Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Cell Biol Toxicol. 2024 Nov 6;40(1):94. doi: 10.1007/s10565-024-09930-0.

Triptolide induces hepatotoxicity by promoting ferroptosis through Nrf2 
degradation.

Guo L(#)(1), Yang Y(#)(1)(2), Ma J(1), Xiao M(3), Cao R(4), Xi Y(1), Li T(2), 
Huang T(5), Yan M(6).

Author information:
(1)Department of Pharmacy, the Second Xiangya Hospital, Central South 
University, Changsha, 410011, China.
(2)Department of Pharmacy, Wuzhou Gongren Hospital, Wuzhou, 543000, China.
(3)School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical 
University, Nanjing, Jiangsu, 210009, China.
(4)School of Integrated Chinese and Western Medicine, Hunan University of 
Chinese Medicine, Changsha, 410011, China.
(5)Department of Orthopaedic Surgery, the Second Xiangya Hospital, Central South 
University, Changsha, 410011, China.
(6)Department of Pharmacy, the Second Xiangya Hospital, Central South 
University, Changsha, 410011, China. yanmiao@csu.edu.cn.
(#)Contributed equally

BACKGROUND: Triptolide (TP), a principal active substance from Tripterygium 
wilfordii, exhibits various pharmacological effects. However, its potential 
hepatotoxicity has always been a significant concern in clinical applications.
PURPOSE: This research aimed to explore the involvement of ferroptosis in 
TP-mediated hepatic injury and the underlying mechanisms.
METHODS: In this study, in vitro and in vivo experiments were involved. 
Hepatocyte damage caused by TP was evaluated using MTT assays, liver enzyme 
measurement and H&E staining technique. Ferroptosis was assessed by measuring 
iron level, lipid peroxide, glutathione (GSH), mitochondrial morphology and the 
key protein/mRNA expression implicated in ferroptosis. To verify the 
contribution of ferroptosis to TP-induced liver damage, the ferroptosis 
inhibitor Ferrostatin-1 (Fer-1) and a plasmid for overexpressing glutathione 
peroxidase 4 (GPX4) were employed. Subsequently, nuclear factor erythroid 
2-related factor 2 (Nrf2) knockout mice and Nrf2 overexpression plasmid were 
utilized to investigate the underlying mechanisms. Nontargeted lipidomics was 
used to analyze lipid metabolism in mouse liver. Moreover, the cellular thermal 
shift assay (CETSA), cycloheximide (CHX) and MG132 treatments, and 
immunoprecipitation (IP) assays were applied to validate the binding of TP to 
Nrf2 and their interactions.
RESULTS: TP triggered ferroptosis in hepatocytes, as indicated by iron 
accumulation and lipid peroxidation. Ferroptosis was responsible for TP-induced 
hepatic injury. During the process of TP-induced liver damage, the Nrf2 
signaling pathway was significantly suppressed. Notably, the deletion of Nrf2 in 
mice aggravated the extent of liver injury and ferroptosis associated with TP, 
whereas enhancing Nrf2 expression in cells significantly reduced TP-induced 
ferroptosis. Additionally, dysregulation of lipid metabolism was associated with 
TP-induced liver injury. TP may directly bind to Nrf2 and enhance its 
degradation through the ubiquitin-proteasome pathway, thereby inhibiting or 
reducing Nrf2 expression.
CONCLUSION: In summary, the suppression of Nrf2 by TP facilitated the occurrence 
of ferroptosis, resulting in liver damage.

© 2024. The Author(s).

DOI: 10.1007/s10565-024-09930-0
PMID: 39503881 [Indexed for MEDLINE]


2. Front Immunol. 2024 Oct 22;15:1473133. doi: 10.3389/fimmu.2024.1473133. 
eCollection 2024.

Leishmania major surface components and DKK1 signalling via LRP6 promote 
migration and longevity of neutrophils in the infection site.

Ihedioha OC(1), Marcarian HQ(1), Sivakoses A(1), Beverley SM(2), McMahon-Pratt 
D(3), Bothwell ALM(1).

Author information:
(1)Department of Pathology, Microbiology, and Immunology, University of Nebraska 
Medical Center, Omaha, NE, United States.
(2)Department of Molecular Microbiology, Washington University School of 
Medicine in St Louis, St. Louis, MO, United States.
(3)Department of Epidemiology of Infectious Diseases, Yale School of Public 
Health, New Haven, CT, United States.

BACKGROUND: Host-related factors highly regulate the increased circulation of 
neutrophils during Leishmania infection. Platelet-derived Dickkopf-1 (DKK1) is 
established as a high-affinity ligand to LRP6. Recently, we demonstrated that 
DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to 
the draining lymph node and Th2 differentiation during Leishmania infection, 
suggesting the potential involvement of the DKK1-LRP6 signalling pathway in 
neutrophil migration in infectious diseases.
RESULTS: In this study, we further explored the potential role of DKK1-LRP6 
signalling in the migration and longevity of activated neutrophils in the 
infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6NKO) or BALB/c 
mice deficient in both PMN LRP6 and platelet DKK1 (LRP6NKO DKK1PKO). Relative to 
the infected wild-type BALB/c mice, reduced neutrophil activation at the 
infection site of LRP6NKO or LRP6NKO DKK1PKO mice was noted. The neutrophils 
obtained from either infected LRP6NKO or LRP6NKO DKK1PKO mice additionally 
showed a high level of apoptosis. Notably, the level of LRP6 expressing 
neutrophils was elevated in infected BALB/c mice. Relative to infected BALB/c 
mice, a significant reduction in parasite load was observed in both LRP6NKO and 
LRP6NKO DKK1PKO infected mice. Notably, DKK1 levels were comparable in the 
LRP6NKO and BALB/c mice in response to infection, indicating that PMN activation 
is the major pathway for DKK1 in promoting parasitemia. Parasite-specific 
components also play a crucial role in modulating neutrophil circulation in 
Leishmania disease. Thus, we further determine the contribution of Leishmania 
membrane components in the migration of neutrophils to the infection site using 
null mutants deficient in LPG synthesis (Δlpg1- ) or lacking all ether 
phospholipids (plasmalogens, LPG, and GIPLs) synthesis (Δads1- ). Relative to 
the WT controls, Δads1- parasite-infected mice showed a sustained decrease in 
neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while 
neutrophils returned to normal in Δlpg1- parasite-infected mice after day 3 PI.
CONCLUSION: Our results suggest that DKK1 signalling and Leishmania 
pathogen-associated molecular patterns appear to regulate the migration and 
sustenance of viable activated neutrophils in the infection site resulting in 
chronic type 2 cell-mediated inflammation.

Copyright © 2024 Ihedioha, Marcarian, Sivakoses, Beverley, McMahon-Pratt and 
Bothwell.

DOI: 10.3389/fimmu.2024.1473133
PMCID: PMC11534728
PMID: 39502693 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare that the research was 
conducted in the absence of any commercial or financial relationships that could 
be construed as a potential conflict of interest.


3. Int J Nanomedicine. 2024 Nov 1;19:11071-11085. doi: 10.2147/IJN.S476164. 
eCollection 2024.

Penetration Enhancer-Free Mixed Micelles for Improving Eprinomectin Transdermal 
c Efficiency in Animal Parasitic Infections Therapy.

Mao Y(#)(1), Hao T(#)(2), Zhang H(#)(2), Gu X(2), Wang J(1), Shi F(1), Chen 
X(1), Guo L(1), Gao J(1), Shen Y(2), Zhang J(3), Yu S(4).

Author information:
(1)Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, Jiangsu, 225300, 
People's Republic of China.
(2)Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 
210009, People's Republic of China.
(3)Jiangsu Institute for Food and Drug Control, Nanjing, Jiangsu Province, 
210019, People's Republic of China.
(4)College of Animal Medicine, Jiangsu Agri-Animal Husbandry Vocational College, 
Taizhou, People's Republic of China.
(#)Contributed equally

INTRODUCTION: Eprinomectin offers promise against parasitic infections. This 
study develops Eprinomectin (EPR) mixed micelles for transdermal delivery, 
aiming to enhance efficacy and convenience against endoparasites and 
ectoparasites. Physicochemical characterization and pharmacokinetic studies were 
conducted to assess its potential as an effective treatment for parasitic 
infections.
METHODS: Blank and EPR mixed micelles were prepared using PEG-40 Hydrogenated 
castor oil (RH-40) and Nonyl phenol polyoxyethylene ether 40 (NP-40). Critical 
micelle concentrations (CMC) determined using the pyrene fluorescence probe 
method. Particle size, EE, DL, in vitro release, permeation, and skin irritation 
were evaluated. In vivo pharmacokinetic studies were conducted in male 
Sprague-Dawley rats.
RESULTS: Results show that EPR mixed micelles present suitable stability, 
physicochemical properties, and safety. Moreover, the rapid release and high 
bioavailability of EPR mixed micelles have also been verified in the study. 
Pharmacokinetic experiments in vivo showed that an improvement in the 
transdermal absorption and bioavailability of EPR after encapsulation in mixed 
micelles formulations.
CONCLUSION: The results proved that the novel mixed micelles are safe and 
effective and are expected to become a promising veterinary nano-delivery 
system.

© 2024 Mao et al.

DOI: 10.2147/IJN.S476164
PMCID: PMC11537163
PMID: 39502637 [Indexed for MEDLINE]

Conflict of interest statement: The authors report no conflicts of interest in 
this work.


4. Birth Defects Res. 2024 Nov;116(11):e2404. doi: 10.1002/bdr2.2404.

Pharmacological Inhibition of the Spliceosome SF3b Complex by Pladienolide-B 
Elicits Craniofacial Developmental Defects in Mouse and Zebrafish.

Hoshino Y(1)(2), Liu S(3), Furutera T(4), Yamada T(1)(5), Koyabu D(6), Nukada 
Y(7), Miyazawa M(7), Yoda T(5), Ichimura K(4), Iseki S(1), Tasaki J(3), Takechi 
M(1)(4).

Author information:
(1)Department of Molecular Craniofacial Embryology and Oral Histology, Graduate 
School of Medical and Dental Sciences, Tokyo Medical and Dental University 
(TMDU), Tokyo, Japan.
(2)Office of Vaccines, Pharmaceuticals and Medical Devices Agency (PMDA), Japan.
(3)R&D, Safety Science Research, Kao Corporation, Kawasaki, Japan.
(4)Department of Anatomy and Life Structure, Juntendo University Graduate School 
of Medicine, Tokyo, Japan.
(5)Department of Maxillofacial Surgery, Graduate School of Medical and Dental 
Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
(6)Research and Development Center for Precision Medicine, University of 
Tsukuba, Ibaraki, Japan.
(7)R&D, Safety Science Research, Kao Corporation, Tochigi, Japan.

BACKGROUND: Mutations in genes encoding spliceosome components result in 
craniofacial structural defects in humans, referred to as spliceosomopathies. 
The SF3b complex is a crucial unit of the spliceosome, but model organisms 
generated through genetic modification of the complex do not perfectly mimic the 
phenotype of spliceosomopathies. Since the phenotypes are suggested to be 
determined by the extent of spliceosome dysfunction, an alternative experimental 
system that can seamlessly control SF3b function is needed.
METHODS: To establish another experimental system for model organisms 
elucidating relationship between spliceosome function and human diseases, we 
administered Pladienolide-B (PB), a SF3b complex inhibitor, to mouse and 
zebrafish embryos and assessed resulting phenotypes.
RESULTS: PB-treated mouse embryos exhibited neural tube defect and exencephaly, 
accompanied by apoptosis and reduced cell proliferation in the neural tube, but 
normal structure in the midface and jaw. PB administration to heterozygous 
knockout mice of Sf3b4, a gene coding for a SF3b component, influenced the 
formation of cranial neural crest cells (CNCCs). Despite challenges in 
continuous PB administration and a high death rate in mice, PB was stably 
administered to zebrafish embryos, resulting in prolonged survival. Brain, 
cranial nerve, retina, midface, and jaw development were affected, mimicking 
spliceosomopathy phenotypes. Additionally, alterations in cell proliferation, 
cell death, and migration of CNCCs were detected.
CONCLUSIONS: We demonstrated that zebrafish treated with PB exhibited phenotypes 
similar to those observed in human spliceosomopathies. This experimental system 
may serve as a valuable research tool for understanding spliceosome function and 
human diseases.

© 2024 The Author(s). Birth Defects Research published by Wiley Periodicals LLC.

DOI: 10.1002/bdr2.2404
PMID: 39494782 [Indexed for MEDLINE]


5. J Sep Sci. 2024 Nov;47(21):e70014. doi: 10.1002/jssc.70014.

Enhanced Lipidomics Analysis of Breast Cancer Cells Using Three-phase Liquid 
Extraction and Ultra High-performance Liquid Chromatography Coupled With 
Quadrupole Time-of-Flight Tandem Mass Spectrometry.

He B(1), Ye F(1), Feng J(1), Zhou T(1).

Author information:
(1)School of Biology and Biological Engineering, South China University of 
Technology, Guangzhou, China.

Lipid extraction of complex biological samples is essential for high-quality 
data in liquid chromatography-mass spectrometry (LC-MS)-based lipidomics. This 
study introduces a three-phase liquid extraction (3PLE)-ultra-high-performance 
LC coupled with quadrupole time-of-flight tandem MS method. This method was 
successfully applied to lipidomics analysis of breast cancer cells, including 
highly metastatic MDA-MB-231 and slightly metastatic MCF7 cells. The 3PLE method 
employed an n-hexane/methyl tert-butyl ether/acetonitrile/water solvent system 
that formed one aqueous and two organic phases. Neutral and polar lipids were 
enriched in the upper and middle organic phases, respectively, and combined for 
detection, thereby reducing analysis time. Compared with the Bligh and Dyer 
method, 3PLE achieved higher sensitivity and detected more features, with over a 
50% increase in the relative abundance of nearly 50% of the differential lipids. 
In total, 21 differential lipids were identified in the MDA-MB-231 group and 22 
in the MCF7 group compared to normal breast epithelial cells (MCF10A). Pathway 
analysis suggested that lipid changes in breast cancer cells were associated 
with glycerophospholipid metabolism, arachidonic acid metabolism, sphingolipid 
metabolism, and linoleic acid metabolism. The study presents a highly efficient 
lipidomics method, providing a scientific foundation for understanding breast 
cancer pathogenesis and aiding in diagnosis.

© 2024 Wiley‐VCH GmbH.

DOI: 10.1002/jssc.70014
PMID: 39494761 [Indexed for MEDLINE]