Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. J Nat Prod. 2024 Aug 23;87(8):1983-1993. doi: 10.1021/acs.jnatprod.4c00406.
Epub  2024 Aug 13.

Identification of an m6A Natural Inhibitor, Lobeline, That Reverses Lenvatinib 
Resistance in Hepatocellular Tumors.

Zhao L(1), Ma H(2), Jiang Y(3), Li Y(3), Qiao L(3), Chen Y(3), Jiang X(4), Wang 
L(3), Wang S(5), Fan X(6).

Author information:
(1)Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of 
China Medical University, Shenyang, Liaoning 110001, China.
(2)Department of Pharmacology, School of Pharmacy, China Medical University, 
Shenyang, Liaoning 110122, China.
(3)Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 
110016, China.
(4)Department of Analysis and Pharmacology of Traditional Chinese Medicine, 
Shenyang Pharmaceutical University, Shenyang 110016, China.
(5)Department of Nuclear Medicine, The First Hospital of China Medical 
University, Shenyang, Liaoning 110001, China.
(6)Department of Pharmacy, Shengjing Hospital of China Medical University, 
Shenyang, Liaoning 110004, China.

Hepatocellular carcinoma (HCC) is an aggressive cancer that has an effect on 
human health. As a first-line drug for HCC, despite its excellent efficacy, 
lenvatinib (Len) is prone to developing drug resistance in HCC patients. The 
N6-methyladenosine (m6A) modification is not only related to the development of 
HCC but also shows great potential in overcoming HCC resistance. Using Dot Blot, 
our group first screened a small molecule m6A regulator, lobeline (Lob), from a 
library of 390 compounds (mostly natural products). In vitro experiments 
demonstrated that Lob could significantly enhance the sensitivity to Len of 
Len-resistant HCC (HCC/Len) and inhibit migration of resistant cells. In 
Len-resistant cell-derived and patient-derived xenograft models, Lob could 
reverse the resistant phenotype, with reductions in tumor volume of 68% and 60%, 
respectively. Furthermore, MeRIP-m6A sequencing results indicated that the 
underlying molecular mechanism of Lob reversal of HCC drug resistance was 
related to UBE3B. Taken together, this study highlighted that Lob, a plant 
derived natural product, could reverse the resistance of HCC to Len by 
regulating the m6A levels. It is hoped that this will provide a pharmacological 
research basis for the clinical treatment of HCC patients.

DOI: 10.1021/acs.jnatprod.4c00406
PMID: 39136667 [Indexed for MEDLINE]


2. Mol Pharm. 2024 Aug 5;21(8):4169-4182. doi: 10.1021/acs.molpharmaceut.4c00651.
 Epub 2024 Jul 22.

Multispectroscopic and Theoretical Investigation on the Binding Interaction of a 
Neurodegenerative Drug, Lobeline with Human Serum Albumin: Perturbation in 
Protein Conformation and Hydrophobic-Hydrophilic Surface.

Rupreo V(1), Tissopi R(1), Baruah K(2), Roy AS(2), Bhattacharyya J(1).

Author information:
(1)Department of Chemistry, National Institute of Technology Nagaland, 
Chumukedima, Nagaland 797103, India.
(2)Department of Chemical & Biological Sciences, National Institute of 
Technology Meghalaya, Shillong 793003, India.

Lobeline (LOB), a naturally occurring alkaloid, has a broad spectrum of 
pharmacological activities and therapeutic potential, including applications in 
central nervous system disorders, drug misuse, multidrug resistance, smoking 
cessation, depression, and epilepsy. LOB represents a promising compound for 
developing treatments in various medical fields. However, despite extensive 
pharmacological profiling, the biophysical interaction between the LOB and 
proteins remains largely unexplored. In the current article, a range of 
complementary photophysical and cheminformatics methodologies were applied to 
study the interaction mechanism between LOB and the carrier protein HSA. 
Steady-state fluorescence and fluorescence lifetime experiments confirmed the 
static-quenching mechanisms in the HSA-LOB system. "K" (binding constant) of the 
HSA-LOB system was determined to be 105 M-1, with a single preferable binding 
site in HSA. The forces governing the HSA-LOB stable complex were analyzed by 
thermodynamic parameters and electrostatic contribution. The research also 
investigated how various metal ions affect complex binding. Site-specific 
binding studies depict Site I as probable binding in HSA by LOB. We conducted 
synchronous fluorescence, 3D fluorescence, and circular dichroism studies to 
explore the structural alteration occurring in the microenvironment of amino 
acids. To understand the robustness of the HSA-LOB complex, we used theoretical 
approaches, including molecular docking and MD simulations, and analyzed the 
principal component analysis and free energy landscape. These comprehensive 
studies of the structural features of biomolecules in ligand binding are of 
paramount importance for designing targeted drugs and delivery systems.

DOI: 10.1021/acs.molpharmaceut.4c00651
PMID: 39037173 [Indexed for MEDLINE]


3. Clin Transl Med. 2024 May;14(5):e1680. doi: 10.1002/ctm2.1680.

Targeting c-Myc transactivation by LMNA inhibits tRNA processing essential for 
malate-aspartate shuttle and tumour progression.

Wang J(1), Hong M(1), Cheng Y(1), Wang X(1)(2), Li D(1), Chen G(1), Bao B(3), 
Song J(3), Du X(1), Yang C(1), Zheng L(3), Tong Q(1).

Author information:
(1)Department of Pediatric Surgery, Union Hospital, Tongji Medical College, 
Huazhong University of Science and Technology, Wuhan, Hubei Province, P. R. 
China.
(2)Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong 
University of Science and Technology, Wuhan, Hubei Province, China.
(3)Department of Pathology, Union Hospital, Tongji Medical College, Huazhong 
University of Science and Technology, Wuhan, Hubei Province, P. R. China.

BACKGROUND: A series of studies have demonstrated the emerging involvement of 
transfer RNA (tRNA) processing during the progression of tumours. Nevertheless, 
the roles and regulating mechanisms of tRNA processing genes in neuroblastoma 
(NB), the prevalent malignant tumour outside the brain in children, are yet 
unknown.
METHODS: Analysis of multi-omics results was conducted to identify crucial 
regulators of downstream tRNA processing genes. Co-immunoprecipitation and mass 
spectrometry methods were utilised to measure interaction between proteins. The 
impact of transcriptional regulators on expression of downstream genes was 
measured by dual-luciferase reporter, chromatin immunoprecipitation, western 
blotting and real-time quantitative reverse transcription-polymerase chain 
reaction (RT-PCR) methods. Studies have been conducted to reveal impact and 
mechanisms of transcriptional regulators on biological processes of NB. Survival 
differences were analysed using the log-rank test.
RESULTS: c-Myc was identified as a transcription factor driving tRNA processing 
gene expression and subsequent malate-aspartate shuttle (MAS) in NB cells. 
Mechanistically, c-Myc directly promoted the expression of glutamyl-prolyl-tRNA 
synthetase (EPRS) and leucyl-tRNA synthetase (LARS), resulting in translational 
up-regulation of glutamic-oxaloacetic transaminase 1 (GOT1) as well as malate 
dehydrogenase 1 (MDH1) via inhibiting general control nonrepressed 2 or 
activating mechanistic target of rapamycin signalling. Meanwhile, lamin A (LMNA) 
inhibited c-Myc transactivation via physical interaction, leading to suppression 
of MAS, aerobic glycolysis, tumourigenesis and aggressiveness. Pre-clinically, 
lobeline was discovered as a LMNA-binding compound to facilitate its interaction 
with c-Myc, which inhibited aminoacyl-tRNA synthetase expression, MAS and tumour 
progression of NB, as well as growth of organoid derived from c-Myc knock-in 
mice. Low levels of LMNA or elevated expression of c-Myc, EPRS, LARS, GOT1 or 
MDH1 were linked to a worse outcome and a shorter survival time of clinical NB 
patients.
CONCLUSIONS: These results suggest that targeting c-Myc transactivation by LMNA 
inhibits tRNA processing essential for MAS and tumour progression.

© 2024 The Author(s). Clinical and Translational Medicine published by John 
Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical 
Bioinformatics.

DOI: 10.1002/ctm2.1680
PMCID: PMC11106511
PMID: 38769668 [Indexed for MEDLINE]

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


4. Biochem Pharmacol. 2024 Oct;228:116189. doi: 10.1016/j.bcp.2024.116189. Epub 
2024 Apr 3.

Vesicular monoamine transporter-2 inhibitor JPC-141 prevents 
methamphetamine-induced dopamine toxicity and blocks methamphetamine 
self-administration in rats.

Chandler CM(1), Nickell JR(2), George Wilson A(1), Culver JP(2), Crooks PA(3), 
Bardo MT(1), Dwoskin LP(4).

Author information:
(1)Department of Psychology, University of Kentucky, Lexington, KY, United 
States.
(2)Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 
United States.
(3)Department of Pharmaceutical Sciences, University of Arkansas for Medical 
Sciences, Little Rock, AR, United States.
(4)Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 
United States. Electronic address: ldwoskin@uky.edu.

Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in 
rat models of methamphetamine use disorder. Here, we report on the neurochemical 
and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), 
a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3H]dopamine 
uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for 
VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. 
Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over 
[3H]dofetilide binding to hERG channels expressed by HEK293, suggesting 
relatively low potential for cardiotoxicity. When administered in vivo to rats, 
JPC-141 prevented the METH-induced reduction in striatal dopamine content when 
given either prior to or after a high dose of METH, suggesting a reduction in 
METH-induced dopaminergic neurotoxicity. In behavioral assays, JPC-141 decreased 
METH-stimulated locomotor activity in METH-sensitized rats at doses of JPC-141 
which did not alter locomotor activity in the saline control group. Moreover, 
JPC-141 specifically decreased iv METH self-administration at doses that had no 
effect on food-maintained responding. These findings support the further 
development of VMAT2 inhibitors as pharmacotherapies for individuals with 
methamphetamine use disorder.

Copyright © 2024 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.bcp.2024.116189
PMID: 38580165 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest 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.


5. bioRxiv [Preprint]. 2024 Feb 29:2024.02.27.582299. doi: 
10.1101/2024.02.27.582299.

Taste evolution in an herbivorous drosophilid.

Peláez JN(1), Bernstein S(1), Okoro J(1), Rodas E(1), Liang I(1), Leipertz A(1), 
Marion-Poll F(2)(3), Whiteman NK(1)(4).

Author information:
(1)Department of Integrative Biology, University of California-Berkeley, 
Berkeley, CA 94720, USA.
(2)Evolution, Genomes, Behaviour and Ecology, IDEEV, CNRS, Université 
Paris-Saclay, IRD, Gif-sur-Yvette, France.
(3)Université Paris-Saclay, AgroParisTech, 91120 Palaiseau, France.
(4)Department of Molecular & Cellular Biology, University of 
California-Berkeley, Berkeley, CA 94720, USA.

Plant secondary metabolites pose a challenge for generalist herbivorous insects 
because they are not only potentially toxic, they also may trigger aversion. On 
the contrary, some highly specialized herbivorous insects evolved to use these 
same compounds as 'token stimuli' for unambiguous determination of their host 
plants. Two questions that emerge from these observations are how recently 
derived herbivores evolve to overcome this aversion to plant secondary 
metabolites and the extent to which they evolve increased attraction to these 
same compounds. In this study, we addressed these questions by focusing on the 
evolution of bitter taste preferences in the herbivorous drosophilid Scaptomyza 
flava, which is phylogenetically nested deep in the paraphyletic Drosophila. We 
measured behavioral and neural responses of S. flava and a set of 
non-herbivorous species representing a phylogenetic gradient (S. pallida, S. 
hsui, and D. melanogaster) towards host- and non-host derived bitter plant 
compounds. We observed that S. flava evolved a shift in bitter detection, rather 
than a narrow shift towards glucosinolates, the precursors of mustard-specific 
defense compounds. In a dye-based consumption assay, S. flava exhibited shifts 
in aversion toward the non-mustard bitter, plant-produced alkaloids caffeine and 
lobeline, and reduced aversion towards glucosinolates, whereas the 
non-herbivorous species each showed strong aversion to all bitter compounds 
tested. We then examined whether these changes in bitter preferences of S. flava 
could be explained by changes in sensitivity in the peripheral nervous system 
and compared electrophysiological responses from the labellar sensilla of S. 
flava, S. pallida, and D. melanogaster. Using scanning electron microscopy, we 
also created a map of labellar sensilla in S. flava and S. pallida. We assigned 
each sensillum to a functional sensilla class based on their morphology and 
initial response profiles to bitter and sweet compounds. Despite a high degree 
of conservation in the morphology and spatial placement of sensilla between S. 
flava and S. pallida, electrophysiological studies revealed that S. flava had 
reduced sensitivity to glucosinolates to varying degrees. We found this 
reduction only in I type sensilla. Finally, we speculate on the potential role 
that evolutionary genetic changes in gustatory receptors between S. pallida and 
S. flava may play in driving these patterns. Specifically, we hypothesize that 
the evolution of bitter receptors expressed in I type sensilla may have driven 
the reduced sensitivity observed in S. flava, and ultimately, its reduced bitter 
aversion. The S. flava system showcases the importance of reduced aversion to 
bitter defense compounds in relatively young herbivorous lineages, and how this 
may be achieved at the molecular and physiological level.

DOI: 10.1101/2024.02.27.582299
PMCID: PMC10925181
PMID: 38464294