JOURNAL OF MOLECULAR STRUCTURE
·
2023
·
IF 3.8
Yongmei Zhao,Jianwu Lv,Hongli Yu,Kang Huang,Zhihan Du,Wen Luo
A novel series of dictamnine derivatives were synthesized and evaluated as dual inhibitors for cholinesterase and β-amyloid aggregation. These molecules exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar to sub-micromolar levels. Compound 7k exhibited the strongest inhibitory activity for both AChE and BChE, with IC 50 values of 0.40 μM and 0.63 μM, respectively, improving results from its precursor dictamnine and the commercial inhibitor galanthamine. Kinetic analyses and molecular modeling results indicated a mixed-type inhibition of AChE by compound 7k . In addition, some of the derivatives revealed potent inhibitory activity of AChE induced β-amyloid (Aβ) aggregation. Moreover, 7k did not show toxicity against SH-SY5Y and HL-7702 cells at the tested concentration. Therefore, these dictamnine derivatives, and especially 7k , are suitable candidates for the treatment of Alzheimer's disease and should be further studied.
研究领域:
药物化学
·
神经生物学
·
有机合成
✓ 已验证
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Wēi Wang,Jian Zhang,Song-Lin Jiang,Zhi-Min Rao,Hui Liu,Lei Wang,Chun-Li Cai,Xin-Chang Xu,Chen-Huan Yu,Wéi Wang
Ethnopharmacological relevance Psoriasis is an immune-mediated genetic skin disease, which is characterized by hyperproliferation and aberrant differentiation of epidermal keratinocytes. Recently, there are not any cures for psoriasis because of the limited availability of safe and effective medications. Dictamni Cortex is the root bark of Dictamnus dasycarpus Turcz. And exhibits anti-inflammatory, antibacterial, hepatoprotective and anticancer activities. It is widely used for preventing various bone and skin diseases, including rheumatoid arthritis, psoriasis, eczema and impetigo. However, the active compounds responsible for treating psoriasis in the herb remain unknown. Aim of the study To investigate the inhibitory effects of active compounds in the herb against the hyperproliferation of human HaCaT keratinocytes in vitro and imiquimod (IMQ)-induced psoriasis-like dermatitis in mice. Materials and methods The effects of each active compound in the herb against the proliferation, apoptosis, migration, and invasion of HaCaT cells were analyzed by MTT, flow cytometry, and Transwell assays, respectively. The profiles of differentially expressed mRNAs between model group and dictamnine (DIC)-treated group were compared by transcriptome sequencing. The levels of inflammatory cytokines and chemokines in the mediums and skin tissues were measured by ELISA assay. IMQ-induced psoriasis-like dermatitis in mice were evaluated by HE stain and immunohistochemical analysis. The expressions of HIF1A and its downstream were measured by western blotting analysis. Results Compared with the methanol extract and other active compounds, DIC displayed the strongest inhibition on the hyperproliferation of KGF-stimulated HaCaT cells. DIC remarkably inhibited the proliferation, migration and invasion of HaCaT cells in a concentration-dependent manner. It also reduced the production of IL-6, IL-23 and VEGF, the activities of GSH and SOD, and the expressions of K17 , CCL20 and CXCL2 mRNAs, but elevated the levels of ROS, Fe 2+ and MDA in KGF-exposed HaCaT cells. Moreover, DIC significantly mitigated imiquimod-induced psoriasis-like dermatitis in mice. Mechanically, DIC promoted the ferroptosis of HaCaT cells via targeting HIF1A, thereby suppressing the nuclear translocation of HIF1A and its dowmstream GPX4 and SLC7A11. These benefits of DIC treatment could be reversed by ferroptotic inhibitor Ferrostatin-1 and HIF1A stabilizer DMOG. Conclusions DIC ameliorated psoriasis in part by triggering HIF1A-dependent ferroptosis in keratinocytes. It suggested that DIC was the main active compound in D. Cortex and has therapeutic potential for the treatment of psoriasis.
研究领域:
药理学
·
皮肤科
·
分子生物学
·
民族药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2018
·
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
·
毒理学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
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
·
毒理学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Dongju Lin,Guangyao Li,Haoran Deng,Shuo Wang
Ethnopharmacological relevance Dictamnine (DIC) is the predominant pharmacological and hepatotoxic component of Cortex Dictamni (CD). CYP3A-mediated metabolic activation plays an important role in DIC-induced hepatotoxicity. Schisandra lignans (SCLs) are the major hepatoprotective ingredients of Schisandra chinensis (SC). CD and SC are frequently used as herb pairs in traditional Chinese medical formulas particularly for the treatment of eczema and urticarial. Our preliminary studies have shown that SC can protect against CD-induced liver injury. However, the underlying protective mechanism of SC against CD-induced liver injury has remained unknown. Aim of the study : This study aims to investigate the effects of SCLs on the hepatotoxicity and metabolic activation of DIC and elucidate the underlying hepatoprotective mechanism from the perspective of the inhibition of CYP3A-mediated metabolic activation. Material and methods The protective effect of SCLs against DIC-induced hepatotoxicity was evaluated by biochemical analysis and liver histological observation. The effect of SCLs on the in vitro metabolic activation of DIC was assessed by detecting the level of DIC-N-acetylcysteine (NAC) conjugates in mouse liver microsomal incubations. The effect of SCLs on the metabolic activation in vivo of DIC was examined by monitoring the toxicokinetic behaviors of DIC, DIC-induced hepatic GSH depletion, the cumulative urine excretion of DIC, the levels of DIC-NAC conjugates in urine and liver of mice, and the formation of DIC-derived cysteine-protein adducts. Results Our findings indicated that SCLs protected against DIC-induced hepatotoxicity in a dose-dependent manner. SCLs exhibited dose-dependent inhibitory effect on the formation of DIC-NAC conjugates in liver microsomal incubations, indicating SCLs inhibited the metabolic activation of DIC in vitro . SCLs increased C max and AUC s of DIC in the blood and liver of mice, leading to the enhancive accumulation of DIC in the circulation. Pretreatment with SCLs relieved hepatic GSH depletion induced by DIC, promoted the urinary excretion of DIC, inhibited the formation of reactive metabolite of DIC in urine and liver of mice, and reduced the production of DIC-derived cysteine-protein adducts, suggesting that SCLs influenced absorption, distribution, metabolism, and excretion (ADME) of DIC by suppressing the metabolic activation of DIC in vivo . Conclusions The study demonstrated the protective effect of SCLs against hepatotoxicity induced by DIC was related to the inhibition of CYP3A-mediated metabolic activation of DIC. Therefore, the study demonstrated that SCLs may serve as the candidate drugs for the intoxication of DIC. Moreover, our findings may interpret the protective mechanism of SC against CD-induced liver injury.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 6
·3181-3193
·
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
·
免疫学
·
中药学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Proteomics
·
2019
·
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
·
毒理学
·
分子生物学
·
系统生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2022
·Vol. 43
·期 5
·662-679
·
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
·
毒理学
·
生物化学
✓ 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）