PHARMACEUTICAL BIOLOGY
·
2017
·
IF 1.916
Xu-Xin Zhang,Yun-Feng Cao,Li-Xuan Wang,Xiao-Lin Yuan,Zhong-Ze Fang
Contents: Danshen is a popular herb employed to treat cardiovascular and cerebrovascular diseases worldwide. Danshen–drug interaction has not been well studied.Objective: The inhibitory effects of four major tanshinones (tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone I) on UDP-glucuronosyltransferases (UGTs) isoforms were determined to better understand the mechanism of danshen–prescription drugs interaction.Materials and methods: In vitro recombinant UGTs-catalyzed 4-methylumbelliferone (4-MU) glucuronidation reaction was employed. Tanshinones (100 μM) was used to perform the initial screening of inhibition capability. High-performance liquid chromatography (HPLC) was used to separate 4-MU and its glucuronide. In vitro–in vivo extrapolation (IV–IVE) was employed to predict in vivo inhibition situation.Results: Cryptotanshinone inhibited UGT1A7 and UGT1A9 with IC50 values of 1.91 ± 0.27 and 0.27 ± 0.03 μM, respectively. Dihydrotanshinone I inhibited UGT1A9-catalyzed 4-MU glucuronidation reaction with the IC50 value of 0.72 ± 0.04 μM. The inhibition of cryptotanshinone towards UGT1A7 and UGT1A9 was best fit to competitive inhibition type, and UGT1A9 was non-competitively inhibited by dihydrotanshinone I. Using in vitro inhibition kinetic parameters (Ki) and in vivo maximum plasma concentration (Cmax) of cryptotanshinone and dihydrotanshinone I, the change of area-under-the-concentration–time curve (AUC) was predicted to be 0.4–4.2%, 3.7–56.3%, and 0.6–6.4% induced by cryptotanshinone and dihydrotanshinone inhibition towards UGT1A7 and UGT1A9, respectively.Discussion and conclusion: The inhibitory effects of tanshinones towards important UGT isoforms were evaluated in the present study, which provide helpful information for exploring the mechanism of danshen–clinical drugs interaction.
研究领域:
药理学
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中药学
·
代谢组学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2015
·Vol. 7
·期 1
·409-416
·
IF 2.791
Kaige Ji,Yudan Zhao,Tianhong Yu,Zhuoyi Wang,Hao Gong,Xin Yang,Yang Liu,Kun Huang
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Lewy bodies that are formed by the aggregated α-synuclein are a major pathological feature of PD. Salvia miltiorrhiza has been used as food and as a traditional medicine for centuries in China, with tanshinone I (TAN I) and tanshinone IIA (TAN IIA) as its major bioactive ingredients. Here, we investigated the effects of TAN I and TAN IIA on α-synuclein aggregation both in vitro and in a transgenic Caenorhabditis elegans PD model (NL5901). We demonstrated that TAN I and TAN IIA inhibited the aggregation of α-synuclein as demonstrated by the prolonged lag time and the reduced thioflavin-T fluorescence intensity; TAN I and TAN IIA also disaggregated preformed mature fibrils in vitro. Moreover, the presence of TAN I or TAN IIA affected the secondary structural transformation of α-synuclein from unstructured coils to β-sheets, and alleviated the membrane disruption caused by aggregated α-synuclein in vitro. Besides, the immuno-dot-blot assay indicated that TAN I and TAN IIA reduce the formation of oligomers and fibrils. We further found that TAN I and TAN IIA extended the life span of NL5901, a strain of transgenic C. elegans that expresses human α-synuclein, possibly by attenuating the aggregation of α-synuclein. Taken together, our results suggested that TAN I and TAN IIA may be explored further as potential candidates for the prevention and treatment of PD.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2020
·Vol. 21
·期 24
·9576
·
IF 4.556
Bin Zhang,Xueying Li,Xiuhong Li,Zhigang Lu,Xiaona Cai,Qing Ou Yang,Pengda Ma,Juane Dong
Tanshinones, the major bioactive components inSalvia miltiorrhizaBunge (Danshen), are synthesized via the mevalonic acid (MVA) pathway or the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway and the downstream biosynthesis pathway. In this study, the bacterial component lipopolysaccharide (LPS) was utilized as a novel elicitor to induce the wild type hairy roots ofS. miltiorrhiza.HPLC analysis revealed that LPS treatment resulted in a significant accumulation of cryptotanshinone (CT) and dihydrotanshinone I (DTI). qRT-PCR analysis confirmed that biosynthesis genes such asSmAACTandSmHMGSfrom the MVA pathway,SmDXSandSmHDRfrom the MEP pathway, andSmCPS,SmKSLandSmCYP76AH1from the downstream pathway were markedly upregulated by LPS in a time-dependent manner. Furthermore, transcription factorsSmWRKY1 andSmWRKY2, which can activate the expression ofSmDXR,SmDXSandSmCPS, were also increased by LPS. Since Ca2+signaling is essential for the LPS-triggered immune response, Ca2+channel blocker LaCl3and CaM antagonist W-7 were used to investigate the role of Ca2+signaling in tanshinone biosynthesis. HPLC analysis demonstrated that both LaCl3and W-7 diminished LPS-induced tanshinone accumulation. The downstream biosynthesis genes includingSmCPSandSmCYP76AH1were especially regulated by Ca2+signaling. To summarize, LPS enhances tanshinone biosynthesis throughSmWRKY1- andSmWRKY2-regulated pathways relying on Ca2+signaling. Ca2+signal transduction plays a key role in regulating tanshinone biosynthesis inS. miltiorrhiza.Keywords:lipopolysaccharide;tanshinones;Ca2+signaling;SmWRKY
研究领域:
植物学
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药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Xue Bai,Shuling Wang,Qin Zhang,Yuhan Hu,Jiawei Zhou,Lianhui Men,Dengyu Li,Jing Ma,Qiuhui Wei,Mengdie Xu,Xiaopu Yin,Tianyuan Hu
Miltiradiene serves as a crucial precursor in the synthesis of various high-value abietane-type diterpenes, exhibiting diverse pharmacological activities. Previous efforts to enhance miltiradiene production have primarily focused on the mevalonate acetate (MVA) pathway. However, limited emphasis has been placed on optimizing the supply of acetyl-CoA and NADPH. In this study, we constructed a platform yeast strain for miltiradiene production by reinforcing the biosynthetic pathway of geranylgeranyl diphosphate (GGPP) and acetyl-CoA, and addressing the imbalance between the supply and demand of the redox cofactor NADPH within the cytoplasm, resulting in an increase in miltiradiene yield to 1.31 g/L. Furthermore, we conducted modifications to the miltiradiene synthase fusion protein tSmKSL1-CfTPS1. Finally, the comprehensive engineering strategies and protein modification strategies culminated in 1.43 g/L miltiradiene in the engineered yeast under shake flask culture conditions. Overall, our work established efficient yeast cell factories for miltiradiene production, providing a foothold for heterologous biosynthesis of abietane-type diterpenes.
研究领域:
生物技术
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代谢工程
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
FITOTERAPIA
·
2013
·
IF 2.231
Ming Cong,Cui-Min Hu,Yun-Feng Cao,Zhong-Ze Fang,Shu-Hong Tang,Jia-Rui Wang,Jun-Sheng Luo
Danshen is one of the most famous herbs in the world, and more and more danshen–prescribed drugs interactions have been reported in recent years. Evaluation of inhibition potential of danshen's major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen–drugs interaction. Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation. In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dixon plot and Lineweaver–Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and dihydrotanshinone I. The second plot using the slopes from the Lineweaver–Burk plot versus the concentrations of cryptotanshinone or dihydrotanshinone I was employed to calculate the inhibition parameters (K i ) to be 0.4 and 1.7 μM, respectively. Using the reported maximum plasma concentration (C max ), the altered in vivo exposure of propofol increased by 10% and 8.2% for the co-administration of dihydrotanshinone I and cryptotanshinone, respectively. All these results indicated the possible danshen–propofol interaction due to the inhibition of dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol.
研究领域:
药理学
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中药学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
Turkish Journal of Gastroenterology
·
2025
·Vol. 36
·期 7
·431
·
IF 1.6
Ying Jiang,Xinjie Wang,Zhenyang Wang,Shengliang Zhang,Jianhua Wang,Xianglong Wang,Yang Zhang
Background/Aims: Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy that carries a dismal prognosis. Tanshinone IIA (Tan-IIA) is involved in the regulation of N6-methyladenosine (m6A) modification and plays an anti-tumor role in HCC, but whether Tan-IIA regulates HCC by mediating m6A modification is unclear. Methods and Materials: Cell apoptosis, invasion, proliferation, viability, and stemness were estimated with flow cytometry, transwell, 5-ethynyl-2’-deoxyuridine, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, and sphere-forming assays. Methyltransferase-like 14 (METTL14) and 3 (METTL3) mRNA and protein levels were detected with reverse transcription-quantitative polymerase chain reaction and western blotting. Total m6A levels were measured using an m6A RNA methylation quantification kit. A possible regulation of tribbles pseudokinase-3 (TRIB3) expression by METTL3 in an m6A-modified manner was predicted through RM2Target and SRAMP and verified by m6A methylated RNA immunoprecipitation (MeRIP) and RIP. Mouse xenograft models assessed the action of Tan-IIA in HCC tumorigenesis. Results: Tanshinone IIA restrained HCC cell viability, proliferation, invasion, and stemness, and induced HCC cell apoptosis invitro, as well as repressed tumor growth in xenograft models. METTL3 and TRIB3 were upregulated in HCC samples and downregulated in Tan-IIA-treated HCC cells and xenograft tumors. METTL3 facilitated HCC cell viability, proliferation, invasion, and stemness by enhancing TRIB3 mRNA stability through m6A modification. Tan-IIA played its role by downregulating TRIB3, and Tan-IIA mediated TRIB3 expression by METTL3. Conclusion: Tanshinone IIA restrained HCC progression by regulating METTL3-mediated m6A modification of TRIB3 mRNA, offering evidence to support the clinical translation of Tan-IIA.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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药理学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2024
·
IF 3.7
Hao Xu,Ning Ning Guo,Chen Ying Zhu,Lin Yan Ye,Xing Yi Yan,Yong Qin Liu,Ze Yan Zhang,Guangji Zhang,Liaqat Hussain
Diterpenoid tanshinones (DTs) are a bioactive fraction extracted from Salvia miltiorrhiza. High-performance liquid chromatography analysis revealed the presence of four compounds, namely, tanshinone IIA, tanshinone I, cryptotanshinone, and dihydrotanshinone. In this study, we aimed to propose a possible mechanism for the anti-lung cancer effect of DT. To do so, we utilized a lung cancer nude mice model and a lung cancer cell line (PC9) to investigate the effect of DT on lung cancer. We employed immunohistochemistry, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, and immunofluorescence to analyze the pharmacological role of DT in the inhibition of lung cancer growth. The results showed that DT inhibited tumor growth, induced apoptosis in the nude mice model, and reduced inflammatory cell infiltration. Additionally, DT inhibited PC9 lung cancer cells, growth, proliferation, and migration. The mechanism of action of DT involves not only directly inhibiting cell proliferation and migration but also improving the tumor microenvironment. DT significantly increased the expression of important intestinal gap junction proteins, such as zonula occludens 1 (ZO-1) and occludin I. This upregulation contributes to the reinforcement of the intestinal mucosal barrier, thereby reducing the paracellular transport of lipopolysaccharides (LPS) through the intestine. Consequently, the decreased LPS levels lead to the inhibition of NF-κB expression and downregulation of macrophage polarization, as indicated by the decreased expression of CD68. In conclusion, this study has confirmed that DT has anti-lung cancer properties by improving the inflammatory tumor microenvironment via regulating macrophage polarization and inhibiting LPS-associated immune response. These results provide new insights into the mechanism of DT action against lung cancer.
研究领域:
肿瘤学
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药理学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-11
·
IF 5.228
Shi Min,Zhou Wei,Zhang Jianlin,Huang Shengxiong,Wang Huizhong,Kai Guoyin
Jasmonic acid (JA) is an important plant hormone involved in regulation of many aspects of plant growth and development including secondary metabolism and JASMONATE ZIM-DOMAIN (JAZ) proteins are key components in JA signal processes. In this study, two new JAZ genes named SmJAZ3 and SmJAZ9 were cloned from S. miltiorrhiza hairy roots and characterized. Expression profiles under methyl jasmonate (MJ) treatment revealed that SmJAZ3 and SmJAZ9 were both MJ-responsive. Subcellular localization assay showed that SmJAZ3 was located in nucleus while SmJAZ9 was preferentially in nucleus. Expression of SmJAZ3 and SmJAZ9 in S. miltiorrhiza hairy roots differently affected the production of tanshinone. Over-expression of SmJAZ3 or SmJAZ9 in hairy roots produced lower level of tanshinone compared with the control, tanshinone production was as low as 0.077 mg/g DW in line SmJAZ3-3 and 0.266 mg/g DW in line SmJAZ9-22 . Whereas, down-regulation of SmJAZs enhanced tanshione production, the content of tanshinone increased to 2.48 fold in anti - SmJAZ3-3 line and 1.35-fold in anti-SmJAZ9-23 line. Our work indicated that SmJAZ3 and SmJAZ9 are involved in regulation of tanshinone biosynthesis and act as repressive transcriptional regulators in the JA signaling pathway, which paves the way to further dissect molecular mechanism in details in the future.
研究领域:
植物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomedicines
·
2023
·Vol. 11
·期 12
·3291
·
IF 4.7
Jingjing Sun,Wei Chen,Zheng Zhou,Xin Chen,You Zuo,Jiaqian He,Hairong Liu
(1) Background: Osteoarthritis (OA) is a crippling condition characterized by chondrocyte dedifferentiation, cartilage degradation, and subsequent cartilage defects. Unfortunately, there is a lack of effective medicines to facilitate the repair of cartilage defects in OA patients. In this study, we investigated the role of lncRNA NEAT1_2 in maintaining the chondrocyte phenotype and identified tanshinone IIA(TAN) as a natural medicine that enhances NEAT1_2 levels, resulting in efficient cartilage regeneration under inflammatory cytokines. (2) Methods: The transcriptional levels of NEAT1_2 and cartilage phenotype-related genes were identified by RT-qPCR. The siRNA interference approach was utilized to silence NEAT1_2; the Alamar Blue assay was performed to determine chondrocyte viability under inflammatory conditions. To evaluate the concentrations of collagen type II and glycosaminoglycans distributed by chondrocytes in vitro and in vivo, immunohistochemical staining and Safranin O staining were used. (3) Results: IL-1β suppresses NEAT1_2 and genes related to the chondrocytic phenotype, whereas TAN effectively upregulates them in a NEAT1_2-dependent manner. Consistently, TAN alleviated chondrocyte oxidative stress inhibited cartilage degradation by modulating the relevant genes and promoted efficient cartilage regeneration in vitro and in vivo when chondrocytes are exposed to inflammatory cytokines. (4) Conclusions: TAN enhances the expression of NEAT1_2 inhibited by IL-1β and affects the transcription of chondrocytic phenotype-related genes, which promotes cartilage regeneration in an inflammatory environment.Keywords:osteoarthritis;tanshinone IIA;NEAT1_2;cartilage defects repair;inflammatory
研究领域:
风湿病学
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药理学
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分子生物学
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2024
·
IF 4.3
Haidong Chen,Yimei Li,Dexuan Chen,Yong Fang,Xuchu Gong,Kaikai Wang,Chaoqun Ma
Chronic and infected wounds, particularly those caused by bacterial infections, present significant challenges in medical treatment. This study aimed to develop a novel nanoparticle formulation to enhance wound healing by combining antimicrobial and photothermal therapy using albumin as a carrier for Tanshinone IIA and the near-infrared photothermal agent IR780. The nanoparticles were synthesized to exploit the antimicrobial effects of Tanshinone IIA and the photothermal properties of IR780 when exposed to near-infrared laser irradiation. Characterization of the nanoparticles was performed using Transmission Electron Microscopy (TEM) and spectroscopic analysis to confirm their successful synthesis. In vitro antibacterial activity was evaluated using cultures of methicillin-resistant Staphylococcus aureus (MRSA), and in vivo efficacy was tested in a mouse model of MRSA-infected wounds. Wound healing progression was assessed over 16 days, with statistical analysis performed using two-way ANOVA followed by Tukey’s post-hoc test. The nanoparticles demonstrated significant photothermal properties, enhancing bacterial eradication and promoting the controlled release of Tanshinone IIA. In vitro studies showed superior antibacterial activity, especially under photothermal activation, leading to a substantial reduction in bacterial viability in MRSA cultures. In vivo, nanoparticle treatment combined with near-infrared laser irradiation significantly improved wound closure rates compared to controls and treatments without photothermal activation. By the 16th day post-treatment, significant improvements in wound healing were observed, highlighting the potential of the combined photothermal and pharmacological approach. These findings suggest that albumin-loaded nanoparticles containing Tanshinone IIA and IR780, activated by near-infrared light, could offer an effective therapeutic strategy for managing chronic and infected wounds, promoting both infection control and tissue repair.
研究领域:
医学
·
纳米技术
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Cancer
·
2020
·
IF 3.565
Yadong Liu,Fanlu Lin,Yaodong Chen,Rui Wang,Jiannan Liu,Yinshan Jin,Ruihua An
Cryptotanshinone (CTT), extracted from the root of Salvia miltiorrhiza Bunge (Danshen), exhibits activities against a variety of human cancers in vitro and in vivo . The purpose of this study was to investigate the potential inhibitory effect of CTT on bladder cancer. In this study, we found that CTT inhibited bladder cancer cell proliferation, migration, and invasion and promoted apoptosis. In addition, CTT modulated the expression of proteins via the PI3K/AKT pathway, and the inhibition of PI3K/AKT signalling was due to induction of PTEN expression. Taken together, the results of the present study demonstrated the anticancer effect of CTT on bladder cancer cells, which might be associated with the downregulation of PI3K/AKT/mTOR and NF-κB signalling pathway proteins, and this inhibition was mediated by the induction of PTEN.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Omega
·
2024
·
IF 3.7
Jinfu Wang,Yan Guo,Huifen Zhou,Yanjie Hua,Haitong Wan,Jiehong Yang
Objective: Cardiac ischemia-reperfusion (I/R) injury has negative effects on the brain and can even lead to the occurrence of ischemic stroke. Clinical evidence shows that Danhong injection (DHI) protects the heart and brain following ischemic events. This study investigated the mechanisms and key active compounds underlying the therapeutic effect of DHI against brain damage induced by cardiac I/R injury. Methods: The gene expression omnibus database provided GSE66360 and GSE22255 data sets. The R programming language was used to identify the common differentially expressed genes (cDEGs). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed, and protein–protein interaction network was constructed. Active compounds of DHI were collected from the Traditional Chinese Medicine Systems Pharmacology database. Molecular docking and molecular dynamics simulations were performed. The MMPBSA method was used to calculate the binding-free energy. The pkCSM server and DruLiTo software were used for Absorption, Distribution, metabolism, excretion, and toxicity (ADMET) analysis and drug-likeness analysis. Finally, in vitro experiments were conducted to validate the results. Results: A total of 27 cDEGs had been identified. The PPI and enrichment results indicated that TNF-α was considered to be the core target. A total of 80 active compounds were retrieved. The molecular docking results indicated that tanshinone I (TSI), tanshinone IIA (TSIIA), and hydroxyl safflower yellow A (HSYA) were selected as core active compounds. Molecular dynamics verification revealed that the conformations were relatively stable without significant fluctuations. MMPBSA analysis revealed that the binding energies of TSI, TSIIA, and HSYA with TNF-α were −36.01, −21.71, and −14.80 kcal/mol, respectively. LEU57 residue of TNF-α has the highest contribution. TSI and TSIIA passed both the ADMET analysis and drug-likeness screening, whereas HSYA did not. Experimental verification confirmed that DHI and TSIIA reduced the expression of TNF-α, NLRP3, and IL-1β in the injured H9C2 and rat brain microvascular endothelial cells. Conclusion: TNF-α can be considered to be a key target for BD-CI/R. TSIIA in DHI exerts a significant inhibitory effect on the inflammatory damage of BD-CI/R, providing new insights for future drug development.
研究领域:
药理学
·
生物信息学
·
神经科学
·
心脏病学
✓ 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）