Drug Design Development and Therapy
·
2022
·
IF 4.319
Minhua Li,Zehui Qin,Qiuxia Yu,Ziwei Huang,Juanjuan Cheng,Linjiang Zhong,Yuhong Liu,Jianhui Xie,Yucui Li,Jiannan Chen,Ruoting Zhan,Ziren Su
Background Berberine (BBR) is the primary active component of Phellodendri Chinensis Cortex (PCC), which has been traditionally used to treat inflammatory diseases. However, the discrepancy between its low bioavailability and significant therapeutic effect remains obscure. The purpose of this study was to explore the previously unsolved enigma of the low bioavailability of BBR and its appreciable anti-inflammatory effect to reveal the action mechanism of BBR and PCC. Methods The quantitative analysis of BBR and its metabolite oxyberberine (OBB) in blood and tissues was performed using high-performance liquid chromatography to investigate the conversion and distribution of BBR/OBB mediated by erythrocytes. Routine blood tests and immunohistochemical staining were used to explore the potential relationship between the amounts of monocyte/macrophage and the drug concentration in erythrocytes and tissues (liver, heart, spleen, lung, kidney, intestine, muscle, brain and pancreas). To comparatively explore the anti-inflammatory effects of BBR and OBB, the acetic acid-induced vascular permeability mice model and lipopolysaccharide-induced RAW 264.7 macrophages were employed. Results Nearly 92% of BBR existed in the erythrocytes in rats. The partition coefficient of BBR between plasma and erythrocytes (Kp/b) decreased with time. OBB was found to be the oxidative metabolite of BBR in erythrocytes. Proportion of BBR/OBB in erythrocytes changed from 9.38% to 16.30% and from 13.50% to 46.24%, respectively. There was a significant relationship between the BBR/OBB concentration in blood and monocyte depletion after a single administration of BBR. BBR/OBB was transported via erythrocytes to various tissues (liver, kidney, spleen, lung, and heart, etc), with the liver achieving the highest concentration. OBB exhibited similar anti-inflammatory effect in vitro and in vivo as BBR with much smaller dosage. Conclusion BBR was prodominantly found in erythrocytes, which was critically participated in the biodistribution, pharmacokinetics, metabolism and target delivery of BBR and its metabolite. The anti-inflammatory activity of BBR and PCC was intimately associated with the metabolism into the active congener OBB and the targeted delivery to monocytes/macrophages mediated by the erythrocytes.
研究领域:
药理学
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中药学
·
生物化学
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DOI
PubMed
高影响因子
ACS Omega
·
2020
·
IF 2.87
Dong-Dong Li,Pan Yu,Zhen-Zhong Wang,Wei Xiao,Xin-Hu Zhou,Lin-Guo Zhao
Berberine (BBR), a well-known alkaloid, exhibits various pharmacological activities, especially hypolipidemic activity, which has attracted much interest from medicinal chemists in the past decade. However, little progress was made on the structural modification of BBR for improving lipid-lowering activity, mainly due to its unclear biological target and low safety. In this study, a new scaffold of 7,9-disulfatetrahydroberberine was discovered unexpectedly, provided with extremely low cytotoxicity. Hence, a novel series of highly safe 7,9-disulfatetrahydroberberines were designed, synthesized, and evaluated for their hypolipidemic activities. In order to investigate the significance of the 9-position substituent, another new series of 7-sulfatetrahydroberberines were designed and synthesized. Lipid-lowering experiments showed that among these compounds, 5f exhibited the best lipid-lowering activity based on two cell models, 3T3-L1 cells and HepG2 cells. Compared with the blank control, the inhibition rate of compound 5f against total cholesterol was over 60%, the inhibition rate against triglyceride was over 70%, the inhibition rate against low-density lipoprotein cholesterol was approximately 75%, and the inhibition rate against high-density lipoprotein cholesterol was close to 50%, which were far superior to the positive control BBR. This result also verified the feasibility of the development of BBR as a lipid-lowering drug via disubstituted modification at the 7- and 9-position.
研究领域:
药物化学
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药理学
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DOI
PubMed
高影响因子
PHARMACEUTICAL CHEMISTRY JOURNAL
·
2024
·Vol. 57
·期 8
·1179-1188
·
IF 0.8
Pan Miao,Yuan Jia,Tang Qin,Wu Yajing,Peng Yu,Zhang Jinyin,Ma Hang,Li Xuegang
Antibiotic resistance is a major problem in the treatment of Helicobacter pylori (H. pylori). Berberine (BBR) has proven to be a promising alternative, though it is less effective than antibiotics. Structurally modified BBR might improve the anti-H. pylori activity. In this study, 8-octyl berberine (OBBR), a BBR derivative, was investigated for the activity and mechanism of action against H. pylori. The results showed that the anti-H. pylori activity of OBBR was significantly higher than that of BBR (about 64 times) and close to amoxicillin. Surprisingly, OBBR was not resistant to H. pylori after 45 generations of induction and showed synergistic effect with amoxicillin in vitro. Regarding the mechanism, OBBR changed the morphological structure of bacteria and caused the outgrowth of phosphatidylserine on the cell membrane, thereby increasing its permeability. Moreover, OBBR inhibited the urease activity, down-regulated the mRNA levels of flagellar genes flaA and flaB, and reduced the motility of H. pylori, thus inhibiting intra-gastric colonization. In an animal model of H. pylori infection, OBBR was found to have a certain effect on the clearance of H. pylori in mice. An excellent anti-H. pylori activity and low drug resistance of OBBR suggest that structural modification of the BBR scaffold may be a favorable approach to the development of promising antibiotics for the treatment of H. pylori.
研究领域:
微生物学
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药理学
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药物化学
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传染病学
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分子生物学
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DOI
高影响因子
PLANTA MEDICA
·
2021
·Vol. 88
·期 11
·921-932
·
IF 3.356
Xinchi Feng,Kun Wang,Shijie Cao,Liqin Ding,Feng Qiu
Rhizoma coptidis has been clinically used for a long time for the treatment of various diseases in China, such as hypertension, diabetes, and inflammation. Previous studies have shown that alkaloid components of Rhizoma coptidis extract could be extensively metabolized and the metabolites were also considered to be the therapeutic material basis. However, until now, pharmacokinetic studies of the in vivo metabolites have not been revealed yet. The aim of the present study was to characterize the pharmacokinetics and excretions of five main alkaloids (berberine, jatrorrhizine, palmatine, epiberberine, and coptisine) and their seven metabolites (berberrubine, demethyleneberberine, jatrorrhizine-3-O-β-D-glucuronide, thalifendine-10-O-β-D-glucuronide, berberrubine-9-O-β-D-glucuronide, demethyleneberberine-2-O-sulfate, and demethyleneberberine-2-O-β-D-glucuronide) in rats after oral administration of Rhizoma coptidis extract. Meanwhile, comparative pharmacokinetics and excretions of these analytes in diabetic model rats were also investigated, since Rhizoma coptidis is widely used for the treatment of diabetes. Our results showed that the in vivo existing forms of alkaloid components were phase II metabolites, highlighting the glucuronidation metabolic pathway. In diabetic model rats, the utilization of Rhizoma coptidis alkaloids was significantly increased and the biotransformation of berberine into berberrubine was significantly inhibited.
研究领域:
药理学
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代谢
·
糖尿病研究
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中药
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2014
·
IF 2.939
Wei He,Guanghui Liu,Hao Cai,Xiuman Sun,Waner Hou,Peiting Zhang,Zhiyong Xie,Qiongfeng Liao
Ethnopharmacological relevance Jiao-Tai-Wan (JTW), an important herbal formula consists of Rhizoma coptidis and Cortex cinnamomi powder, is a famous prescription which has been used for centuries to treat insomnia in Traditional Chinese Medicine . The purpose of this study is to compare the pharmacokinetic properties of five protoberberine-type alkaloids (i.e. berberine , palmatine , coptisine , epiberberine and jatrorrhizine), the main bioactive constituents in JTW, between normal and insomnic rats. We also investigate the differences between single-dose and multiple-dose pharmacokinetics of five protoberberine-type alkaloids. Materials and methods The insomnic rat models were induced by intraperitoneal injection of one-dose para-chlorophenylalanine acid (PCPA). Quantification of five protoberberine-type alkaloids in rat plasma was achieved by using a rapid LC–MS/MS method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time and estimate pharmacokinetic parameters . An unpaired Student׳s t test was used for comparisons with SPSS 17.0. Results The five protoberberine-type alkaloids of single-dose normal groups had slow absorption and low bioavailability, as well as a delay of peak time. In the single-dose oral administration, the C max and T max of five ingredients in insomnic rats had significant differences compared with those of normal rats. In the multiple-dose oral administration, the pharmacokinetic parameters of five protoberberine-type alkaloids varied greatly in insomnic rats. In the normal rats, there were significant differences ( P <0.05) in the principal pharmacokinetic parameters such as C max and T max between single-dose and multiple-dose oral administration. In the insomnic rats, the five ingredients of multiple-dose groups showed better absorption than the single-dose groups. Particularly, three peaks were observed in multiple-dose model group of plasma–concentration curves. Conclusions The pharmacokinetic behavior of five protoberberine-type alkaloids was described in this paper. In both normal groups and model groups, the pharmacokinetic behavior of multiple-dose had significant differences comparing with the single-dose; either single-dose or multiple-dose, the pharmacokinetic behavior of insomnic rats had significant differences comparing the normal rats. Multiple dosing may improve the absorption of JTW in insomnic rats, which will increase the bioavailability and bring into active role in therapeutical effect.
研究领域:
药理学
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中医药学
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民族药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Yun Yang,Yuan Xiong,Guanghao Zhu,Mengru Sun,Kun Zou,Yitian Zhao,Yong Zhang,Zhijian Xu,Yiming Li,Weiliang Zhu,Qi Jia,Bo Li,Guangbo Ge
Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapy-induced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC 50 = 1.66 μM) and excellent selectivity over hCES1A (IC 50 > 100 μM). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated K i value of 1.035 μM. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors.
研究领域:
药理学
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SEPARATION SCIENCE
·
2023
·Vol. 46
·期 14
·2300094
·
IF 3.1
Qin Li,Zihan Chen,Jianrong Zhang,Qiuying Yan,Li Liu,Dongxin Tang,Liu Li,Jinge Zhang,Cheng Hu,Jiayi Ma,Haibo Cheng,An Kang,Dongdong Sun
Coptis chinensis Franch. and Sophora flavescens Ait. is a herbal pair frequently used in treating ulcerative colitis. However, the bio-disposition profile of the major components in the inflamed gut remains unclear, which is essential to understand the pharmacological material basis of this herb pair. Here we established an integral quantitative and chemometric method to deduce the colonic metabolism differences of this herbal pair in normal and colitis mice. With this LC-MS method, a total of 41 components have been found in the Coptis chinensis Franch. and Sophora flavescens Ait. extract, and 28 metabolites were found in the colon after oral administration. Alkaloid and its phase I metabolites were the main components in the colon of normal and colitis mice. The results of principal component analysis at 6 h after oral administration showed significant colonic metabolism differences between normal and colitis mice. Heamap results showed that colitis induced significant changes in the colonic bio-disposition of this herbal pair extract. In particular, in the context of colitis, the phase I metabolism of berberine, coptisine, jatrorrhizine, palmatine,and epiberberine has been inhibited. These results may provide a basis for understanding the pharmacological material basis of Coptis chinensis Franch. and Sophora flavescens Ait. in treating ulcerative colitis.
研究领域:
药理学
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分析化学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Menglan Wang,Lewei Li,Lifang Tang,Zuowei Xiao,Hong Yang,Qian Luo,Shiyang Fu,Zehui Fan,Xiaojun Tao,Chunlian He,Xiong Wu
Chemoresistance remains a major barrier to the effective treatment of triple-negative breast cancer (TNBC). To enhance the targeting and chemosensitivity of paclitaxel (PTX) for TNBC treatment, we developed a dual-drug-loaded nanodelivery system (BBR@PTX NPs) using BI-PEG-PTX polymer as the carrier, with berberine (BBR) loaded at an optimal ratio (PTX:BBR =1:10) determined by synergistic toxicity assays. The BBR@PTX NPs in this study demonstrated loading efficiencies of 9.5% for PTX and 28.06% for BBR, with an average particle size of 130-150 nm and a uniform distribution. In in vitro cellular assays, BBR potentiates PTX, achieving synergistic anti-tumor efficacy. The BBR@PTX NP co-delivery system enhances bioavailability by evading macrophage phagocytosis and lysosomal capture. The ability to inhibit cell growth, metastasis, and induce apoptosis was significantly enhanced after the NPs were taken up by tumor cells. In vivo experiments demonstrated that the BBR@PTX NP nanomicellar system enhanced tumor targeting, anti-tumor activity, and biosafety compared to single-agent formulations. These findings establish an effective approach to develop high-performance, selective, and low-toxicity nanocellular aggregates for combined therapy of solid triple-negative breast cancer.
研究领域:
肿瘤学
·
药剂学
·
纳米医学
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产品关联
DOI
高影响因子
Pharmacology Research & Perspectives
·
2025
·Vol. 13
·期 3
·e70126
·
IF 2.3
Yuanxia Yang,Yue Zhang,Yingdong Qu,Liwan Cui
Sirolimus is a third-generation immunosuppressant with multiple efficacies, including antifungal, antitumor, and immunosuppressive properties. We conducted a pharmacokinetic study to determine the effect of berberine hydrochloride (BBR) on the pharmacokinetics of sirolimus in rats. Thirty-six rats were randomly divided into six groups, and blood samples were collected from the posterior orbital venous plexus at different time points after the last administration to determine the plasma concentration of sirolimus. Liquid chromatography tandem mass spectrometry (LC–MS/MS) was used for detection, and DAS 2.0 software was employed for pharmacokinetic analysis. A single administration of BBR significantly reduced the pharmacokinetic parameter AUC 0-12h of sirolimus. Repeated administration of BBR resulted in an upward trend in C max AUC 0-12h , AUC 0-∞ , and CLz all show an upward trend. This study indicates that BBR has a certain impact on the pharmacokinetics of sirolimus in rats. However, further validation of the role of gene polymorphism in pharmacokinetics and clinical efficacy is needed for further research in a wider population.
研究领域:
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2025
·
IF 12.5
Min Qiu,Jiaxin Li,Huijuan Xie,Jiamin Feng,Qi Huang,Yin Tian,Haozhou Huang,Li Han,Dingkun Zhang
Bitterness masking is a crucial technical hurdle in the development and application of oral liquid medicines. Small-molecule excipients, such as cyclodextrin, often provide insufficient bitterness masking, thus prompting the exploration of large-molecule excipients, especially polysaccharides. In this study, the bitterness-masking effects of 10 polysaccharides were assessed using berberine as a model. Only iota-carrageenan significantly reduced the bitterness of berberine, decreasing it from strong to slight. A comparative study of the bitterness-masking mechanisms of three polysaccharides revealed that carrageenan polymer chains formed an interwoven network, decreasing the release of berberine by 40 %. Moreover, -OSO₃ − groups on the polymer chains exhibited strong electrostatic interactions with the N + in berberine, significantly reducing the electron cloud density of N + . This combined effect traps berberine within the “net-hook” structure of the iota-carrageenan, markedly weakening the activation of bitter receptors by the berberine. Ultrasonic treatment-induced disruption of the iota-carrageenan network structure yielded a 29 % reduction in bitterness-masking efficacy, while carrageenan with a lower -OSO₃ − content achieved a 40 % reduction in efficacy. In conclusion, the “net-hook” structure of natural polysaccharides is a necessary condition for them to exert a bitterness-masking effect. This finding provides a scientific basis for expanding the applications of natural polysaccharides in taste-masking.
研究领域:
药学
·
食品科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jiangmei Zhao,Cheng Ji,Chong Peng,Yuanfei Wang,Shuyi Yang,Yun Li,E. Tao
MnSO 4 -modified biochar (Mn-BC) was synthesized to remove berberine hydrochloride (BH) from wastewater by utilizing tea waste as raw material and MnSO 4 as modifier. Brunel Emmett Taylor (BET) analysis reveals that the specific surface area (SSA) and average pore size (D ave ) of Mn-BC are 1.4 and 7 times higher than those of pristine biochar apart, attributing to the dissociation effect can promote the dispersion of MnSO 4 in the pores of the biochar. Meanwhile, the doping of Mn not only introduces additional oxygen-containing functional groups (OCFGs), but also modulates the π electron density. Furthermore, Response surface method (RSM) analysis reveals that Mn-BC dosage has the most significant effect on BH removal, followed by BH concentration and pH value. Kinetic and isothermal studies reveal that the BH adsorption process of Mn-BC was mainly dominated by chemical and monolayer adsorption. Meanwhile, density functional theory (DFT) calculations confirm the contribution of Mn doping to the conjugation effect in the adsorption system. Originally proposed Mn-BC is one potentially propitious material to eliminate BH from wastewater, meanwhile this also provides a newfangled conception over the sustainable utilization of tea waste resources.
研究领域:
环境科学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Current Computer-Aided Drug Design
·
2024
·
IF 1.5
Lingxiao Zhang,Chenghao Yang,Xinyue Ding,Hui Zhang,Yuling Luan,Yueer Tang,Zongjun Liu
Background: Berberine (BBR), also known as berberine hydrochloride, was isolated from the rhizomes of the Coptis chinensis. Studies have reported that BBR plays an important role in glycolipid metabolism, including insulin (IR). The targets, and molecular mechanisms of BBR against hyperlipid-induced IR is worthy to be further studied. Material and methods: The related targets of BBR were identified via Pharmmapper database and relevant targets of diabetes were obtained through GeneCards and Online Mendelian Inheritance in Man (OMIM) database. The common targets were employed with the STRING database and visualized with the protein-protein interactions (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to explore the biological progress and pathways. In vitro, human hepatocellular carcinomas (HepG2) cell was used as experimental cell line, and an insulin resistant HepG2 cell model (IR-HepG2) was constructed using free fatty acid induction. After intervention with BBR, glucose consumption and uptake in HepG2 cells were observed. Molecular docking was used to test the interaction between BBR and key targets, and real-time fluorescence quantitative PCR was used to detect the regulatory effect of BBR on related targets. Results: 262 overlapped targets were extracted from BBR and diabetes. In the KEGG enrichment analysis, the peroxisome proliferator activated receptor (PPAR) signaling pathway was included. In vitro experiments, BBR can significantly increase sugar consumption and uptake in IR HepG2 cells, while PPAR inhibitors can weaken the effect of BBR on IR-HepG2. Conclusion: The PPAR signaling pathway is one of the important pathways for BBR to improve high-fat-induced insulin resistance in HepG2 cells.
研究领域:
药理学
·
分子生物学
·
内分泌学
·
转化医学
·
代谢疾病研究
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）