Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Animal Model Exp Med. 2024 Oct 22. doi: 10.1002/ame2.12483. Online ahead of 
print.

Repetitive transcranial magnetic stimulation elicits weight loss and improved 
insulin sensitivity in type 2 diabetic rats.

Chen X(1), Wang R(1), Wang X(1), Liu M(1), Liu Z(1), Yin T(1), Li C(1).

Author information:
(1)Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical 
Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, 
Tianjin, China.

BACKGROUND: Type 2 diabetes (T2D) accounts for the majority of diabetes 
incidences and remains a widespread global chronic disorder. Apart from early 
lifestyle changes, intervention options for T2D are mainly pharmaceutical.
METHODS: Repetitive transcranial magnetic stimulation (rTMS) has been approved 
by the FDA as a therapeutic intervention option for major depressive disorders, 
with further studies also indicating its role in energy metabolism and appetite. 
Considering its safe and non-invasive properties, we evaluated the effects of 
rTMS on systemic metabolism using T2D rats.
RESULTS: We observed that rTMS improved glucose tolerance and insulin 
sensitivity in T2D rats after a 10-day exposure. Improved systemic insulin 
sensitivity was maintained after a 21-day treatment period, accompanied by 
modest yet significant weight loss. Circulating serum lipid levels, including 
those of cholesteryl ester, tryglyceride and ceramides, were also reduced 
following rTMS application. RNA-seq analyses further revealed a changed 
expression profile of hepatic genes that are related to sterol production and 
fatty acid metabolism. Altered expression of hypothalamic genes that are related 
to appetite regulation, neural activity and ether lipid metabolism were also 
implicated.
CONCLUSION: In summary, our data report a positive impact of rTMS on systemic 
insulin sensitivity and weight management of T2D rats. The underlying mechanisms 
via which rTMS regulates systemic metabolic parameters partially involve lipid 
utilization in the periphery as well as central regulation of energy intake and 
lipid metabolism.

© 2024 The Author(s). Animal Models and Experimental Medicine published by John 
Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory 
Animal Sciences.

DOI: 10.1002/ame2.12483
PMID: 39439134


2. J Lipid Res. 2024 Oct 10:100670. doi: 10.1016/j.jlr.2024.100670. Online ahead
of  print.

6-O-Alkyl 4-methylumbelliferyl-β-D-glucosides as selective substrates for GBA1 
in the discovery of glycosylated sterols.

Bannink S(1), Bila KO(1), van Weperen J(1), Ligthart NAM(1), Ferraz MJ(1), Boot 
RG(1), van der Vliet D(2), Boer DEC(1), Overkleeft HS(3), Artola M(4), Aerts 
JMFG(5).

Author information:
(1)Medical Biochemistry, Leiden Institute of Chemistry (LIC), Leiden University, 
2300 RA Leiden, The Netherlands.
(2)Molecular Physiology, Leiden Institute of Chemistry (LIC), Leiden University, 
2300 RA Leiden, The Netherlands.
(3)Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden 
University, 2300 RA Leiden, The Netherlands.
(4)Medical Biochemistry, Leiden Institute of Chemistry (LIC), Leiden University, 
2300 RA Leiden, The Netherlands. Electronic address: 
m.e.artola@lic.leidenuniv.nl.
(5)Medical Biochemistry, Leiden Institute of Chemistry (LIC), Leiden University, 
2300 RA Leiden, The Netherlands. Electronic address: 
j.m.f.g.aerts@lic.leidenuniv.nl.

Gaucher disease (GD) is a lysosomal storage disorder (LSD) resulting from 
inherited glucocerebrosidase (GBA1) deficiency. GD diagnosis relies on GBA1 
activity assays, typically employing 4-methylumbelliferyl-β-D-glucopyranoside 
(4MU-β-Glc) as fluorogenic substrate. However, these assays suffer from 
background 4MU release by the non-lysosomal GBA2 and cytosolic GBA3 enzymes. 
Here we developed GBA1-selective fluorogenic substrates by synthesizing a series 
of 6-O-acyl-4MU-β-Glc substrates with diverse fatty acid tails. Because of 
chemical and enzymatic instability of the ester bonds, analogues of 
6-O-palmitoyl-4MU-β-Glc (3) with different chemical linkages were synthesized. 
6-O-alkyl-4MU-β-Glc 9, featuring an ether linkage, emerged as the most optimal 
GBA1 substrate, exhibiting both a low Km and compared to substrate 3 a high 
Vmax. Importantly, substrate 9 is not hydrolyzed by GBA2 and GBA3, and therefore 
acts as superior substrate for GD diagnosis. Plants contain glycosyl 
phytosterols (campesterol, β-sitosterol and sigmasterol) that may also be 
acylated at C-6. LC-MS/MS analysis revealed that 6-O-acylated and regular 
glycosylcholesterol (HexChol) tend to be increased in GD patient spleens. 
Moreover, significant increases in 6-O-acyl-glycosyl-phytosterols were detected 
in GD spleens. Our findings suggest uptake of (6-O-acyl)-glycosyl-phytosterols 
from plant food and subsequent lysosomal processing by GBA1, and comprise the 
first example of accumulation of an exogenous class of glycolipids in GD. 
Excessive exposure of rodents to glycosylated phytosterols has been reported to 
induce manifestations of Parkinson's disease (PD). Further investigation is 
warranted to determine whether (6-O-acyl)-glycosyl-phytosterols could contribute 
to the enigmatic link between inherited defects in GBA1 and the risk for PD.

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jlr.2024.100670
PMID: 39395789


3. J Exp Clin Cancer Res. 2024 Jul 25;43(1):207. doi: 10.1186/s13046-024-03133-5.

Aptamer-functionalized triptolide with release controllability as a promising 
targeted therapy against triple-negative breast cancer.

Chen Y(#)(1), Yang J(#)(1), Wang C(#)(1), Wang T(#)(2), Zeng Y(#)(1), Li X(1), 
Zuo Y(1), Chen H(1), Zhang C(1), Cao Y(1), Sun C(1), Wang M(3), Cao X(1), Ge 
X(1), Liu Y(4), Zhang G(5), Deng Y(6), Peng C(7), Lu A(8), Lu J(9)(10).

Author information:
(1)State Key Laboratory of Southwestern Chinese Medicine Resources, School of 
Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, 
China.
(2)Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & 
Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of 
Electronic Science and Technology of China, Chengdu, 610041, China.
(3)Clinical Research Center, The First Affiliated Hospital of Shantou University 
Medical College, Shantou, 515000, Guangdong Province, China.
(4)Hematology Department, The General Hospital of the Western Theater Command 
PLA, Chengdu, 611137, China.
(5)Institute for Advancing Translational Medicine in Bone & Joint Diseases, 
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, 
China.
(6)State Key Laboratory of Southwestern Chinese Medicine Resources, School of 
Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, 
China. dengyun2000@hotmail.com.
(7)State Key Laboratory of Southwestern Chinese Medicine Resources, School of 
Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, 
China. pengchengchengdu@126.com.
(8)Institute for Advancing Translational Medicine in Bone & Joint Diseases, 
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, 
China. aipinglu@hkbu.edu.hk.
(9)State Key Laboratory of Southwestern Chinese Medicine Resources, School of 
Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, 
China. ljaaa111@163.com.
(10)Institute for Advancing Translational Medicine in Bone & Joint Diseases, 
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, 
China. ljaaa111@163.com.
(#)Contributed equally

Targeted delivery and precise release of toxins is a prospective strategy for 
the treatment of triple-negative breast cancer (TNBC), yet the flexibility to 
incorporate both properties simultaneously remains tremendously challenging in 
the X-drug conjugate fields. As critical components in conjugates, linkers could 
flourish in achieving optimal functionalities. Here, we pioneered a 
pH-hypersensitive tumor-targeting aptamer AS1411-triptolide conjugate (AS-TP) to 
achieve smart release of the toxin and targeted therapy against TNBC. The 
multifunctional acetal ester linker in the AS-TP site-specifically blocked 
triptolide toxicity, quantitatively sustained aptamer targeting, and ensured the 
circulating stability. Furthermore, the aptamer modification endowed triptolide 
with favorable water solubility and bioavailability and facilitated endocytosis 
of conjugated triptolide by TNBC cells in a nucleolin-dependent manner. The 
integrated superiorities of AS-TP promoted the preferential intra-tumor 
triptolide accumulation in xenografted TNBC mice and triggered the in-situ 
triptolide release in the weakly acidic tumor microenvironment, manifesting 
striking anti-TNBC efficacy and virtually eliminated toxic effects beyond 
clinical drugs. This study illustrated the therapeutic potential of AS-TP 
against TNBC and proposed a promising concept for the development of nucleic 
acid-based targeted anticancer drugs.

© 2024. The Author(s).

DOI: 10.1186/s13046-024-03133-5
PMCID: PMC11270970
PMID: 39054545 [Indexed for MEDLINE]

Conflict of interest statement: The authors confirm that they have no conflicts 
of interest with respect to the work described in this manuscript.


4. Genes (Basel). 2024 Jun 19;15(6):810. doi: 10.3390/genes15060810.

Multifactor Analyses of Frontal Cortex Lipids in the APP/PS1 Model of Familial 
Alzheimer's Disease Reveal Anomalies in Responses to Dietary n-3 PUFA and 
Estrogenic Treatments.

Díaz M(1)(2).

Author information:
(1)Membrane Physiology and Biophysics, Department of Physics, School of 
Sciences, University of La Laguna, 38206 Tenerife, Spain.
(2)Instituto Universitario de Neurociencias (IUNE), University of La Laguna, 
38206 Tenerife, Spain.

Brain lipid homeostasis is an absolute requirement for proper functionality of 
nerve cells and neurological performance. Current evidence demonstrates that 
lipid alterations are linked to neurodegenerative diseases, especially 
Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic 
regulation has hampered the identification of critical processes associated with 
the onset and progression of AD. While most experimental studies have focused on 
the effects of known factors on the development of pathological hallmarks in AD, 
e.g., amyloid deposition, tau protein and neurofibrillary tangles, 
neuroinflammation, etc., studies addressing the causative effects of lipid 
alterations remain largely unexplored. In the present study, we have used a 
multifactor approach combining diets containing different amounts of 
polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic 
backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid 
phenotype of the frontal cortex in middle-aged female mice. First, we observed 
that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) 
composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 
LCPUFAs, ether-linked fatty acids, and saturates were also changed by the 
dietary condition, but the extent of changes was dependent on the genetic 
background and hormonal condition. Likewise, brain cortex phospholipids were 
mostly modified by the genotype (FAD>WT) with nuanced effects from dietary 
treatment. Cholesterol (but not sterol esters) was modified by the genotype 
(WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT 
mice). However, the effects of estrogen treatment were mostly observed in 
relation to phospholipid remodeling in a genotype-dependent manner. Analyses of 
lipid-derived variables indicate that nerve cell membrane biophysics were 
significantly affected by the three factors, with lower membrane microviscosity 
(higher fluidity) values obtained for FAD animals. In conclusion, our 
multifactor analyses revealed that the genotype, diet, and estrogen status 
modulate the lipid phenotype of the frontal cortex, both as independent factors 
and through their interactions. Altogether, the outcomes point to potential 
strategies based on dietary and hormonal interventions aimed at stabilizing the 
brain cortex lipid composition in Alzheimer's disease neuropathology.

DOI: 10.3390/genes15060810
PMCID: PMC11202691
PMID: 38927745 [Indexed for MEDLINE]

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


5. Pestic Biochem Physiol. 2024 Jun;202:105950. doi:
10.1016/j.pestbp.2024.105950.  Epub 2024 May 7.

Integrating metabolomics and network toxicology to reveal the mechanism of 
hypoaconitine-induced hepatotoxicity in mice.

Yin Y(1), Qi Y(1), Zhang K(1), Wu J(2), Fan J(1), Xu W(3), Dong L(4).

Author information:
(1)School of Life Sciences, Beijing University of Chinese Medicine, Liangxiang 
Town, Fangshan District, Beijing 102488, China.
(2)School of Chinese Materia Medica, Beijing University of Chinese Medicine, 
Liangxiang Town, Fangshan District, Beijing 102488, China.
(3)School of Life Sciences, Beijing University of Chinese Medicine, Liangxiang 
Town, Fangshan District, Beijing 102488, China. Electronic address: 
cathy_xwj@126.com.
(4)School of Life Sciences, Beijing University of Chinese Medicine, Liangxiang 
Town, Fangshan District, Beijing 102488, China. Electronic address: 
dongling@bucm.edu.cn.

Hypoaconitine (HA), a major secondary metabolite of aconite (a plant-derived 
rodenticide), is a highly toxic di-ester alkaloidal constituent. The toxicity of 
HA is intense with a low LD50. However, studies on its toxicity mechanism have 
mainly focused on cardiotoxicity, with few reports on the mechanism of 
hepatotoxicity. In this study, we combined metabolomics and network toxicology 
to investigate the effects of HA on the liver and analyzed the mechanisms by 
which it causes hepatotoxicity. The results of metabolomics studies indicated 
diethylphosphate, sphingosine-1-phosphate, glycerophosphorylcholine, 
2,8-quinolinediol, guanidinosuccinic acid, and D-proline as differential 
metabolites after HA exposure. These metabolites are involved in eight metabolic 
pathways including arginine and proline metabolism, ether lipid metabolism, 
β-alanine metabolism, sphingolipid metabolism, glutathione metabolism, and 
glycerophospholipid metabolism. Network toxicology analysis of HA may affect the 
HIF-1 signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, 
MAPK signaling pathway, and so on by regulating the targets of ALB, HSP90AA1, 
MMP9, CASP3, and so on. Integrating the results of metabolomics and network 
toxicology, it was concluded that HA may induce hepatotoxicity by triggering 
physiological processes such as oxidative stress, inflammatory response, and 
inducing apoptosis in hepatocytes.

Copyright © 2024 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.pestbp.2024.105950
PMID: 38879305 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest The authors 
declared that there are no conflicts of interest in this paper.