Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Heliyon. 2024 Aug 14;10(16):e36241. doi: 10.1016/j.heliyon.2024.e36241. 
eCollection 2024 Aug 30.

Network pharmacology and in vivo experimental studies reveal the protective 
effects of 6-hydroxygenistein against hypobaric hypoxia-induced brain injury.

Shi Z(1)(2), Zhang J(1), Ma H(2), Jing L(1)(2).

Author information:
(1)Department of Pharmacy, the First Affiliated Hospital of Xi'an Jiaotong 
University, Xi'an, Shaanxi, 710061, China.
(2)Department of Pharmacy, the 940th Hospital of Joint Logistics Support Force 
of PLA, Lanzhou, Gansu, 730050, China.

Hypobaric hypoxia-induced brain injury (HHBI) is a progressive neurodegenerative 
disease that has still not been effectively treated. There are several different 
mechanisms involved in HHBI. Among them, oxidative stress and inflammation 
response predominate. 6-hydroxygenistein (4',5,6,7-tetrahydroxyisoflavone, 
6-OHG) is a hydroxylated derivative of genistein with excellent antioxidant 
activity, however, the protective effects and underlying mechanisms against HHBI 
have not been clarified. In the present study, we aimed to explore the 
mechanisms of action of 6-OHG on HHBI using network pharmacology and 
experimental validation. Network pharmacology analysis revealed 186 candidate 
targets through the intersection of the targets of 6-OHG and related genes in 
HHBI, which were mainly enriched in oxidative stress and inflammation response. 
Moreover, key targets of 6-OHG against HHBI, namely Nrf2 and NF-κB, were 
screened and found to be closely related to oxidative stress and inflammation 
response. Subsequent in vivo experiments revealed that 6-OHG treatment 
attenuated oxidative stress and inflammation response, prevented energy disorder 
and apoptosis as well as maintained the BBB integrity in HHBI mice. In addition, 
6-OHG administration up-regulated the expressions of Nrf2 and HO-1 and 
down-regulated the expressions of NF-κB and NLRP3, thereby inhibiting oxidative 
stress and inflammation response. Hence, the present study demonstrates that 
6-OHG protects against HHBI by stimulating the Nrf2/HO-1 signaling pathway and 
suppressing the NF-κB/NLRP3 signaling pathway.

© 2024 The Authors. Published by Elsevier Ltd.

DOI: 10.1016/j.heliyon.2024.e36241
PMCID: PMC11382173
PMID: 39253263

Conflict of interest statement: The authors declare that they have no known 
competing financial interests or personal relationships that could have appeared 
to influence the work reported in this paper.


2. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Feb 28;49(2):236-246. doi: 
10.11817/j.issn.1672-7347.2024.230228.

Synthesis, antioxidant and anti-hypoxia activities of 6-hydroxygenistein and its 
methylated derivatives.

[Article in Chinese, English; Abstract available in Chinese from the publisher]

Zhang P(1)(2)(3), Zhang J(4)(5), Tian Y(4)(5), Shi Z(4)(5), Ma H(6)(7), Jing 
L(8).

Author information:
(1)Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong 
University, Xi'an 710061. ZPP15127860030@163.com.
(2)Department of Pharmacy, 940th Hospital of Joint Logistics Support Force of 
Chinese People's Liberation Army, Lanzhou 730050. ZPP15127860030@163.com.
(3)College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730020, 
China. ZPP15127860030@163.com.
(4)Department of Pharmacy, 940th Hospital of Joint Logistics Support Force of 
Chinese People's Liberation Army, Lanzhou 730050.
(5)College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730020, 
China.
(6)Department of Pharmacy, 940th Hospital of Joint Logistics Support Force of 
Chinese People's Liberation Army, Lanzhou 730050. mahuiping2022@aliyun.com.
(7)College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730020, 
China. mahuiping2022@aliyun.com.
(8)Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong 
University, Xi'an 710061. lfjinglinlin@163.com.

OBJECTIVES: Hypoxia is a common pathological phenomenon, usually caused by 
insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated 
and methoxylated flavonoids have significant anti-hypoxia activity. This study 
aims to explore the synthesis, antioxidant and anti-hypoxia activities of 
6-hydroxygenistein (6-OHG) and its methoxylated derivatives.
METHODS: The 6-OHG and its methoxylated derivatives, including 
4',6,7-trimethoxy-5-hydroxyisoflavone (compound 3), 
4',5,6,7-tetramethoxyisoflavone (compound 4), 
4',6-imethoxy-5,7-dihydroxyisoflavone (compound 6), and 
4'-methoxy-5,6,7-trihydroxyisoflavone (compound 7), were synthesized by 
methylation, bromination, methoxylation, and demethylation using biochanin A as 
raw material. The structure of these products were characterized by 
1hydrogen-nuclear magnetic resonance spectroscopy (1H-NMR) and mass spectrometry 
(MS). The purity of these compounds was detected by high pressure chromatography 
(HPLC). The antioxidant activity in vitro was investigated by 
1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging assay. PC12 
cells were divided into a normal group, a hypoxia model group, rutin 
(1×10-9-1×10-5 mol/L) groups, and target compounds (1×10-9-1×10-5 mol/L) groups 
under normal and hypoxic conditions. Cell viability was detected by cell 
counting kit-8 (CCK-8) assay, the target compounds with excellent anti-hypoxia 
activity and the drug concentration at the maximum anti-hypoxia activity were 
screened. PC12 cells were treated with the optimal concentration of the target 
compound or rutin with excellent anti-hypoxia activity, and the cell morphology 
was observed under light microscope. The apoptotic rate was determined by flow 
cytometry, and the expressions of hypoxia inducible factor-1α (HIF-1α) and 
vascular endothelial growth factor (VEGF) were detected by Western blotting.
RESULTS: The structure of 6-OHG and its 4 methylated derivatives were correct, 
and the purity was all more than 97%. When the concentration was 4 mmol/L, the 
DPPH free radical removal rates of chemical compounds 7 and 6-OHG were 81.16% 
and 86.94%, respectively, which were higher than those of rutin, the positive 
control. The removal rates of chemical compounds 3, 4, and 6 were all lower than 
20%. Compared with the normal group, the cell viability of the hypoxia model 
group was significantly decreased (P<0.01). Compared with the hypoxia model 
group, compounds 3, 4, and 6 had no significant effect on cell viability under 
hypoxic conditions. At all experimental concentrations, the cell viability of 
the 6-OHG group was significantly higher than that of the hypoxia model group 
(all P<0.05). The cell viability of compound 7 group at 1×10-7 and 1×10-6 mol/L 
was significantly higher than that of the hypoxia model group (both P<0.05). The 
anti-hypoxia activity of 6-OHG and compound 7 was excellent, and the optimal 
drug concentration was 1×10-6 and 1×10-7 mol/L. After PC12 cells was treated 
with 6-OHG (1×10-6 mol/L) and compound 7 (1×10-7 mol/L), the cell damage was 
reduced, the apoptotic rate was significantly decreased (P<0.01), and the 
protein expression levels of HIF-1α and VEGF were significantly decreased in 
comparison with the hypoxia model group (both P<0.01).
CONCLUSIONS: The optimized synthesis route can increase the yield of 6-OHG and 
obtain 4 derivatives by methylation and selective demethylation. 6-OHG and 
compound 7 have excellent antioxidant and anti-hypoxia activities, which are 
related to the structure of the A-ring ortho-triphenol hydroxyl group in the 
molecule.

Publisher: 目的: 
缺氧是一种常见的病理现象，通常由机体组织供氧不足或无法有效利用氧导致。羟基化及甲氧基化黄酮类化合物具有显著的抗缺氧活性。本研究旨在探索6-羟基染料木素(6-hydroxygenistein，6-OHG)及其甲基化衍生物的合成方法和抗氧化与抗缺氧活性。方法: 
以鹰嘴豆芽素A为原料，经甲基化反应、溴化反应、甲氧基化反应及去甲基化反应得到6-OHG及其4个甲基化衍生物[4',6,7-三甲氧基-5-羟基异黄酮(化合物3)、4',5,6,7-四甲氧基异黄酮(化合物4)、4',6-二甲氧基-5,7-二羟基异黄酮(化合物6)、4'-甲氧基-5,6,7-三羟基异黄酮(化合物7)]。采用氢-1核磁共振波谱法(1H-nuclear 
magnetic resonance spectroscopy，1H-NMR)和质谱法(mass 
spectrometry，MS)表征产物结构；高压液相色谱法检测化合物的纯度；1,1-二苯基-2-三硝基苯肼(1,1-diphenyl-2-picrylhydrazyl，DPPH)自由基清除实验检测化合物的体外抗氧化活性。将PC12细胞分为正常组、缺氧模型组、芦丁组(1×10-9~1×10-5 
mol/L)，以及常氧和缺氧条件下的目标化合物组(1×10-9~1×10-5 mol/L)，采用细胞计数试剂盒-8(cell counting 
kit-8，CCK-8)检测细胞活力，筛选得到抗缺氧活性优异的目标化合物及其最佳抗缺氧活性时的药物浓度。分别用抗缺氧活性优异的目标化合物、芦丁的最佳药物浓度处理PC12细胞后，在光镜下观察细胞形态，采用流式细胞术测定细胞凋亡率，蛋白质印迹法检测缺氧诱导因子-1α(hypoxia 
inducible factor-1α，HIF-1α)和血管内皮生长因子(vascular endothelial growth 
factor，VEGF)的蛋白质表达水平。结果: 6-OHG及其4个甲基化衍生物的结构无误，纯度均>97%。当浓度为4 
mmol/L时，化合物7和6-OHG的DPPH自由基清除率分别为81.16%和86.94%，均高于阳性对照芦丁，而化合物3、4、6的清除率均低于20%。与正常组相比，缺氧模型组的细胞活力显著下降(P<0.01)；与缺氧模型组相比，化合物3、4、6对缺氧条件下的细胞活力无显著影响；在所有实验浓度下，6-OHG组的细胞活力均显著高于缺氧模型组(均P<0.05)；在给药浓度为1×10-7或1×10-6 
mol/L时，化合物7组的细胞活力显著高于缺氧模型组(均P<0.05)。6-OHG和化合物7的抗缺氧活性优异，最佳药物浓度分别为1×10-6和1×10-7 
mol/L。采用6-OHG(1×10-6 mol/L)和化合物7(1×10-7 
mol/L)处理PC12细胞后，与缺氧模型组相比，细胞损伤明显减轻，细胞凋亡率显著下降(P<0.01)，HIF-1α和VEGF蛋白质的表达水平显著下调(均P<0.01)。结论: 
优化后的合成路线可提高6-OHG的产率，通过甲基化和选择性去甲基化得到4个衍生物。6-OHG和其衍生物化合物7表现出优异的体外抗氧化和抗缺氧活性，该活性与其分子中存在的A环邻三酚羟基结构有关。.

OBJECTIVE: Hypoxia is a common pathological phenomenon, usually caused by 
insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated 
and methoxylated flavonoids have significant anti-hypoxia activity. This study 
aims to explore the synthesis, antioxidant and anti-hypoxia activities of 
6-hydroxygenistein (6-OHG) and its methoxylated derivatives.
METHODS: The 6-OHG and its methoxylated derivatives, including 
4',6,7-trimethoxy-5-hydroxyisoflavone (compound 3), 
4',5,6,7-tetramethoxyisoflavone (compound 4), 
4',6-imethoxy-5,7-dihydroxyisoflavone (compound 6), and 
4'-methoxy-5,6,7-trihydroxyisoflavone (compound 7), were synthesized by 
methylation, bromination, methoxylation, and demethylation using biochanin A as 
raw material. The structure of these products were characterized by 
1hydrogen-nuclear magnetic resonance spectroscopy (1H-NMR) and mass spectrometry 
(MS). The purity of these compounds was detected by high pressure chromatography 
(HPLC). The antioxidant activity in vitro was investigated by 
1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging assay. PC12 
cells were divided into a normal group, a hypoxia model group, rutin 
(1×10-9-1×10-5 mol/L) groups, and target compounds (1×10-9-1×10-5 mol/L) groups 
under normal and hypoxic conditions. Cell viability was detected by cell 
counting kit-8 (CCK-8) assay, the target compounds with excellent anti-hypoxia 
activity and the drug concentration at the maximum anti-hypoxia activity were 
screened. PC12 cells were treated with the optimal concentration of the target 
compound or rutin with excellent anti-hypoxia activity, and the cell morphology 
was observed under light microscope. The apoptotic rate was determined by flow 
cytometry, and the expressions of hypoxia inducible factor-1α (HIF-1α) and 
vascular endothelial growth factor (VEGF) were detected by Western blotting.
RESULTS: The structure of 6-OHG and its 4 methylated derivatives were correct, 
and the purity was all more than 97%. When the concentration was 4 mmol/L, the 
DPPH free radical removal rates of chemical compounds 7 and 6-OHG were 81.16% 
and 86.94%, respectively, which were higher than those of rutin, the positive 
control. The removal rates of chemical compounds 3, 4, and 6 were all lower than 
20%. Compared with the normal group, the cell viability of the hypoxia model 
group was significantly decreased (P<0.01). Compared with the hypoxia model 
group, compounds 3, 4, and 6 had no significant effect on cell viability under 
hypoxic conditions. At all experimental concentrations, the cell viability of 
the 6-OHG group was significantly higher than that of the hypoxia model group 
(all P<0.05). The cell viability of compound 7 group at 1×10-7 and 1×10-6 mol/L 
was significantly higher than that of the hypoxia model group (both P<0.05). The 
anti-hypoxia activity of 6-OHG and compound 7 was excellent, and the optimal 
drug concentration was 1×10-6 and 1×10-7 mol/L. After PC12 cells was treated 
with 6-OHG (1×10-6 mol/L) and compound 7 (1×10-7 mol/L), the cell damage was 
reduced, the apoptotic rate was significantly decreased (P<0.01), and the 
protein expression levels of HIF-1α and VEGF were significantly decreased in 
comparison with the hypoxia model group (both P<0.01).
CONCLUSION: The optimized synthesis route can increase the yield of 6-OHG and 
obtain 4 derivatives by methylation and selective demethylation. 6-OHG and 
compound 7 have excellent antioxidant and anti-hypoxia activities, which are 
related to the structure of the A-ring ortho-triphenol hydroxyl group in the 
molecule.

DOI: 10.11817/j.issn.1672-7347.2024.230228
PMCID: PMC11103059
PMID: 38755719 [Indexed for MEDLINE]

Conflict of interest statement: 作者声称无任何利益冲突。


3. Molecules. 2024 Mar 20;29(6):1392. doi: 10.3390/molecules29061392.

Detection of Adulterated Naodesheng Tablet (Naodesheng Pian) via In-Depth 
Chemical Analysis and Subsequent Reconstruction of Its Pharmacopoeia Q-Markers.

Li C(1), Li X(1), Zeng J(1), Cai R(1)(2), Chen S(1), Chen B(3), Zhao X(1).

Author information:
(1)School of Chinese Herbal Medicine, Guangzhou Higher Education Mega Center, 
Guangzhou University of Chinese Medicine, Waihuang East Road No. 232, Guangzhou 
510006, China.
(2)College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 
Chengdu 611137, China.
(3)Key Laboratory of Fermentation Engineering, Cooperative Innovation Center of 
Industrial Fermentation, Ministry of Education & Hubei Province, Hubei 
University of Technology, Wuhan 430068, China.

Naodesheng Tablet (Naodesheng Pian), a traditional Chinese medicine formula for 
stroke treatment, is made up of five herbal medicines, i.e., Sanqi, Gegen, 
Honghua, Shanzha, and Chuanxiong. However, the current Pharmacopoeia 
quality-marker (Q-marker) system cannot detect possible adulteration. Our study 
tried to use a new strategy, i.e., standards-library-dependent 
ultra-high-performance liquid chromatography-quadrupole-Orbitrap mass 
spectrometry (UHPLC-Q-Orbitrap MS/MS) putative identification, to reconstruct 
the Q-marker system. Through the strategy, 30 isomers were successfully 
differentiated (such as 2'-hydroxygenistein, luteolin, and kaempferol; 
ginsenoside Rg2 and ginsenoside Rg3; ginsenoside Rf and ginsenoside Rg1). In 
particular, 11 compounds were unexpectedly found in Naodesheng, including 
2'-hydroxygenistein, 7,4'-dihydroxyflavone, pectolinarigenin, 
7-methoxy-4'-hydroxyisoflavone, scoparone, matrine, 
3,3',4',5,6,7,8-heptamethoxyflavone, 5-hydroxyflavone, diosgenin, chloesteryl 
acetate, and (+)-4-cholesten-3-one. In total, 68 compounds were putatively 
identified and fully elucidated for their MS spectra. Subsequently, relevant 
compounds were further investigated using UV-vis scanning experiments, 
semi-quantitative analysis, and quantum chemical calculation. Finally, five 
adulterated Naodesheng Tablets were used for validation experiments. The 
experiment successfully detected five adulterated ones via a lower-version LC-MS 
analysis. On this basis, three new candidates (hydroxy safflor yellow A (HSYA), 
citric acid, and levistilide A), along with puerarin and notoginsenoside R1, are 
re-nominated as the Q-markers for LC-MS analysis. The LC-MS analysis of 
puerarin, notoginsenoside R1, HSYA, citric acid, and levistilide A can clearly 
detect adulteration regarding all five herbal medicines mentioned above. 
Therefore, the reconstructed Q-markers are described as a "perfect" quality 
control system to detect adulteration in Naodesheng and will offer a valuable 
recommendation for the Pharmacopoeia Commission.

DOI: 10.3390/molecules29061392
PMCID: PMC10974483
PMID: 38543029 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflicts of interest.


4. J Agric Food Chem. 2024 Mar 13;72(10):5477-5490. doi:
10.1021/acs.jafc.3c07139.  Epub 2024 Feb 28.

Integrated Metabolomics and Transcriptomics Analyses Highlight the Flavonoid 
Compounds Response to Alkaline Salt Stress in Glycyrrhiza uralensis Leaves.

Lv X(1)(2), Zhu L(3), Ma D(3), Zhang F(3), Cai Z(4), Bai H(2), Hui J(2), Li 
S(2), Xu X(1), Li M(5).

Author information:
(1)College of Forestry and Prataculture, Ningxia University, Yinchuan 750021, 
China.
(2)Agricultural Biotechnology Research Center, Ningxia Academy of Agriculture 
and Forestry Sciences, Yinchuan 750002, China.
(3)College of Ecology and Environment, Ningxia University, Yinchuan 750021, 
China.
(4)Department of Life and Food Science, Ningxia University, Yinchuan 750021, 
China.
(5)Institute of Forestry and Grassland Ecology, Ningxia Academy of Agriculture 
and Forestry Sciences, Yinchuan 750002, China.

Glycyrrhiza uralensis is a saline-alkali-tolerant plant whose aerial parts are 
rich in flavonoids; however, the role of these flavonoids in saline-alkali 
tolerance remains unclear. Herein, we performed physiological, metabolomics, and 
transcriptomics analyses in G. uralensis leaves under alkaline salt stress for 
different durations. Alkaline salt stress stimulated excessive accumulation of 
reactive oxygen species and consequently destroyed the cell membrane, causing 
cell death, and G. uralensis initiated osmotic regulation and the antioxidant 
system to respond to stress. In total, 803 metabolites, including 244 
flavonoids, were detected via metabolomics analysis. Differentially altered 
metabolites and differentially expressed genes were coenriched in 
flavonoid-related pathways. Genes such as novel.4890, Glyur001511s00039602, and 
Glyur000775s00025737 were highly expressed, and flavonoid metabolites such as 
2'-hydroxygenistein, apigenin, and 3-O-methylquercetin were upregulated. Thus, 
flavonoids as nonenzymatic antioxidants play an important role in stress 
tolerance. These findings provide novel insights into the response of G. 
uralensis to alkaline salt stress.

DOI: 10.1021/acs.jafc.3c07139
PMID: 38416716 [Indexed for MEDLINE]


5. Plants (Basel). 2023 Jul 28;12(15):2801. doi: 10.3390/plants12152801.

Chemical Constituents from Ficus sagittifolia Stem Bark and Their Antimicrobial 
Activities.

Taiwo OM(1)(2), Olaoluwa OO(1), Aiyelaagbe OO(1), Schmidt TJ(2).

Author information:
(1)Department of Chemistry, University of Ibadan, Ibadan 200284, Nigeria.
(2)University of Münster, Institute of Pharmaceutical Biology and Phytochemistry 
(IPBP), PharmaCampus, Corrensstrasse 48, D-48149 Münster, Germany.

The phytochemical investigation of the ethylacetate fraction of an ethanolic 
extract obtained from the stem bark of Ficus sagittifolia (Moraceae) led to the 
isolation of four flavonoids: (2R)-eriodictyol (1), 2'- hydroxygenistein (2), 
erycibenin A (3), and genistein (4); a dihydrobenzofuran: moracin P (5); a 
coumarin: peucedanol (6); and an apocarotenoid terpenoid: dihydrophaseic acid 
(7). These were identified via 1D and 2D nuclear magnetic resonance spectroscopy 
(NMR) and ultra-high-resolution liquid chromatography-quadrupole time-of-flight 
mass spectroscopy (UHPLC-QTOF MS). Moracin P (5) is being reported for the first 
time in the genus Ficus, while the others are known compounds (1-4 and 6-7) 
isolated previously from the genus but being reported for the first time from 
the species F. sagittifolia. Their antimicrobial activity against various 
pathogens (five bacteria: Escherichia coli, Klebsiella pneumoniae, Pseudomonas 
aeruginosa, Staphylococcus aureus, and Salmonella typhi; two fungi: Aspergillus 
niger and Candida albicans) was tested. The mixture of genistein and moracin P 
(4+5) exhibited strong activity against K. pneumoniae (MIC < 0.0039 mg/mL), 
whereas dihydrophaseic acid (7) was the most active against P. aeruginosa and A. 
niger (MIC = 0.0078 and <0.0039 mg/mL, respectively). These compounds might be 
considered potential antimicrobial agents with the potential to be starting 
points for the development of antimicrobial drugs.

DOI: 10.3390/plants12152801
PMCID: PMC10420693
PMID: 37570957

Conflict of interest statement: The authors declare no conflict of interest.