity of CES1 and CES2, respectively, through in vitro culturing with human liver microsomes. Benzbromarone and lesinurad exhibited strong inhibition towards CESs with Ki values of 2.16 and 5.15 μM for benzbromarone towards CES1 and CES2, respectively, and 2.94 μM for lesinurad towards CES2. In vitro-in vivo extrapolation (IVIVE) indicated that benzbromarone and lesinurad might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CESs. In silico docking showed that hydrogen bonds and hydrophobic interactions contributed to the intermolecular interactions of antigout drugs on CESs. Therefore, vigilant monitoring of potential drug-drug interactions (DDIs) is imperative when co-administering antigout drugs in clinical practice.
研究领域:
药理学
·
临床药理学
·
药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2022
·
IF 4.271
Yan Zhou,Mengmeng Wei,Mingkang Zhang,Jianping Zhang,Fabing Tang,Xin’an Wu
Organic anion transporters 1 (OAT1) and OAT3 are responsible for transporting adefovir (ADV) into renal tubular epithelial cells. Our previous research found that ADV accumulated in the renal interstitium and caused renal interstitial fibrosis when Oat1/3 were inhibited by OATs inhibitor probenecid for long-term. Mast cells (MCs) in the interstitial space are considered to be key drivers of renal fibrosis. The current work investigated the effect of ADV on MCs in vitro and during the development of interstitial fibrosis in rats. Results indicate that ADV triggers chymase release from cultured RBL-2H3 mast cells in a time-and concentration-dependent manner. Angiotensin II (Ang II) in renal interstitium is generated mainly by chymase, renin and other products released from MCs, and has a direct effect on fibrosis through the angiotensin receptor. The concentrations of Ang II and fibrosis was significantly increased after administration of ADV alone or with probenecid for 4 weeks. The MCs membrane stabilizer sodium cromoglycate (SCG) and the angiotensin receptor antagonist Valsartan (VAL) could ameliorate ADV-induced nephrotoxicity. Additionally, SCG or VAL could reduce the accumulation of ADV in the renal interstitium by upregulating the expression of Oat1/3 and multidrug resistance-associated protein 4. Therefore, ADV accumulation in the renal interstitium could promote the degranulation of interstitial MCs and drive the development of renal fibrosis. SCG or VAL could ameliorate ADV-associated fibrosis by decreasing degranulation of MCs and accelerating renal clearance of ADV.
研究领域:
药理学
·
肾病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2018
·
IF 3.616
Lili Wu,Yulian Chen,Han Liu,Zhikun Zhan,Zhi Liang,Tao Zhang,Zheng Cai,Ling Ye,Menghua Liu,Jie Zhao,Shuwen Liu,Lan Tang
Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150 mg/kg) hepatotoxicity was exacerbated by probenecid (100 mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC ) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%–58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro , indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.
研究领域:
药理学
·
毒理学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
·
2025
·
IF 4.5
Wen Peng Shan,Shi Lei Yan,Yuan Yuan Guo,Hua Ke Yang,Jing Chun Wang,Jie Xiang
Background: Parkinson’s disease (PD) is a common neurodegenerative disorder. It is marked by motor dysfunction and cognitive decline. In recent years, scientific studies have found that PD’s pathogenesis may be tied to an imbalance in the gut microbiota. This offers new perspectives for PD treatment. Modulating the gut microbiota is recognized as a potential way to enhance PD symptoms. While aerobic exercise can positively influence the gut microbiota, research on how the gut microbiota mediates aerobic exercise’s effects on PD cognitive impairment is still limited. Thus, this study aimed to explore the potential mechanisms by which aerobic exercise improves cognitive impairment in PD patients. It does so by modulating the gut microbiota’s structure and, in turn, improving cognitive function. Through this study, we hope to offer new strategies and a theoretical basis for treating PD cognitive impairment.Methods: This study focused on the potential neuroprotective effects of long-term aerobic exercise in an MPTP-induced PD mouse model. Research methods included using 16S rRNA gene sequencing and plasma untargeted metabolomics to precisely describe the composition of the mouse gut microbiota and its metabolite changes. We also monitored the mice’s motor and cognitive functions via behavioral assessments. Pathological features and molecular-level changes in PD mice were analyzed using morphological and molecular biology techniques. To further study the role of gut microbes in aerobic exercise, we conducted antibiotic treatment experiments on mice. Finally, Pearson correlation analysis was used to explore the correlation between gut microbiota, plasma metabolite outcomes, and molecules related to cognitive function.Results: Our results showed that aerobic exercise effectively intervened in PD mice. It alleviated PD-related pathological impairments and cognitive deficits and promoted the secretion of FNDC5 and BDNF, producing neuroprotective effects. Aerobic exercise regulated the gut flora imbalance in PD mice. 16S rRNA analysis revealed a significant increase in the abundance of Alloprevotella, Akkermansia, Lachnospiraceae_NK4A136_group, Bacteroides, and Prevotellaceae_UCG-001. In contrast, the abundance of Parabacteroides, Helicobacter, Alistipes, and Odaribacter decreased significantly. The gut flora mediated the role of aerobic exercise by regulating FNDC5 secretion through PGC1-α/CREB and influencing BDNF production.Conclusion: Aerobic exercise improves gut flora imbalance in PD mice. It also attenuates PD-related pathological impairments and cognitive deficits. However, its efficacy on non-motor symptoms can be nullified by antibiotics. The gut flora-mediated aerobic exercise exerts neuroprotective effects on PD by regulating FNDC5 secretion via PGC1-α/CREB.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF SEPARATION SCIENCE
·
2025
·Vol. 48
·期 12
·e70326
·
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.
研究领域:
环境毒理学
·
分析化学
·
农药残留监测
·
生态风险评估
✓ 已验证
产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2025
·Vol. 17
·期 11
·8712
·
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.
研究领域:
神经科学
·
分子生物学
·
生物信息学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2024
·
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.
研究领域:
药理学
·
分子生物学
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 16
·
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.
研究领域:
细胞生物学
·
生物医学工程
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
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.
研究领域:
癌症研究
·
神经科学
·
纳米技术
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）