JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2018
·
IF 3.638
Cailan Li,Ping Huang,Kambo Wong,Yifei Xu,Lihua Tan,Hanbin Chen,Qiang Lu,Chaodan Luo,Chunlai Tam,Lixiang Zhu,Ziren Su,Jianhui Xie
In this study, we examined the anti-Helicobactor pylori effects of the main protoberberine-type alkaloids in Rhizoma Coptidis. Coptisine exerted varying antibacterial and bactericidal effects against three standard H. pylori strains and eleven clinical isolates, including four drug-resistant strains, with minimum inhibitory concentrations ranging from 25 to 50 μg/mL and minimal bactericidal concentrations ranging from 37.5 to 125 μg/mL. Coptisine’s anti-H. pylori effects derived from specific inhibition of urease in vivo. In vitro, coptisine inactivated urease in a concentration-dependent manner through slow-binding inhibition and involved binding to the urease active site sulfhydryl group. Coptisine inhibition of H. pylori urease (HPU) was mixed type, while inhibition of jack bean urease was non-competitive. Importantly, coptisine also inhibited HPU by binding to its nickel metallocentre. Besides, coptisine interfered with urease maturation by inhibiting activity of prototypical urease accessory protein UreG and formation of UreG dimers and by promoting dissociation of nickel from UreG dimers. These findings demonstrate that coptisine inhibits urease activity by targeting its active site and inhibiting its maturation, thereby effectively inhibiting H. pylori. Coptisine may thus be an effective anti-H. pylori agent.
研究领域:
微生物学
·
药理学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2020
·
IF 4.225
Zhao Junli,Wang Yaqian,Gao Jie,Jing Yang,Xin Wenkuan
Previous studies showed that berberine, an alkaloid from Coptis Chinensis Franch, might exert a positive inotropic effect on the heart. However, the underlying mechanisms were unclear. Here, we reported that berberine at 10–20 µM increased the left ventricular (LV) developed pressure and the maximal rate of the pressure rising, and it increased the maximal rate of the pressure descending at 20 µM in Langendorff-perfused isolated rat hearts. These effects diminished with the concentration of berberine increasing to 50 µM. In the concentration range of 50–300 µM, berberine increased the isometric tension of isolated left ventricular muscle (LVM) strips with or without electrical stimulations, and it (30–300 µM) also increased the intracellular Ca2+ level in the isolated LV myocytes. The removal of extracellular Ca2+ hindered the berberine-induced increases in the tension of LVM strips and the intracellular Ca2+ level of LV myocytes. These suggested that berberine might exert its positive inotropic effects via enhancing Ca2+ influx. The blockade of L-type Ca2+ channels (LTCCs) with nifedipine significantly attenuated 300 μM berberine-induced tension increase in LVM strips but not the increase in the intracellular Ca2+ level. Berberine (300 μM) further increased the LVM tension following the treatment with the LTCC opener FPL-64716 (10 μM), indicating an LTCC-independent effect of berberine. Lowering extracellular Na+ attenuated the berberine-induced increases in both the tension of LVM strips and the intracellular Ca2+ level of LV myocytes. In conclusion, berberine might exert a positive inotropic effect on the isolated rat heart by enhancing the Ca2+ influx in LV myocytes; these were extracellular Na+-dependent.
研究领域:
药理学
·
心血管生理学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 20
·12064
·
IF 6.208
Yan Zhou,Yuehan Wang,Chi Teng Vong,Yanyan Zhu,Baojun Xu,Cheng-Chao Ruan,Yitao Wang,Wai San Cheang
Jatrorrhizine (JAT) is one of the major bioactive protoberberine alkaloids found in rhizoma coptidis, which has hypoglycemic and hypolipidemic potential. This study aimed to evaluate the vasoprotective effects of JAT in diabetes and obesity and the underlying mechanism involved. Mouse aortas, carotid arteries and human umbilical cord vein endothelial cells (HUVECs) were treated with risk factors (high glucose or tunicamycin) with and without JAT ex vivo and in vitro. Furthermore, aortas were obtained from mice with chronic treatment: (1) control; (2) diet-induced obese (DIO) mice fed a high-fat diet (45% kcal% fat) for 15 weeks; and (3) DIO mice orally administered JAT at 50 mg/kg/day for the last 5 weeks. High glucose or endoplasmic reticulum (ER) stress inducer tunicamycin impaired acetylcholine-induced endothelium-dependent relaxations (EDRs) in mouse aortas, induced oxidative stress in carotid arteries and HUVECs, downregulated phosphorylations of Akt at Ser473 and eNOS at Ser1177 and enhanced ER stress in mouse aortas and HUVECs, and these impairments were reversed by cotreatment with JAT. JAT increased NO release in high-glucose-treated mouse aortas and HUVECs. In addition, chronic JAT treatment restored endothelial function with EDRs comparable to the control, increased Akt/eNOS phosphorylation, and attenuated ER stress and oxidative stress in aortas from DIO mice. Blood pressure, glucose sensitivity, fatty liver and its morphological change, as well as plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and plasma lipid profile, were also normalized by JAT treatment. Collectively, our data may be the first to reveal the vasoprotective effect of JAT that ameliorates endothelial dysfunction in diabetes and obesity through enhancement of the Akt/eNOS pathway and NO bioavailability, as well as suppression of ER stress and oxidative stress.Keywords:diabetes;endothelial dysfunction;jatrorrhizine;endoplasmic reticulum stress;oxidative stress
研究领域:
药理学
·
内分泌学
·
心血管科学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Chemistry
·
2017
·
IF 1.3
Xiaofei Jiang,Nengling Zhang,Nanqian Xiong,Yi Liu,Jianfeng Cao,ShengXiang Qiu
Jatrorrhizine was considered as one of the active constituents of Coptis chinensis Franch. Herein, jatrorrhizine derivatives with substituted amino groups linked at the 3-position were designed, synthesized, and biologically evaluated as inhibitors of acetylcholinesterase. Jatrorrhizine derivatives inhibited the activity of acetylcholinesterase (AChE) to a greater extent than the lead compound jatrorrhizine. All these jatrorrhizine derivatives were proved to be potent inhibitors of acetylcholinesterase (AChE) with submicromolar IC50 values, but less sensitive to butyrylcholinesterase (BuChE), which suggests that these jatrorrhizine derivatives are selective for AChE/BuChE. Compound 3g gave the most potent inhibitor activity for AChE (IC50 = 0.301 μM), which is greater than the lead compound jatrorrhizine. All these results demonstrated that these jatrorrhizine derivatives are potential inhibitors for AChE.
研究领域:
药理学
·
有机化学
·
神经科学
✓ 已验证
DOI
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2018
·Vol. 40
·期 1
·133-142
·
IF 3.562
Zhang Yi-ting,Yu Yu-qi,Yan Xiao-xia,Wang Wen-jie,Tian Xiao-ting,Wang Le,Zhu Wei-liang,Gong Li-kun,Pan Guo-yu
Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P-glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine ~ jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities.
研究领域:
药理学
·
生物信息学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYST
·
2019
·Vol. 144
·期 13
·4081-4085
·
IF 4.019
Yuan-Min Liu,Xiu-Yu Fang,Fang Fang,Zhi-Yong Wu
Chelerythrine (CHE) is one of the potential drugs for cancer treatments. The interaction between hairpin DNA and CHE has been investigated by spectral and mass spectrometry methods. In this paper, the stability of hairpin DNA with different loop bases and its interaction with CHE were explored with a single α-hemolysin (α-HL) nanopore sensing interface. The results showed that the characteristic current pulses not only relate to the loop composition changes of the hairpin DNA, but also provide interaction information between CHE and the hairpin DNA molecules. The dwell time of current pulses for hairpin DNA was significantly increased (hundreds of ms) due to the addition of CHE, and two characteristic current distributions were recognized for the hairpin with T3 and C3 loops. The two characteristic current groups could be ascribed to the hairpin DNA and the ones with CHE. This study indicates that it is possible to study the interaction between single CHE and single hairpin DNA molecules by the single-nanopore sensing interface as an alternative method to conventional spectrometric methods for therapeutic mechanism and drug screening purposes.
研究领域:
生物物理
·
分子生物学
·
纳米技术
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2018
·Vol. 34
·期 4
·571-577
·
IF 1.248
Han Xie,Shao Kaiyuan,Hu Wenxiang
Hyperglycemia is frequently accompanying with hyperlipidemia. To explore the potent drugs with dual-activity and dual-site effects that could reduce blood glucose and blood lipid at the same time, fibrate group with lipid-lowering effect on the 9th position of berberine(BBR) was introduced using the drug design combination principle and the multitarget collaborative treatment method. Moreover, the molecular structure of BBR was modified, and six 9-substituted derivatives of BBR were designed and synthesized, among which, five compounds have never been reported before. In addition, the molecular structures of these derivatives were identified using liquid chromatography-mass spectrometry(LC-MS), 1 H nuclear magnetic resonance( 1 H NMR) and 13 C NMR, respectively. Furthermore, the microwave irradiation experimental technique was applied in the synthesis reaction using the novel microwave synthesizer, which accelerated the reaction rate, enhanced the reaction yield, reduced the reaction by-products, and simplified the post-processing steps. In the meantime, the 9-position regioselective demethylation of BBR was explored through quantum chemical calculation during the synthesis of berberrubine. The computations were consistent with the experimental results, which contributed to deducing the mechanism of its selective methylation.
研究领域:
药物化学
·
合成化学
·
计算化学
✓ 已验证
产品关联
DOI
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2023
·
IF 5.9
Yong Zhu,Hailun Li,Huiran Jin,Jingrui Ma,Zhandong Ye,Bingmin Wu,Ying Zhang,Qingping Xiong,Shijie Ding,Jing Chen,Song Huang
Alkaloids are the most medicinally valuable ingredients in plant crop Coptis chinensis ( C. chinensis ). However, the separation of these small-molecule compounds is challenging because C. chinensis also contains a lot of impurities such as proteins and saccharides . Adsorption separation stands out in the field of biological separation by virtue of its efficiency and greenness. Here, this paper aimed to selectively separate the total alkaloids during extraction of C. chinensis by resorcinol-formaldehyde (RF) aerogel based on electrostatic interaction and size-sieving effect. First, RF aerogels with different surface area (40.6–674.9 m 2 /g) and pore size (2–25 nm approximately) were synthesized by adjusting the ratio of catalyst (C). The results of static adsorption showed that the optimum alkaloids selective separation was achieved at R/C of 10/1: alkaloids adsorption capacity ( Q e ), protein retention ratio ( Pr ), saccharides retention ratio ( Sr ) and the coefficient of selectivity were 487.93 mg/g, 87.40 %, 95.90 % and 2.23, respectively. Methanol containing 1 % hydrochloric acid was considered as the most suitable eluent with the desorption efficiency of 95.88 %. In addition, the adsorption process conformed to pseudo-second-order kinetics, intra-particle diffusion and Langmuir isotherm models, and was a spontaneous endothermic process. It was found from the dynamic adsorption experiment that the dynamic adsorption capacity was 497.81 mg/g, and the purity of total alkaloids increased from 39.19 % to 90.22 %. Compared with resin adsorption and salt precipitation method, RF aerogel separation could more efficiently separate the alkaloids from C. chinensis (the total alkaloids yield of 57.40 mg/g C. chinensis ). In addition, the alkaloids separated by RF aerogel had better antioxidant and antibacterial activities than that separated by salt precipitation method. In summary, RF aerogel separation was potential as an efficient and green method for the separation of total alkaloids from C. chinensis .
研究领域:
植物化学
·
药物分离工程
·
生物医学
✓ 已验证
产品关联
DOI
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2022
·
IF 6.819
Zhan Yujuan,Chen Qiugu,Song Yue,Wei Xianli,Zhao Tingxiu,Chen Bonan,Li Chengxi,Zhang Wenbo,Jiang Yanjun,Tan Yuhui,Du Biaoyan,Xiao Jianyong,Wang Kun
Autophagy is typically activated in cancer cells as a rescue strategy in response to cellular stress (e.g., chemotherapy). Herein, we found that Berbamine Hydrochloride (Ber) can act as an effective inhibitor of the late stage of autophagic flux, thereby potentiating the killing effect of chemotherapy agents. Lung carcinoma cells exposed to Ber exhibited increased autophagosomes, marked by LC3-II upregulation. The increased level of p62 after Ber treatment indicated that the autophagic flux was blocked at the late stage. The lysosome staining assay and cathepsin maturation detection indicated impaired lysosomal acidification. We found that Nox2 exhibited intensified co-localization with lysosomes in Ber-treated cells. Nox2 is a key enzyme for superoxide anion production capable of transferring electrons into the lysosomal lumen, thereby neutralizing the inner protons; this might explain the aberrant acidification. This hypothesis is further supported by the observed reversal of lysosomal cathepsin maturation by Nox2 inhibitors. Finally, Ber combined with cisplatin exhibited a synergistic killing effect on lung carcinoma cells. Further data suggested that lung carcinoma cells co-treated with Ber and cisplatin accumulated excessive reactive oxygen species (ROS), which typically activated MAPK-mediated mitochondria-dependent apoptosis. The enhanced anti-cancer effect of Ber combined with cisplatin was also confirmed in an in vivo xenograft mouse model. These findings indicate that Ber might be a promising adjuvant for enhancing the cancer cell killing effect of chemotherapy via the inhibition of autophagy. In this process, Nox2 might be a significant mediator of Ber-induced aberrant lysosomal acidification. Graphical abstract
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Ying Hu,Lixin Chen,Yulin Wu,Jun Zhang,Zhixia Sheng,Ziyi Zhou,Yufeng Xie,Guiyou Tian,Jiaxing Wan,Xiaorun Zhang,Na Cai,Yatong Zhou,Yi Cao,Tengjiang Yang,Xiaomei Chen,Dalong Liao,Yurui Ge,Bo Cheng,Keyuan Zhong,Erli Tian,Jin Lu,Huiqiang Lu,Yan Zhao,Wei Yuan
Aristolochic acid (AA) is renowned for engendering nephrotoxicity and teratogenicity. Previous literature has reported that AA treatment resulted in heart failure (HF) via inflammatory pathways. Yet, its implications in HF remain comparatively uncharted territory, particularly with respect to underlying mechanisms. In our study, the zebrafish model was employed to delineate the cardiotoxicity of AA exposure and the restorative capacity of a phytogenic alkaloid palmatine (PAL). PAL restored morphology and blood supply in AA-damaged hearts by o-dianisidine staining, fluorescence imaging, and Hematoxylin and Eosin staining. Furthermore, PAL attenuated the detrimental effects of AA on ATPase activity, implying myocardial energy metabolism recovery. PAL decreased the co-localization of neutrophils with cardiomyocytes, implying an attenuation of the inflammatory response induced by AA. A combination of network pharmacological analysis and qPCR validation shed light on the therapeutic mechanism of PAL against AA-induced heart failure via upregulation of the epidermal growth factor receptor (EGFR) signaling pathway. Subsequent evaluations using a transcriptological testing, inhibitor model, and molecular docking assay corroborated PAL as an IKBKB enzyme activator. The study underscores the possible exploitation of the EGFR pathway as a potential therapeutic target for PAL against AA-induced HF, thus furthering the continued investigation of the toxicology and advancement of protective pharmaceuticals for AA.
研究领域:
毒理学
·
药理学
·
心脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2014
·Vol. 6
·期 9
·2998-3008
·
IF 1.938
Guanghui Liu,Wei He,Hao Cai,Xiuman Sun,Waner Hou,Manna Lin,Zhiyong Xie,Qiongfeng Liao
A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously determine berberine, palmatine, coptisine, epiberberine and jatrorrhizine in rat plasma, using tetrahydropalmatine as an internal standard. The separation of the five compounds was carried out on a C18 column using a mobile phase consisting of acetonitrile and water (containing 5 mmol ammonium acetate adjusted to pH 5.0 with formic acid). The detection was performed in the multiple reaction monitoring (MRM) mode via the electrospray ionization (ESI) source operating in the positive ionization mode. Linear calibration curves were obtained over the concentration range of 0.20–200.0 ng ml−1 for berberine, and 0.20–100.0 ng ml−1 for palmatine, coptisine, epiberberine and jatrorrhizine. The accuracy, precision and extraction recovery of the five analytes were all satisfactory. The validated method was successfully applied to study the pharmacokinetic differences of the five protoberberine-type alkaloids after the oral administration of Rhizoma coptidis (RC) and Jiao-Tai-Wan (JTW) extract. It was found that the Tmax values of the five ingredients in the JTW extract were significantly increased (P < 0.05) when compared with those in RC. In addition, the AUC0–t of palmatine, coptisine and epiberberine were significantly increased (P < 0.05).
研究领域:
药理学
·
分析化学
·
中医药学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Lei Wang,Jinchun Wang,Lei Han,Tong Chen
The present work was conducted to research the potential mechanism of palmatine (PAL) on lipopolysaccharide (LPS)-caused acute lung injury (ALI). Network pharmacology and bioinformatic analyses were carried out. Mice were intragastrically treated with PAL and intratracheally stimulated with LPS. LPS-induced RAW264.7 cells were employed for the in vitro model. The MPO activity, W/D ratio, neutrophils, total cell number in BALF, and histopathological alteration were examined. The levels of TNF-α, IL-1β, IL-6, IL-18, IL-4, and IL-10 in serum, BALF, and supernatant were examined by ELISA. The mRNA expressions of iNOS, CD68, Arg1, Ym1, and CD206 and protein expressions of NAMPT, TLR2, CCR1, and NLRP3 inflammasome were detected by PCR, WB, and immunofluorescence. The NAMPT inhibitor FK866, TLR2 inhibitor C29, CCR1 inhibitor BX471, NAMPT-overexpression (OE) plasmid, and TLR2-OE plasmid were used for mechanism research. As a result, PAL relieved the symptoms of ALI. PAL inhibited M1 phenotype indices and promoted M2 phenotype indices in both LPS-induced mice and RAW264.7 cells. PAL also inhibited the expressions of NAMPT, TLR2, CCR1, and NLRP3 inflammasome. The treatments with FK866, NAMPT-OE plasmid, C29, TLR2-OE plasmid, and BX471 proved that PAL exerted its effect via NAMPT/TLR2/CCR1. Molecular docking suggested that PAL might combine with NAMPT. In conclusion, PAL ameliorated LPS-induced ALI by inhibiting M1 phenotype macrophage polarization via NAMPT/TLR2/CCR1 signaling.
研究领域:
药理学
·
免疫学
·
呼吸病学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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