Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Inflammopharmacology. 2024 Oct 29. doi: 10.1007/s10787-024-01573-1. Online
ahead  of print.

Anti-inflammatory effects of a methanol extract from Montanoa grandiflora DC. 
(Asteraceae) leaves on in vitro and in vivo models.

Sánchez-Canul M(1), Villa-de la Torre F(1), Borges-Argáez R(2), Huchin-Chan 
C(3), Valencia-Pacheco G(4), Yáñez-Barrientos E(5), Romero-Hernández M(5), 
Alonso-Castro AJ(6), Arana-Argáez VE(7).

Author information:
(1)Laboratorio de Farmacología, Facultad de Química, Universidad Autónoma de 
Yucatán, Calle 43, No 613 x calle 90, Col. Inalámbrica, CP. 97069, Mérida, 
Yucatán, México.
(2)Centro de Investigación Científica de Yucatán, Unidad de Biotecnología, 
Mérida, Yucatán, México.
(3)Laboratorio de Análisis Clínicos y de Servicio a La Comunidad, Facultad de 
Química, Universidad Autónoma de Yucatán, Mérida, Yucatán, México.
(4)Laboratorio de Hematología, Centro de Investigaciones Regionales "Dr. Hideyo 
Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán, México.
(5)Departamento de Química, División de Ciencias Naturales y Exactas, 
Universidad de Guanajuato, Guanajuato, México.
(6)Departamento de Farmacia, División de Ciencias Naturales y Exactas, 
Universidad de Guanajuato, Guanajuato, México.
(7)Laboratorio de Farmacología, Facultad de Química, Universidad Autónoma de 
Yucatán, Calle 43, No 613 x calle 90, Col. Inalámbrica, CP. 97069, Mérida, 
Yucatán, México. victor.arana@correo.uady.mx.

BACKGROUND: Montanoa grandiflora, a plant species native from Mexico to Central 
America, locally known as "Teresita" in Yucatán, México, is used to alleviate 
anxiety, rheumatism, and stomach issues. This study aims to investigate the 
anti-inflammatory properties of the methanol extract of Montanoa grandiflora 
leaves (MMG) in experimental models of inflammation.
METHODS: Gas chromatography-mass spectroscopy was used to characterize the MMG; 
cytotoxicity was assessed by MTT assay on murine macrophages and hemolysis 
assay. The in vitro anti-inflammatory activity was evaluated on LPS-stimulated 
murine macrophages by measuring of pro- and anti-inflammatory cytokines, NO and 
H2O2 release. The in vivo anti-inflammatory activity was evaluated using 
carrageenan-induced mouse paw edema, 12-O-tetradecanoylphorbol 13-acetate 
induced-ear edema, and 1-fluoro-2,4-dinitrobenzene induced-delayed-type 
hypersensitivity. In addition, the serum levels of prostaglandins and 
leukotrienes were assessed.
RESULTS: The main compounds found in MMG were terpenes (i.e., β-caryophyllene, 
(-)-α-cubebene, alloaromadendrene, ( +)-δ-cadinene, β-eudesmol), alkaloid 
(( ±)-nor-β-hydrastine), cyclic polyol (quinic acid), carbohydrates and their 
derivatives, and fatty acids (octadecatrienoic acid and octadecanoic acid). MMG 
did not exhibit cytotoxic or hemolytic activity. However, it demonstrated in 
vitro anti-inflammatory effects by increasing the production of IL-10, 
decreasing the levels of TNF-α, IL-1β, IL-6, NO and H2O2. MMG significantly 
reduced carrageenan-induced paw edema, TPA-induced ear edema, and DNFB-induced 
delayed-type hypersensitivity in mice with effects comparable to those of 
standard drugs, as well as serum levels of prostaglandins and leukotrienes.
CONCLUSION: The anti-inflammatory activity of MMG is associated with increased 
IL-10 levels and inhibiting inflammatory cell migration mechanisms, without 
causing cytotoxic or hemolytic damage in both in vitro and in vivo assays.

© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland 
AG.

DOI: 10.1007/s10787-024-01573-1
PMID: 39472421


2. Chem Biodivers. 2024 Oct 10:e202401886. doi: 10.1002/cbdv.202401886. Online 
ahead of print.

In-silico and In-vitro Investigation of Flavonoids and Alkaloids from Artocarpus 
heterophyllus, Tinospora cordifolia, and Glycosmis pentaphylla as Potential 
NF-κB Inhibitors in Oral Cancer.

Gotsurve KN(1), Das J(2), Kutre S(3), Teja PK(3), Rathod R(4), Chauthe SK(3), 
Behera SK(5).

Author information:
(1)NIPER Ahmedabad, Biotechnology, Gandhinagar, Gandhinagar, INDIA.
(2)National Institute of Pharmaceutical Education and Research Ahmedabad, 
Natural Products, Gandhinagar, Gandhinagar, INDIA.
(3)National Institute of Pharmaceutical Education and Research Ahmedabad, 
Natural Products, Gandhinagar, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION 
AND RESEARCH, Ahmedabad, Gandhina, Gandhinagar, 382355, Gandhinagar, INDIA.
(4)National Institute of Pharmaceutical Education and Research Ahmedabad, CIF, 
Gandhinagar, NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH, 
Ahmedabad, Gandhina, Gandhinagar, 382355, Gandhinagar, INDIA.
(5)National Institute of Pharmaceutical Education and Research Ahmedabad, 
Biothechnology, Opposite air force station, Palaj, Gandhinagar, 382355, 
Gandhinagar, INDIA.

Oral cancer is a global health concern, particularly because of its aggressive 
tissue invasion and metastases, holding 16th position on occurrence among all 
carcinoma worldwide. The aberrated transcription factor NF-κB1 influences 
development and spread of oral cancer, making it a potential therapeutic target. 
This study investigated the therapeutic potential of a few natural compounds 
from Artocarpus heterophyllus, Tinospora cordifolia, and Glycosmis pentaphylla 
in the treatment of oral cancer. Two FDA-approved drugs (5-fluorouracil, 
Docetaxel) and 16 natural compounds, including Artocarpin, Artocarpanone, 
Cycloartocarpin from Artocarpus heterophyllus; Berberine, Hydrastine, 
Magnoflorine, Palmatine Chloride, Tetrahydropalmatine from Tinospora cordifolia; 
and 5-Hydroxyarborinine, 5-Hydroxynoracronycine, 
1-Hydroxy-3-methoxy-10-methyl-9-acridone, Des-N-methylacronycine, 
Des-N-methylnoracronycine, Kokusagenine, Noracronycin, Skimmianine from 
Glycosmis pentaphylla were examined using in-silico techniques. Among the 16 
natural compounds studied, Hydrastine shown the highest binding energy (-6.87 
kcal/mol) against NF-κB1, surpassing all other drugs, including the standards 
5-fluorouracil (-4.04 kcal/mol) and docetaxel (-2.4 kcal/mol). Further molecular 
dynamics simulations and in-vitro experiments verified Hydrastine's exceptional 
anti-cancer activity. The results of in-vitro were well-aligned with the 
findings of in-silico, revealing considerable cytotoxicity, apoptosis induction, 
and cell cycle arrest. The findings revealed natural compounds' potential as 
safer, more effective alternatives to current cancer therapeutics, opening up 
new avenues for oral cancer treatment.

© 2024 Wiley‐VCH GmbH.

DOI: 10.1002/cbdv.202401886
PMID: 39387347


3. Front Neurosci. 2023 Oct 24;17:1259742. doi: 10.3389/fnins.2023.1259742. 
eCollection 2023.

Analysis of damage-associated molecular patterns in amyotrophic lateral 
sclerosis based on ScRNA-seq and bulk RNA-seq data.

Shi Y(1), Zhu R(1).

Author information:
(1)Department of Neurology, The First Affiliated Hospital of China Medical 
University, Shenyang, China.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating 
neurodegenerative disorder characterized by the progressive loss of motor 
neurons. Despite extensive research, the exact etiology of ALS remains elusive. 
Emerging evidence highlights the critical role of the immune system in ALS 
pathogenesis and progression. Damage-Associated Molecular Patterns (DAMPs) are 
endogenous molecules released by stressed or damaged cells, acting as danger 
signals and activating immune responses. However, their specific involvement in 
ALS remains unclear.
METHODS: We obtained single-cell RNA sequencing (scRNA-seq) data of ALS from the 
primary motor cortex in the Gene Expression Omnibus (GEO) database. To better 
understand genes associated with DAMPs, we performed analyses on cell-cell 
communication and trajectory. The abundance of immune-infiltrating cells was 
assessed using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. 
We performed univariate Cox analysis to construct the risk model and utilized 
the least absolute shrinkage and selection operator (LASSO) analysis. Finally, 
we identified potential small molecule drugs targeting ALS by screening the 
Connectivity Map database (CMap) and confirmed their potential through molecular 
docking analysis.
RESULTS: Our study annotated 10 cell types, with the expression of genes related 
to DAMPs predominantly observed in microglia. Analysis of intercellular 
communication revealed 12 ligand-receptor pairs in the pathways associated with 
DAMPs, where microglial cells acted as ligands. Among these pairs, the SPP1-CD44 
pair demonstrated the greatest contribution. Furthermore, trajectory analysis 
demonstrated distinct differentiation fates of different microglial states. 
Additionally, we constructed a risk model incorporating four genes (TRPM2, 
ROCK1, HSP90AA1, and HSPA4). The validity of the risk model was supported by 
multivariate analysis. Moreover, external validation from dataset GSE112681 
confirmed the predictive power of the model, which yielded consistent results 
with datasets GSE112676 and GSE112680. Lastly, the molecular docking analysis 
suggested that five compounds, namely mead-acid, nifedipine, nifekalant, 
androstenol, and hydrastine, hold promise as potential candidates for the 
treatment of ALS.
CONCLUSION: Taken together, our study demonstrated that DAMP entities were 
predominantly observed in microglial cells within the context of ALS. The 
utilization of a prognostic risk model can accurately predict ALS patient 
survival. Additionally, genes related to DAMPs may present viable drug targets 
for ALS therapy.

Copyright © 2023 Shi and Zhu.

DOI: 10.3389/fnins.2023.1259742
PMCID: PMC10628000
PMID: 37942135

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.


4. Drug Metab Dispos. 2023 Nov;51(11):1483-1489. doi: 10.1124/dmd.123.001360.
Epub  2023 Aug 10.

Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases 
Metformin Systemic Exposure in Mice.

Oyanna VO(1), Garcia-Torres KY(1), Bechtold BJ(1), Lynch KD(1), Call MR(1), 
Horváth M(1), Manwill PK(1), Graf TN(1), Cech NB(1), Oberlies NH(1), Paine 
MF(1), Clarke JD(2).

Author information:
(1)Department of Pharmaceutical Sciences, Washington State University, Spokane, 
Washington (V.O.O., K.Y.G.-T., B.J.B., K.D.L., M.R.C., M.F.P., J.D.C.); 
Department of Chemistry and Biochemistry, University of North Carolina at 
Greensboro, North Carolina (P.K.M., T.N.G., N.B.C., N.H.O.); SOLVO 
Biotechnology, Szeged, Hungary (M.H.); and Center of Excellence for Natural 
Product Drug Interaction Research, Spokane, Washington (N.B.C., N.H.O., M.F.P., 
J.D.C.).
(2)Department of Pharmaceutical Sciences, Washington State University, Spokane, 
Washington (V.O.O., K.Y.G.-T., B.J.B., K.D.L., M.R.C., M.F.P., J.D.C.); 
Department of Chemistry and Biochemistry, University of North Carolina at 
Greensboro, North Carolina (P.K.M., T.N.G., N.B.C., N.H.O.); SOLVO 
Biotechnology, Szeged, Hungary (M.H.); and Center of Excellence for Natural 
Product Drug Interaction Research, Spokane, Washington (N.B.C., N.H.O., M.F.P., 
J.D.C.) j.clarke@wsu.edu.

Goldenseal is a perennial plant native to eastern North America. A recent 
clinical study reported goldenseal decreased metformin Cmax and area under the 
blood concentration versus time curve (AUC) by 27% and 23%, respectively, but 
half-life and renal clearance were unchanged. These observations suggested 
goldenseal altered processes involved in metformin absorption. The underlying 
mechanism(s) remain(s) unknown. One mechanism for the decreased metformin 
systemic exposure is inhibition by goldenseal of intestinal uptake transporters 
involved in metformin absorption. Goldenseal extract and three goldenseal 
alkaloids (berberine, (-)-β-hydrastine, hydrastinine) were tested as inhibitors 
of organic cation transporter (OCT) 3, plasma membrane monoamine transporter 
(PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells 
overexpressing each transporter. The goldenseal extract, normalized to berberine 
content, was the strongest inhibitor of each transporter (IC50: 4.9, 13.1, and 
5.8 μM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice 
compared the effects of berberine, (-)-β-hydrastine, goldenseal extract, and 
imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract 
and imatinib significantly decreased metformin Cmax by 31% and 25%, 
respectively, and had no effect on half-life. Berberine and (-)-β-hydrastine had 
no effect on metformin pharmacokinetics, indicating neither alkaloid alone 
precipitated the interaction in vivo. A follow-up murine study involving 
intravenous metformin and oral inhibitors examined the contributions of 
basolateral enteric/hepatic uptake transporters to the goldenseal-metformin 
interaction. Goldenseal extract and imatinib had no effect on metformin AUC and 
half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake 
transporters. Results may have implications for patients taking goldenseal with 
drugs that are substrates for OCT3 and THTR2. SIGNIFICANCE STATEMENT: Goldenseal 
is used to self-treat respiratory infections and digestive disorders. We 
investigated potential mechanisms for the clinical pharmacokinetic interaction 
observed between goldenseal and metformin, specifically inhibition by goldenseal 
of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin 
absorption. Goldenseal extract inhibited all three transporters in vitro and 
decreased metformin systemic exposure in mice. These data may have broader 
implications for patients co-consuming goldenseal with other drugs that are 
substrates for these transporters.

Copyright © 2023 by The Author(s).

DOI: 10.1124/dmd.123.001360
PMCID: PMC10586506
PMID: 37562957 [Indexed for MEDLINE]


5. J Pharmacol Exp Ther. 2023 Dec;387(3):252-264. doi: 10.1124/jpet.123.001681. 
Epub 2023 Aug 4.

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic 
Goldenseal-Midazolam Interaction: Application of In Vitro Assays and 
Physiologically Based Pharmacokinetic Models to Understand Clinical 
Observations.

Nguyen JT(1), Tian DD(1), Tanna RS(1), Arian CM(1), Calamia JC(1), Rettie AE(1), 
Thummel KE(1), Paine MF(2).

Author information:
(1)Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical 
Sciences, Washington State University, Spokane, Washington (J.T.N., D.-D.T., 
R.S.T., M.F.P.); Department of Pharmaceutics (C.M.A., J.C.C., K.E.T.) and 
Department of Medicinal Chemistry (A.E.R.), School of Pharmacy, University of 
Washington, Seattle, Washington; and Center of Excellence for Natural Product 
Drug Interaction Research, Spokane, Washington (A.E.R, K.E.T., M.F.P.).
(2)Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical 
Sciences, Washington State University, Spokane, Washington (J.T.N., D.-D.T., 
R.S.T., M.F.P.); Department of Pharmaceutics (C.M.A., J.C.C., K.E.T.) and 
Department of Medicinal Chemistry (A.E.R.), School of Pharmacy, University of 
Washington, Seattle, Washington; and Center of Excellence for Natural Product 
Drug Interaction Research, Spokane, Washington (A.E.R, K.E.T., M.F.P.) 
mary.paine@wsu.edu.

The natural product goldenseal is a clinical inhibitor of CYP3A activity, as 
evidenced by a 40%-60% increase in midazolam area under the plasma concentration 
versus time curve (AUC) after coadministration with goldenseal. The predominant 
goldenseal alkaloids berberine and (-)-β-hydrastine were previously identified 
as time-dependent CYP3A inhibitors using human liver microsomes. Whether these 
alkaloids contribute to the clinical interaction, as well as the primary 
anatomic site (hepatic vs. intestinal) and mode of CYP3A inhibition (reversible 
vs. time-dependent), remain uncharacterized. The objective of this study was to 
mechanistically assess the pharmacokinetic goldenseal-midazolam interaction 
using an integrated in vitro-in vivo-in silico approach. Using human intestinal 
microsomes, (-)-β-hydrastine was a more potent time-dependent inhibitor of 
midazolam 1'-hydroxylation than berberine (KI and kinact: 8.48 μM and 0.041 
minutes-1, respectively, vs. >250 μM and ∼0.06 minutes-1, respectively). Both 
the AUC and Cmax of midazolam increased by 40%-60% after acute (single 3-g dose) 
and chronic (1 g thrice daily × 6 days) goldenseal administration to healthy 
adults. These increases, coupled with a modest or no increase (≤23%) in 
half-life, suggested that goldenseal primarily inhibited intestinal CYP3A. A 
physiologically based pharmacokinetic interaction model incorporating berberine 
and (-)-β-hydrastine successfully predicted the goldenseal-midazolam interaction 
to within 20% of that observed after both chronic and acute goldenseal 
administration. Simulations implicated (-)-β-hydrastine as the major alkaloid 
precipitating the interaction, primarily via time-dependent inhibition of 
intestinal CYP3A, after chronic and acute goldenseal exposure. Results highlight 
the potential interplay between time-dependent and reversible inhibition of 
intestinal CYP3A as the mechanism underlying natural product-drug interactions, 
even after acute exposure to the precipitant. SIGNIFICANCE STATEMENT: Natural 
products can alter the pharmacokinetics of an object drug, potentially resulting 
in increased off-target effects or decreased efficacy of the drug. The objective 
of this work was to evaluate fundamental mechanisms underlying the clinically 
observed goldenseal-midazolam interaction. Results support the use of an 
integrated approach involving established in vitro assays, clinical evaluation, 
and physiologically based pharmacokinetic modeling to elucidate the complex 
interplay between multiple phytoconstituents and various pharmacokinetic 
processes driving a drug interaction.

Copyright © 2023 by The Author(s).

DOI: 10.1124/jpet.123.001681
PMCID: PMC10658920
PMID: 37541764 [Indexed for MEDLINE]