Frontiers in Pharmacology
·
2024
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IF 4.4
Chu Simeng,Yang Wei,Lu Yujie,Li Junjie,Peng Jiamin,Liu Wenjuan,Jiang Min,Bai Gang
Introduction: Tetrandrine (Tet) is the main pharmacological component of Stephania tetrandra S. Moore, which is a well-documented traditional Chinese medicine known for its diuretic and antihypertensive properties. Unraveling the specific targets and mechanisms of Tet involved in inducing diuresis and mitigating hypertension can provide valuable insights into its therapeutic effects. This study aimed to explore the diuretic and antihypertensive targets and mechanisms of Tet using chemical biology coupled with activity analyses in vivo and in vitro.Methods: The diuretic effects of Tet were evaluated using a water-loaded mouse model. The direct target proteins for the diuretic and antihypertensive effects of Tet were determined using chemical biology. Furthermore, the molecular mechanism of Tet binding to target proteins was analyzed using a multidisciplinary approach based on the structure and function of the proteins. Finally, the effects of the Tet-targeted protein on downstream signaling pathways and blood pressure were evaluated in hypertensive model rats.Results: Tet exhibited significant antihypertensive and potassium-preserving diuretic effects. The mechanism underlying these effects involves the modulation of the enzyme activity by covalent binding of Tet to Cys423 of CYP11A1. This interaction alters the stability of heme within CYP11A1, subsequently impeding electron transfer and inhibiting aldosterone biosynthesis.Discussion: This study not only revealed the mechanism of the diuretic and antihypertensive effects of Tet but also discovered a novel covalent inhibitor of CYP11A1. These findings contribute significantly to our understanding of the therapeutic potential of Tet and provide a foundation for future research in the development of targeted treatments for hypertension.
研究领域:
药理学
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化学生物学
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心血管研究
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分子生物学
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DOI
PubMed
高影响因子
Arabian Journal of Chemistry
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2024
·
IF 5.3
Xiaohai Chen,Fengsheng Hong,Hualu Wu,Yuxin Shen,Hailun Xia,Ren-ai Xu,Lu Shi
The primary objective of this study was to investigate the effects of baicalein and fangchinoline on the metabolism of abemaciclib. We hypothesized that these two natural compounds could significantly affect the metabolism of abemaciclib by inhibiting the activity of the CYP3A4 enzyme, thus potentially increasing its concentration in the body. In vitro , rat liver microsomes (RLM) and human liver microsomes (HLM) were employed to explore the inhibitory effects and mechanisms of baicalein and fangchinoline on abemaciclib. In vivo , twelve healthy male Sprague-Dawley (SD) rats were randomly assigned to three groups: Group A (control group), Group B (baicalein), and Group C (fangchinoline). The concentrations of abemaciclib and its metabolite N-desethylabemaciclib (M2) were evaluated using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Finally, molecular docking method was employed to understand the interaction between abemaciclib and baicalein. It was indicated by the in vitro findings that both baicalein and fangchinoline inhibited abemaciclib metabolism in RLM through a mixed mechanism of competitive and non-competitive inhibition pathway. In HLM, baicalein inhibited abemaciclib metabolism by employing a hybrid mechanism of uncompetitive and non-competitive inhibition, while fangchinoline exhibited its inhibition in a competitive manner. In vivo , pharmacokinetic experiments revealed significant increases for AUC (0-t) and AUC (0-∞) of abemaciclib in Group B and Group C when compared to Group A, while the plasma clearance (CLz/F) of abemaciclib exhibited significant reductions. Moreover, molecular docking studies showed that both abemaciclib and baicalein docked to the active pocket of CYP3A4. This study demonstrated that the co-administration of baicalein or fangchinoline significantly affected the metabolism of abemaciclib, providing valuable insights for its clinical application.
研究领域:
药理学
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分子生物学
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临床医学
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产品关联
DOI
高影响因子
JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES
·
2014
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IF 0.638
Zhisheng Xie,Xinjun Xu,Chunyan Xie,Zhikun Liang,Mei Yang,Jieyun Huang,Depo Yang
Tetrandrine and fangchinoline were successfully separated by reversed-phase flash chromatography on a manually-packed C18 column from Radix Stephania tetrandra. After recrystallization by acetone, 13 mg of fangchinoline and 21 mg of tetrandrine were obtained from 100 mg Stephania tetrandra extract, with their relative content 98.78% and 98.19%, respectively. Their structures were characterized by UV, IR, MS, and NMR. The established method was simple, fast, and reproducible, which can be applied to the preparation of reference substances of tetrandrine and fangchinoline.
研究领域:
植物化学
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药物化学
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产品关联
DOI
高影响因子
Analytical Methods
·
2025
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IF 2.6
Yingzhen Wang,Bingyue Cao,Shanshan Shi,Shulin Gao,Dandan Ge
A supramolecular solvent (SUPRAS) based ultrasound-assisted extraction method was developed for the extraction of fangchinoline and tetrandrine from Radix Stephaniae tetrandrae. SUPRASs were prepared in aqueous solutions containing hexafluorobutanol (HFB) and alkanols for the first time. HFB was used as a coacervation agent and density-regulating agent for the SUPRAS preparation. The biosurfactants, namely hexanol, octanol, and decanol were selected as the amphiphiles. The possible mechanism of the new SUPRAS formation was studied. The hydrogen-bond and hydrophobic interactions between HFB and alkanols are the main driving forces for the new SUPRAS formation. The crucial parameters influencing the extraction yields of FAN and TET, such as type and content of amphiphile, type and content of coacervation agent, volume of SUPRAS, ultrasound time, and extraction temperature were investigated and optimized. HFB-hexanol SUPRAS was found to be the most effective extraction solvent for the extraction of fangchinoline and tetrandrine from Stephaniae tetrandrae. Under the optimized conditions, HFB-hexanol SUPRAS showed extraction yields of 7.11 and 13.89 mg g-1 for FAN and TET, respectively. The values were higher than those of obtained with other extraction methods. The developed method has a great potential for extracting alkaloids from natural plant materials.
研究领域:
植物化学
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分析化学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Simeng Chu,Yujie Lu,Wenjuan Liu,Xiaoyao Ma,Jiamin Peng,Xiaoying Wang,Min Jiang,Gang Bai
Background Tetrandrine (TET), a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, is the only approved medicine in China for silicosis. However, TET-induced hepatotoxicity has raised safety concerns. The underlying toxic targets and mechanism induced by TET remain unclear; there are no targeted detoxification strategies developed for TET-induced hepatotoxicity. Ursolic acid (UA), a pentacyclic triterpene with liver protective effects, may have detoxification effects on TET-induced hepatotoxicity. Purpose This study aims to explore toxic targets and mechanism of TET and present UA as a potential targeted therapy for alleviating TET-induced hepatotoxicity. Methods A TET-induced liver-injury model was established to evaluate TET toxicity and the potential UA detoxification effect. Alkenyl-modified TET and UA probes were designed to identify potential liver targets. Pharmacological and molecular biology methods were used to explore the underlying toxicity/detoxification mechanism. Results TET induced liver injury by covalently binding to the substrate-binding pocket (H-site) of glutathione S-transferases (GSTs) and inhibiting GST activity. The covalent binding led to toxic metabolite accumulation and caused redox imbalance and liver injury. UA protected the liver from TET-induced damage by competitively binding to the GST H-site. Conclusion The mechanism of TET-induced hepatotoxicity is related to irreversible binding with the GST H-site and GST-activity inhibition. UA, a natural antidote, competed with TET on H-site binding and reversed the redox imbalance. This study revealed the hepatotoxic mechanism of TET and provided a targeted detoxifying agent, UA, to alleviate hepatotoxicity caused by GST inhibition.
研究领域:
药理学
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毒理学
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分子生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Oncology Letters
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2017
·Vol. 14
·期 5
·5307-5312
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IF 1.39
Binggao Wang,Zhibo Xing,Fengmei Wang,Xinyan Yuan,Yanhui Zhang
In order to improve outcomes after breast cancer treatment, it is essential to understand the mechanisms of action of potential therapeutic agents. The effect of fangchinoline (FAN) on migration and apoptosis of human breast cancer MDA-MB-231 cells and its underlying mechanisms were investigated. MDA-MB-231 cells were treated with different concentrations of FAN, growth inhibition rates were measured by MTT assay and morphological changes of apoptotic cells were observed by Hoechst staining. The wound-healing assay was used to determine of the effect of FAN on the migration of MDA-MB-231 cells. ELISA was used to detect the expression of MMP-2 and -9 in MDA-MB-231 cells treated with different concentrations of FAN and western blot analysis was used to quantify expression of NF-κβ and Iκβ proteins in the same cells. Our results showed that FAN significantly inhibited the growth of MDA-MB-231 cells in concentration-dependent manner and it induced MDA-MB‑231 cell apoptosis. With the high FAN concentrations and long exposure times, the levels of MMP-2 and -9 decreased and the expression of NF-κβ decreased, while the expression of Iκβ protein increased. Based on these results, the antitumor effects of FAN on breast cancer cells can be explained at least partially by inducing apoptosis and inhibiting the migration of MDA-MB-231 cells.
研究领域:
肿瘤学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2018
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IF 3.04
Yuntao Ou,Man Su,Yong Ling,Qianqian Wei,Fei Pan,Jiejia Li,Jun-Xu Li,Qing Zhu
Sinomenine , a major bioactive ingredient isolated from traditional Chinese medicine Sinomenium acutum , has been reported to have analgesic effects in various pain animal models. N -demethylsinomenine, the N -demethylated product of sinomenine, has been identified to be the major metabolite of sinomenine and is also a natural component extracted from Sinomenium acutum . This study examined the anti-allodynic effects of N -demethylsinomenine in a mouse model of postoperative pain . A significant and sustained mechanical allodynia that lasted for 4 days was induced by making a surgical incision on the right hind paw in mice. Acute treatment with N -demethylsinomenine (10–40 mg/kg, s.c.) relieved the mechanical allodynia in a dose-dependent manner. Although there was no difference in maximal analgesic effect between N -demethylsinomenine (40 mg/kg, s.c.) and sinomenine (40 mg/kg, s.c.), the onset of action of N- demethylsinomenine was quicker than sinomenine. Repeated treatment with N- demethylsinomenine (10–40 mg/kg/day, s.c.) also dose-dependently exerted sustained antinociception against postoperative allodynia and did not produce analgesic tolerance and carry-over effect. The anti-allodynia induced by N -demethylsinomenine (40 mg/kg, s.c.) was attenuated by bicuculline , a selective γ-aminobutyric acid type A (GABA A ) receptor antagonist. In addition, the doses of N -demethylsinomenine used here did not alter the locomotor activity in mice. Our findings demonstrated that N -demethylsinomenine exerts behaviorally-specific anti-allodynia against postoperative allodynia mediated through the GABA A receptors, suggesting it may be a useful novel pharmacotherapy for the control of postoperative pain.
研究领域:
药理学
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疼痛研究
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神经科学
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产品关联
DOI
PubMed
高影响因子
TALANTA
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2020
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IF 5.339
Qidan Cai,Jiang Meng,Yuewei Ge,Yan Gao,Yu Zeng,Haifang Li,Yue Sun
A new method for fishing antitumor ingredients by G-quadruplex recognition from Macleaya cordata seeds extracts was established using a three-phase-laminar-flow-chip (TPL chip). The TPL chip integrated the separation of drugs from the complex ingredients and organic solvent extraction, simplifying pretreatment processes and reducing reagents and time. In addition, the chip method showed a lower false negative result, owing to the gentle membrane-free filtration process based on diffusion separation in microchannel. Four ligands with high content in alkaloids of Macleaya cordata seeds were selected, those are chelerythrine (CHE), sanguinarine (SAN), protopine (PRO), and allocryptopine (ALL), which demonstrated affinity with G-quadruplex and were potential for antitumor.
研究领域:
药理学
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分子生物学
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药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 1
·e70197
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IF 5
Weiwei Rong,Xunjia Qian,Yujian Yin,Yipeng Gu,Weiyi Su,Jie‐Jia Li,Yue Xu,Hongyan Zhu,Junxu Li,Qing Zhu
NDSM demonstrates good analgesic efficacy in preclinical pain models with fewer side effects than sinomenine. The analgesic effects of NDSM are mediated primarily by GABRA2 and partially by GABRA3. NDSM shows promise as a novel analgesic candidate for chronic pain management.
研究领域:
药理学
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疼痛研究
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2018
·Vol. 15
·期 1
·1-12
·
IF 5.193
Gao Bo,Wu Yu,Yang Yuan-Jian,Li Wei-Zu,Dong Kun,Zhou Jun,Yin Yan-Yan,Huang Da-Ke,Wu Wen-Ning
Background Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy.Methods The chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits.Results SN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner.Conclusion sSN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.
研究领域:
神经病学
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药理学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2018
·Vol. 18
·期 4
·3691-3698
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IF 1.922
Yan Zhou,Hanyang Liu,Jun Song,Liang Cao,Liming Tang,Chunjian Qi
Sinomenine (SIN), a pure alkaloid isolated from Sinomenium acutum, has been widely used in arthritis for its anti‑inflammatory effect, but little is known about the effect of SIN on human ulcerative colitis (UC). In the present study, the effect and mechanism of SIN was examined in a dextran sulfate sodium (DSS)‑induced murine colitis model, which mimics human UC. Oral administration of SIN significantly suppressed the elevated disease activity index and ameliorated colonic histological damage in a DSS‑induced colitis model. Tumor necrosis factor‑α, interleukin‑6 and inducible nitric oxide synthase levels were also reduced as detected by reverse transcription‑quantitative polymerase chain reaction. In addition, SIN reversed the decreased colon length and colonic superoxide dismutase activity. Furthermore, western blot analysis revealed that nuclear factor‑erythroid 2‑related factor 2 (Nrf2) and its downstream genes, heme oxygenase‑1 and NADP(H) quinone oxidoreductase 1 (NQO‑1), were markedly activated by SIN. The current results indicated that SIN alleviated DSS‑induced colitis in mice, which may be due to its antioxidant properties and was at least in part dependent on the Nrf2/NQO‑1 signaling pathway. Therefore, SIN may have potential applications as a protective drug for patients with UC.
研究领域:
药理学
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免疫学
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胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 9
·e18354
·
IF 4.3
Longfei Yang,Xiaonan Wang,Zhiming Ma,Yujie Sui,Xin Liu
Infections caused by Candida species, especially Candida albicans , threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis-benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans , with MIC no more than 50 μg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans , such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH-DA staining suggested its anti- Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N-acetyl-cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti- Candida therapies.
研究领域:
微生物学
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药理学
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真菌学
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天然产物
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抗菌剂
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）