PHYTOTHERAPY RESEARCH
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2021
·Vol. 35
·期 6
·3181-3193
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IF 5.882
Rui Liu,Shiling Hu,Yuanyuan Ding,Jue Wang,Yuejin Wang,Jiapan Gao,Langchong He
Anaphylactoid reactions are potentially fatal allergic diseases caused by mast cells (MCs), which release histamine and lipid mediators under certain stimuli. Therefore, there is an urgent need to develop new drug candidates to treat anaphylactoid reactions. The MrgX2 receptor mediates anaphylactoid reactions that cause inflammatory diseases. Cortex dictamni is a Chinese herb used for treating allergy-related diseases; however, its active compound is still unknown and its mechanism of action has not yet been reported. The aim of this study was to screen the anti-anaphylactoid compound from C . dictamni extracts. An MrgX2/CMC-HPLC method was established for screening MrgX2-specific compounds retained from the alcohol extract of C . dictamni . A mouse model of hindpaw extravasation was used to evaluate the anti-anaphylactoid effect of this ingredient. Intracellular Ca 2+ mobilization was assessed using a calcium imaging assay. Enzyme immunoassays were performed to measure cytokine and chemokine release levels. The molecular signaling pathways were explored by western blotting. As a result, dictamnine was identified as an effective compound using the MrgX2/CMC method, which remarkably suppressed MC intracellular Ca 2+ mobilization and the release of de novo degranulated substances, and inhibited PKC-PLCγ-IP3R-associated protein signaling molecules. Hence, dictamnine is a novel therapeutic candidate for anaphylactoid reactions via MrgX2.
研究领域:
药理学
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免疫学
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中药学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
Peijun Liu,Weihua Tang,Dong Zhao,Pan Zhou,Ke Hu
Background: Notopterygium incisum K.C. Ting ex H.T. Chang, a synonym of Hansenia weberbaueriana (Fedde ex H. Wolff) Pimenov & Kljuykov, is an anti-inflammatory medicinal plant. Although abrnotopterol has been reported to be its primary active metabolite, the other metabolites and their mechanisms of action remain unclear. This study aims to investigate the potential mechanisms by which its active metabolites treat Obstructive Sleep Apnea Syndrome (OSAS) through network analysis and experimental assessment. Methods: The metabolites and potential targets of Notopterygium incisum were extracted from public databases. We searched for OSAS-related genes in the Genecards, OMIM, PharmGkb, TTD, and DrugBank databases. Cytoscape 3.9.0 was used to construct the drug-target-disease network and screen for hub genes. Human bronchial epithelial (HBE) cells were cultivated in normoxia and chronic intermittent hypoxia (CIH) medium for 24 h. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and prostaglandin E2 (PGE2) were quantified using enzyme-linked immunosorbent assay (ELISA). Prostaglandin-endoperoxide synthase 2(PTGS2) mRNA was detected using RT-qPCR, while PTGS2 and nuclear factor-kappa B (NF-κB) proteins were identified using Western blot analysis. Co-Immunoprecipitation (CoIP) and Western blotting were utilized to evaluate the ubiquitination of PTGS2 in HBE cells. Results: Pterostilbene and notopterol, isolated from Notopterygium incisum , had potential therapeutic effects on OSAS. The PTGS2 and estrogen receptor alpha (ESR1) hub genes were associated with OSAS. The pathway enrichment analysis focuses on the NF-κB, apoptosis, and HIF-1A pathways. In response to CIH, pterostilbene and notopterol decreased IL-6, TNF-α, and PGE2 levels. The NF-κB pathway was activated by an increase in PTGS2 levels. Pterostilbene promoted proteasome-mediated ubiquitination of PTGS2 protein and reduced PTGS2 levels, inhibiting the NF-κB pathway. Conclusion: This study reveals the active metabolites of Notopterygium incisum and hub genes involved in treating OSAS, which provide a basis for the follow-up development and exploitation of the botanical drug.
研究领域:
药理学
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分子生物学
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网络分析
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实验生物学
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睡眠障碍
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2023
·
IF 3.5
Qi Luo,Yang Shen,Guohong Zhai,Lin Chen,Furong Ou,Luxi Yi,Danli Yang,Hong Pan,Fuguo Shi
Dictamnine is a representative furan-containing hepatotoxic compound. Administration of dictamnine caused acute liver injury in mice and the metabolic activation of furan to reactive epoxy intermediate was responsible for the hepatotoxicity. This study aimed to characterize the protein adduction by endogenous hepatic aldehydes and investigate its role in dictamnine-induced hepatotoxicity. In the liver sample of dictamnine-treated mice, the protein adduction by five aldehydes was characterized as lysine residue-aldehyde adducts using high-resolution UPLC-Q/Orbitrap MS after exhaustive proteolytic digestion. The levels of protein adduct were increased at 2–3 h after the treatment with dictamnine. The formation of protein adduction increased with increasing doses of dictamnine. Inhibition of the bioactivation by CYP3A inhibitor ketoconazole prevented the protein adduction. Treatment with 2,3-dihydro-dictamnine, an analog of dictamnine that was unable to form the epoxy intermediate, did not lead to an increase in protein adduction. Application of aldehyde dehydrogenase-2 activator ALDA-1 or nucleophilic trapping reagent N -acetyl-L-lysine significantly reduced the protein adduction and attenuated dictamnine-induced liver injury without affecting the bioactivation. In conclusion, the metabolic activation of the furan ring of dictamnine resulted in the protein adduction by multiple hepatic aldehydes and the protein modification played a crucial role in dictamnine-induced liver injury.
研究领域:
药理学
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毒理学
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肝病学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
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2024
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IF 3.7
Dong Liu,Tingting Hou,Chunye Geng,Lu Song,Xuefeng Hou,Yanjun Chen,Fang Wang,Wei Wang,Bangxing Han,Leilei Gao
Poor stability and difficult uptake of natural polysaccharides have been the main problems in their application. The purpose of this study was to optimize the preparation conditions of Polygonatum cyrtonema Hua polysaccharides liposomes (PCPL) and to investigate the immune enhancement activity of PCPL in vitro and in vivo, with a view to discovering new ways of natural polysaccharide application. The optimal preparation conditions of PCPL were as follows: the adding amount of Tween 80 of 0.5 %, the ultrasound time of 2 min and the ultrasound times of once. Under these conditions, the entrapment efficiency, drug loading rate and particle size of PCPL were 38.033 %±0.050, 2.172 %±0.003 and 146 nm, which indicated that PCPL with small particle size could be prepared by the reverse-phase evaporation method. Furthermore, PCPL promoted proliferation, phagocytosis, and secretion of nitric oxide and related cytokines in RAW264.7 cells. Moreover, PCPL improved spleen and thymus indices, increased the number or proportion of red blood cells, platelets, and lymphocytes in the blood, and ameliorated spleen and thymus atrophy in immunosuppressed mice. This study provides a new idea for applying Polygonatum cyrtonema Hua polysaccharides (PCP) and references for studying other polysaccharides.
研究领域:
药学
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免疫学
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生物技术
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DOI
PubMed
高影响因子
Journal of Proteomics
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2019
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IF 3.537
Zhuo-Qing Li,Ling-Li Wang,Jing Zhou,Xian Zheng,Yan Jiang,Ping Li,Hui-Jun Li
Dictamnine (DTN), a major furoquinoline alkoloid from Dictamni Cortex, was reported to induce hepatotoxicity. However, the underlying mechanism is unclear. In the present study, integrated transcriptomic and metabolomics analysis of mouse liver was performed in combination with serum biochemical and histopathological evaluation to investigate the potential mechanism. The results suggested that 640 mg/kg DTN significantly increased serum alanine transaminase and aspartate transaminase levels and induced serious cellular degeneration, with no changes occurring with 4 mg/kg DTN. Integrated analysis suggested that the metabolism of xenobiotics by cytochrome P450 , drug metabolism-other enzymes , bile secretion and glutathione metabolism were the major metabolic pathways involved in DTN-induced hepatotoxicity. Notably, 640 mg/kg DTN exposure increased hepatic GSH, GSH peroxidase , superoxide dismutase and malondialdehyde, and decreased ROS , together with altered expression of Idh2 and Nedd9. Representative genes, including Mup12 , Lipc, NTCP , MRP3, MRP4, CYP2E1 , CYP2D9 and UGT1A9 , in altered pathways were verified through PCR and Western blot . Collectively, the combined strategy of transcriptomics and metabolomics profiling could facilitate a better understanding for the discovery of metabolic pathways and that oxidative damage, ABC transporters and lipid metabolism might be the mechanisms linked to DTN-induced hepatotoxicity in mice. Significance Dictamnine (DTN) was reported to induce hepatotoxicity. Nevertheless, the underlying mechanism is unknown. This study is the first to utilize integrated transcriptomics and metabolomics in combination with general toxicity evaluation to characterize the potential molecular mechanism in DTN-induced hepatotoxicity in mice. We found that acute exposure to higher dose of DTN induced hepatocellular liver injury with more changes in biochemical parameters, genes and metabolites. Gene expression and metabolite profiles were more sensitive than general toxicity studies for detecting earlier hepatotoxicity. Integrated analysis suggested that oxidative damage, ABC transporters and lipid metabolism were closely correlated with DTN-induced hepatotoxicity. Overall, our results provide insights into the mechanism responsible for DTN-induced hepatotoxicity.
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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系统生物学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2022
·Vol. 43
·期 5
·662-679
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IF 3.628
Zhuo-Qing Li,Cai Zhang,Song Fan,Ling-Li Wang,Yan Jiang,Hui-Jun Li
Dictamnine (DTN), a furoquinoline alkaloid isolated from Dictamni Cortex, is responsible for the liver injury caused by Dictamni Cortex and the preparations. Discovering new biomarkers with high specificity and sensitivity for diagnosis and tracing the source of DTN-induced liver injury is urgently needed. Considering that metabolic activation of DTN has been suggested as a primary trigger initiating hepatotoxicity, the present study aimed to investigate the bio-activation process of DTN in vitro and in mice and to explore whether the adducts could be developed as exposure biomarkers. When trapping with N -acetyl-cysteine (NAC) and glutathione (GSH) in mouse liver microsomes and CYP3A4 overexpressed L02 cells, two isomers of DTN-NAC adducts were detected in both systems and one DTN-GSH adduct was found in mouse liver microsomes. As expected, one DTN-NAC adduct was also found in plasma and bile of mice with liver injury after DTN exposure. Moreover, mouse liver microsomes were used to simulate the conjugation of serum albumin with metabolically activated DTN. The sole modified peptide 25 DAHKSEVAHR 34 was found, and the oxidative metabolites of DTN might bind to the side chain amino of albumin at Arg34. The above findings not only provided confirmative evidence that DTN was metabolically activated to induce liver injury but also suggested that the adducts had the potential to be developed as exposure biomarkers of DTN-induced liver injury.
研究领域:
药理学
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毒理学
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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY A
·
2023
·
IF 4.1
Changqing Yu,Tiantian Xie,Sihan Liu,Ligai Bai
A monolithic adsorbent was designed aiming to the structure of osthole and columbianadin, and fabricated using diallyl phthalate as the monomer and ethylene dimethacrylate as the crosslinker with the addition of bamboo biochar, via polymerization reaction in a stainless-steel tube. The prepared composite adsorbent packed in the tube was used as a solid-phase extraction column for the extraction and determination of two coumarins (osthole and columbianadin) in Angelicae Pubescentis Radix , combing with a C18 analytical column through an HPLC instrument, which show excellent matrix-removal ability and good selectivity to osthole and columbianadin. Furthermore, the present adsorbent shows good applicability, which was used for the extraction of osthole from Duhuo Jisheng Pill. Compared to the commercial C18 and phenyl adsorbent, the present adsorbent own better selectivity and higher resolution. These results attributed to the enhanced specific surface area (141 m 2 /g) and enriched interaction sites of the resulting composite adsorbent, due to the doping of bamboo biochar, which can produce hydrogen bond, dipole-dipole, π-π and hydrophobic force interactions with the osthole and columbianadin. The methodology validation indicated that the present method showed good precision and good accuracy, and the composite adsorbent showed good preparative repeatability, which can be reused for no less than 100 times with the relative standard deviation ≤4.6 % ( n = 100). The present work provided a simple and efficient method for the extraction and determination osthole and columbianadin from Angelicae Pubescentis Radix .
研究领域:
分析化学
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药学
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材料科学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2018
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IF 3.831
Li Zhuo-Qing,Jiang Li-Long,Zhao Dong-Sheng,Zhou Jing,Wang Ling-Li,Wu Zi-Tian,Zheng Xian,Shi Zi-Qi,Li Ping,Li Hui-Jun
Dictamni Cortex (DC) has been reported to be associated with acute hepatitis in clinic and may lead to a selective sub-chronic hepatotoxicity in rats. Nevertheless, the potent toxic ingredient and the underlying mechanism remain unknown. Dictamnine (DTN), the main alkaloid from DC, possesses a furan ring which was suspected of being responsible for hepatotoxicity via metabolic activation primarily by CYP3A4. Herein, the present study aimed to evaluate the role of CYP3A4 in DTN-induced liver injury. The in vitro results showed that the EC50 values in primary human hepatocytes (PHH), L02, HepG2 and NIH3T3 cells were correlated with the CYP3A4 expression levels in corresponding cells. Furthermore, the toxicity was increased in CYP3A4-induced PHH by rifampicin, and CYP3A4 over-expressed (OE) HepG2 and L02 cells. Contrarily, the cytotoxicity was decreased in CYP3A4-inhibited PHH and CYP3A4 OE HepG2 and L02 cells inhibited by ketoconazole (KTZ). In addition, the hepatotoxicity of DTN in enzyme induction/inhibition mice was further investigated in the aspects of biochemistry, histopathology, and pharmacokinetics. Administration of DTN in combination with KTZ resulted in attenuated liver injury, including lower alanine transaminase and aspartate transaminase activities and greater AUC and Cmax of serum DTN, whereas, pretreatment with dexamethasone aggravated the injury. Collectively, our findings illustrated that DTN-induced hepatotoxicity correlated well with the expression of CYP3A4, namely inhibition of CYP3A4 alleviated the toxicity both in vitro and in vivo, and induction aggravated the toxicity effects.
研究领域:
药理学
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毒理学
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药学
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DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2021
·Vol. 18
·期 12
·e2100633
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IF 2.408
Ying-Hui He,Xiao-Fei Shang,Hai-Xin Li,An-Ping Li,Chen Tang,Bao-Qi Zhang,Zhi-Jun Zhang,Rui Wang,Yue Ma,Sha-Sha Du,Yong-Mei Hu,Tian-Lin Wu,Wen-Bin Zhao,Cheng-Jie Yang,Ying-Qian Liu
The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC 50 value of 21 μg mL −1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the β-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner in vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.
研究领域:
植物病理学
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植物化学
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分子生物学
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杀菌剂
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产品关联
DOI
PubMed
高影响因子
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