Worldwide, there are plants known as psychoactive plants that naturally contain psychedelic active components. They have a high concentration of neuroprotective substances that can interact with the nervous system to produce psychedelic effects. Despite these plants' hazardous potential, recreational use of them is on the rise because of their psychoactive properties. Early neuroscience studies relied heavily on psychoactive plants and plant natural products (NPs), and both recreational and hazardous NPs have contributed significantly to the understanding of almost all neurotransmitter systems. Worldwide, there are many plants that contain psychoactive properties, and people have been using them for ages. Psychoactive plant compounds may significantly alter how people perceive the world.
1. Bioorg Med Chem. 2024 Oct 3;115:117938. doi: 10.1016/j.bmc.2024.117938. Online ahead of print. 2-Arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropanoic acids as selective and effective carboxylesterase inhibitors with powerful antioxidant potential. Burgart YV(1), Makhaeva GF(2), Khudina OG(1), Krasnykh OP(3), Kovaleva NV(2), Elkina NA(1), Boltneva NP(2), Rudakova EV(2), Lushchekina SV(4), Shchegolkov EV(1), Triandafilova GA(3), Malysheva KO(3), Serebryakova OG(2), Borisevich SS(5), Ilyina MG(5), Zhilina EF(1), Saloutin VI(1), Charushin VN(1), Richardson RJ(6). Author information: (1)Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Science, S. Kovalevskaya St., 22, Ekaterinburg 620108, Russia. (2)Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Severny proezd 1, Chernogolovka 142432, Russia. (3)Perm National Research Polytechnic University, Komsomolsky Av., 29, Perm 614990,Russia. (4)Department of Brain Sciences, Weizmann Institute of Science, Rehovot 761001, Israel. (5)Ufa Institute of Chemistry of Russian Academy of Science, Octyabrya Av., 71, Ufa 450078, Russia. (6)Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Institute for Computational Discovery and Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Michigan Institute for Data and AI in Society, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: rjrich@umich.edu. A series of 2-arylhydrazinylidene-3-oxo acids (AHOAs) was prepared by dealkylation of alkyl-2-arylhydrazinylidene-3-oxo-3-alkanoates with AlBr3. Using X-Ray, NMR spectroscopy, and quantum mechanical calculations (QM), the existence of AHOAs in a thermodynamically favorable Z-form stabilized by two intramolecular H-bonds was established. All AHOAs had acceptable ADME parameters. The esterase profile study showed that polyfluoroalkyl-AHOAs were effective and selective carboxylesterase (CES) inhibitors, while they were inactive against acetyl- and butyrylcholinesterase. In agreement with molecular docking, the most effective CES inhibitors (IC50 as low as 42 nM) were compounds bearing long polyfluoroalkyl substituents. The acids were also active against hCES1 and hCES2, and CF3-containing acids possessed selectivity against hCES2. Non-fluorinated acids did not inhibit CES, but they exhibited potent antioxidant capability. AHOAs having unsubstituted phenyl or electron-donating groups in the arylhydrazinylidene moiety displayed high primary antioxidant activity in the ABTS, FRAP, and ORAC tests, which did not depend on the substituent in the acyl fragment in the ABTS and ORAC assays. The radical-scavenging mechanism of AHOAs was investigated using QM calculations, showing a preference for cleavage of NH rather than OH bonds. For the lead antioxidants, 4-methoxysubstituted AHOAs, protective effects on erythrocyte membranes in AAPH-induced oxidative stress conditions were shown, including membrane stabilizing activity, inhibition of AAPH-induced lipid peroxidation of erythrocyte membranes, and Fe(II)-chelating ability. Thus, a new class of potent and selective CES inhibitors with powerful antioxidant potential has been developed as promising co-drugs capable of regulating the metabolism of esterified drugs and scavenging reactive radicals that form during Phase I biotransformation. Copyright © 2024 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.bmc.2024.117938 PMID: 39504592 Conflict of interest statement: Declaration of competing interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Rudy J. Richardson reports a relationship with NeuroX1 that includes: board membership. All other 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. Molecules. 2024 Oct 16;29(20):4900. doi: 10.3390/molecules29204900. Mirror-Image RNA: A Right-Handed Z-Form RNA and Its Ligand Complex. Song Y(1), Wang S(1), Xu Y(1). Author information: (1)Division of Chemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Until now, Z-form RNAs were believed to only adopt a left-handed double-helix structure. In this study, we describe the first observation of a right-handed Z-form RNA in NMR solution formed by L-nucleic acid RNA and present the first resolution of structure of the complex between a right-handed Z-form RNA and a curaxin ligand. These results provide a platform for the design of topology specific to Z-form-targeting compounds and are valuable for the development of new potent anticancer drugs. DOI: 10.3390/molecules29204900 PMCID: PMC11510240 PMID: 39459268 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no conflicts of interest. 3. J Phys Chem Lett. 2024 Nov 7;15(44):10944-10949. doi: 10.1021/acs.jpclett.4c02685. Epub 2024 Oct 25. Isomer-Specific, Cryogenic Ion Vibrational Spectroscopy Investigation of D(2)- and N(2)-Tagged, Protonated Formic Acid Complexes Using Two-Color, IR-IR Photobleaching. Bocanegra EL(1), Rana A(1), McCoy AB(2), Johnson MA(1). Author information: (1)Sterling Chemistry Laboratory, Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States. (2)Department of Chemistry, University of Washington, Seattle, Washington 98195-1700, United States. Here we analyze cryogenic ion vibrational spectra of tagged protonated formic acid (PFA) with electronic structure and anharmonic vibrational calculations to establish the isomers generated by electrospray ionization (ESI) followed by buffer gas cooling to ∼25 K. Two isomers are identified (the trans form (E,Z) and the cis form (E,E)) and generated in comparable abundance despite the fact that the calculated E,E structure lies 6.40 kJ mol-1 above the E,Z form. A large (∼60 kJ mol-1) barrier separates them such that the E,E form can be kinetically trapped upon cooling in the ion trap. The anticooperativity between the H-bonds of the OH groups is explored by measuring the shift in the D2-bound OH fundamental when a second D2 is attached. Both isomers are observed in the N2-tagged counterparts, displaying the expected red-shifted OH bands. These results indicate that ESI generates both isomers and both must be considered when analyzing cluster spectra based on the PFA core ion. DOI: 10.1021/acs.jpclett.4c02685 PMID: 39451162 4. Cell Death Dis. 2024 Jul 9;15(7):487. doi: 10.1038/s41419-024-06889-y. ZBP1 condensate formation synergizes Z-NAs recognition and signal transduction. Xie F(#)(1), Wu D(#)(1), Huang J(2), Liu X(1), Shen Y(1), Huang J(3), Su Z(4), Li J(5). Author information: (1)Department of Neurology, Huashan Hospital and School of Life Sciences, State Key Laboratory of Genetic Engineering, Fudan University, 200438, Shanghai, China. (2)Department of Parasitology, School of Basic Medical Science, Central South University, Changsha, 410083, Hunan, China. (3)Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China. (4)Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. drsuzhipeng@wmu.edu.cn. (5)Department of Neurology, Huashan Hospital and School of Life Sciences, State Key Laboratory of Genetic Engineering, Fudan University, 200438, Shanghai, China. lijixi@fudan.edu.cn. (#)Contributed equally Z-DNA binding protein 1 (ZBP1) is a crucial player in the intracellular recognition of Z-form nucleic acids (Z-NAs) through its Zαβ domain, initiating downstream interactions with RIPK1 and RIPK3 via RHIM domains. This engagement leads to the assembly of PANoptosomes, ultimately inducing programmed cell death to curb pathogen dissemination. How Zαβ and RHIM domain cooperate to trigger Z-NAs recognition and signal transduction remains unclear. Here, we show that ZBP1 condensate formation facilitates Z-NAs binding and antiviral signal transduction. The ZBP1 Zαβ dimerizes in a concentration-dependent manner, forming characteristic condensates in solutions evidenced by DLS and SAXS methods. ZBP1 exhibits a binding preference for 10-bp length CG (10CG) DNA and Z-RNA ligand, which in turn enhanced Zαβ dimerization, expediting the formation of droplet condensates in vitro and amyloid-like puncta in cells. Subsequent investigations reveal that Zαβ could form condensates with liquid-liquid phase separation property upon HSV and IAV infections, while full-length ZBP1 forms amyloid-like puncta with or without infections. Furthermore, ZBP1 RHIM domains show typical amyloidal fibril characterizations and cross-polymerize with RIPK1 depending on the core motif of 206IQIG209, while mutated ZBP1 could impede necroptosis and antiviral immunity in HT-29 cells. Thus, ZBP1 condensate formation facilitates the recognition of viral Z-NAs and activation of downstream signal transduction via synergic action of different domains, revealing its elaborated mechanism in innate immunity. © 2024. The Author(s). DOI: 10.1038/s41419-024-06889-y PMCID: PMC11233663 PMID: 38982083 [Indexed for MEDLINE] Conflict of interest statement: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. 5. J Biol Chem. 2024 Aug;300(8):107504. doi: 10.1016/j.jbc.2024.107504. Epub 2024 Jun 27. Novel Z-DNA binding domains in giant viruses. Romero MF(1), Krall JB(2), Nichols PJ(2), Vantreeck J(2), Henen MA(2), Dejardin E(3), Schulz F(4), Vicens Q(5), Vögeli B(6), Diallo MA(7). Author information: (1)DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, California, USA. (2)Department of Biochemistry and Molecular Genetics, University of Colorado at Denver, Aurora, Colorado, USA. (3)GIGA I3 - Molecular Immunology and Signal Transduction, University of Liège, Liège, Belgium. (4)DOE Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, California, USA. Electronic address: fschulz@lbl.gov. (5)Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA. Electronic address: qvicens@central.uh.edu. (6)Department of Biochemistry and Molecular Genetics, University of Colorado at Denver, Aurora, Colorado, USA. Electronic address: beat.vogeli@cuanschutz.edu. (7)GIGA I3 - Molecular Immunology and Signal Transduction, University of Liège, Liège, Belgium. Electronic address: mdiallo@uliege.be. Z-nucleic acid structures play vital roles in cellular processes and have implications in innate immunity due to their recognition by Zα domains containing proteins (Z-DNA/Z-RNA binding proteins, ZBPs). Although Zα domains have been identified in six proteins, including viral E3L, ORF112, and I73R, as well as, cellular ADAR1, ZBP1, and PKZ, their prevalence across living organisms remains largely unexplored. In this study, we introduce a computational approach to predict Zα domains, leading to the revelation of previously unidentified Zα domain-containing proteins in eukaryotic organisms, including non-metazoan species. Our findings encompass the discovery of new ZBPs in previously unexplored giant viruses, members of the Nucleocytoviricota phylum. Through experimental validation, we confirm the Zα functionality of select proteins, establishing their capability to induce the B-to-Z conversion. Additionally, we identify Zα-like domains within bacterial proteins. While these domains share certain features with Zα domains, they lack the ability to bind to Z-nucleic acids or facilitate the B-to-Z DNA conversion. Our findings significantly expand the ZBP family across a wide spectrum of organisms and raise intriguing questions about the evolutionary origins of Zα-containing proteins. Moreover, our study offers fresh perspectives on the functional significance of Zα domains in virus sensing and innate immunity and opens avenues for exploring hitherto undiscovered functions of ZBPs. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.jbc.2024.107504 PMCID: PMC11298590 PMID: 38944123 [Indexed for MEDLINE] Conflict of interest statement: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article.