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. Commun Biol. 2024 Oct 29;7(1):1410. doi: 10.1038/s42003-024-07100-w. Two ubiquitous aldo-keto reductases in the genus Papaver support a patchwork model for morphine pathway evolution. Carr SC(1)(2), Rehman F(1), Hagel JM(1)(3), Chen X(1), Ng KKS(4), Facchini PJ(5). Author information: (1)Department of Biological Sciences, University of Calgary, Calgary, AB, Canada. (2)Department of Natural Product Biosynthesis, Max Planck Institute for Chemical Ecology, Jena, Germany. (3)Enveric Biosciences Inc., Calgary, AB, Canada. (4)Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada. (5)Department of Biological Sciences, University of Calgary, Calgary, AB, Canada. pfacchin@ucalgary.ca. The evolution of morphinan alkaloid biosynthesis in plants of the genus Papaver includes permutation of several processes including gene duplication, fusion, neofunctionalization, and deletion resulting in the present chemotaxonomy. A critical gene fusion event resulting in the key bifunctional enzyme reticuline epimerase (REPI), which catalyzes the stereochemical inversion of (S)-reticuline, was suggested to precede neofunctionalization of downstream enzymes leading to morphine biosynthesis in opium poppy (Papaver somniferum). The ancestrally related aldo-keto reductases 1,2-dehydroreticuline reductase (DRR), which occurs in some species as a component of REPI, and codeinone reductase (COR) catalyze the second and penultimate steps, respectively, in the pathway converting (S)-reticuline to morphine. Orthologs for each enzyme isolated from the transcriptomes of 12 Papaver species were shown to catalyze their respective reactions in species that capture states of the metabolic pathway prior to key evolutionary events, including the gene fusion event leading to REPI, thus suggesting a patchwork model for pathway evolution. Analysis of the structure and substrate preferences of DRR orthologs in comparison with COR orthologs revealed structure-function relationships underpinning the functional latency of DRR and COR orthologs in the genus Papaver, thus providing insights into the molecular events leading to the evolution of the pathway. © 2024. The Author(s). DOI: 10.1038/s42003-024-07100-w PMCID: PMC11522673 PMID: 39472466 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests. 2. Eur J Case Rep Intern Med. 2024 Aug 5;11(9):004688. doi: 10.12890/2024_004688. eCollection 2024. An Unusual Case of HHV-8 Negative, Idiopathic, Multicentric Castleman Disease Following Chronic Lymphocytic Leukaemia. Sansen PY(1), Vellemans H(1), Depaus J(1), Fervaille C(2), Krug B(3), Sonet A(1), Collinge E(1). Author information: (1)Department of Hematology, CHU UCL Yvoir, Namur, Belgium. (2)Department of Pathology, CHU UCL Yvoir, Namur, Belgium. (3)Department of Nuclear Medicine, CHU UCL Yvoir, Namur, Belgium. BACKGROUND: Castleman disease is a rare condition characterised by polytypic lymphocytes proliferation and lymphadenopathy generally with a benign course. Whereas high grade lymphoma (Richter syndrome) is a classical complication seen in chronic lymphocytic leukaemia with a poor outcome, benign conditions mimicking this entity are infrequent. CASE DESCRIPTION: We describe the case of an 81-year-old Caucasian male who developed a human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) following a treated Binet C chronic lymphocytic leukaemia (CLL). The clinical and radiological pattern raised initially the suspicion of a classical Richter transformation. Blood analysis showed auto-immune haemolytic anaemia and thrombocytopenia. He had normal immunoglobulin levels. The anatomopathological analysis of a cervical adenomegaly showed hypervascularisation and a polytypic plasmocytic proliferation compatible with a plasmocytic iMCD type. Interestingly, bone marrow examination showed reticuline fibrosis but, in the absence of anasarca or generalised oedema, we were not allowed to conclude to the diagnosis of a TAFRO syndrome. We excluded all other mimicking conditions, comprising haematological malignancies, infections, and auto-immune diseases He was first treated with corticosteroids with poor results but dramatically responded to tocilizumab (anti-Il6). CONCLUSION: To our knowledge, this the first case described of a Castleman disease following CLL and surprisingly mimicking Richter syndrome. Clinicians should be aware of this rare misleading condition. LEARNING POINTS: Castleman disease can mimic a Richter transformation in a CLL patient. © EFIM 2024. DOI: 10.12890/2024_004688 PMCID: PMC11379110 PMID: 39247244 Conflict of interest statement: Conflicts of Interests: The Authors declare that there are no competing interests. 3. J Ethnopharmacol. 2024 Sep 7;337(Pt 1):118807. doi: 10.1016/j.jep.2024.118807. Online ahead of print. Extract of Tinospora sinensis alleviates LPS-induced neuroinflammation in mice by regulating TLR4/NF-κB/NLRP3 signaling pathway. Xie Y(1), Fang C(2), Lu L(2), Wang J(2), Wu L(1), Wang S(2), Guo Q(2), Yan W(2), Wei J(2), Duan F(3), Huang L(4). Author information: (1)School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, China; College of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang, China. (2)School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, China. (3)School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, China. Electronic address: dfphunan111@126.com. (4)School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, China; Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, Nanchang, China. Electronic address: jxnchlp@163.com. ETHNOPHARMACOLOGICAL RELEVANCE: The dried rattan stem of Tinospora sinensis (Lour.) Merr. is valued for its efficacy of clearing heat and removing toxicity, calming and soothing the nerves. It is widely used in Tibetan medicine for the treatment of rheumatic and aging diseases. Studies have confirmed its anti-inflammatory and ameliorating effects on Alzheimer's disease; however, the anti-neuroinflammation efficacy and mechanism remain unclear. AIM: This study aimed to explore the anti-neuroinflammation efficacy, major effective ingredients, and potential mechanism of extract of Tinosporae sinenisis (TIS). METHODS: UPLC-Q-TOF/MS was used to identify the compounds of TIS and the plasma components of rats after gastric administration of TIS. C57BL/6 J mice were continuously intraperitoneally injected with lipopolysaccharide (LPS) (250 μg/kg) for 14 d to establish a neuroinflammation model. The effects of TIS (4.5 g/kg, 9 g/kg) on the learning and memory abilities in mice with neuroinflammation was evaluated using spontaneous activity, novel object recognition, and Morris water maze tests. Pathological changes in the hippocampus were observed using hematoxylin and eosin staining. Gene and protein levels of inflammatory factors in the brain were detected using qRT-PCR and ELISA kits. Iba-1 levels in the brain were detected using immunofluorescence to assess the degree of microglial activation. Network pharmacology, based on the components absorbed into plasma of TIS, was used to predict potential targets and pathways. Proteomics was used to study the differentially expressed proteins and related pathways in the brain tissue of mice with neuroinflammation. Finally, correlation analysis was performed on the results of network pharmacology and proteomics, and proteins related the anti-neuroinflammatory effect of TIS were detected by western blot. RESULTS: A total of 39 compounds were identified in TIS: genipingentiobioside, isocorydin, reticuline, (-)-argemonine, tinosineside A, tinosinenside A, and costunolide were absorbed into the plasma. After continuous intraperitoneal injection of LPS into C57BL/6 J mice, microglia in the brain tissue were activated and the gene and protein levels of IL-1β, TNF-α, IL-6, and iNOS were increased in the brain tissue, suggesting that the neuroinflammation model was successfully established. TIS reduced Iba-1 levels and gene expression and protein levels of inflammatory factors in the brain of mice with neuroinflammation. Furthermore, TIS improved the pathological changes in the hippocampus and learning and memory abilities caused by neuroinflammation. Network pharmacology has predicted that TNF, IL-1β, and IκBKB are closely related to neuroinflammation. Proteomics identified key differentially expressed proteins, including TNF, NF-κB2, NF-κBIA, and TLR4. Toll-like receptor (TLR), NF-κB, and NOD-like receptor (NLR) signaling pathways are involved in neuroinflammation-related pathways. Correlation analysis revealed TLR, TNF and NLR signaling pathways were closely related to the anti-neuroinflammatory effects of TIS. We observed that TIS alleviated neuroinflammation by inhibiting the TLR4/NF-κB/NLRP3 pathway. CONCLUSION: Thirty-nine compounds were identified from TIS, among which seven were absorbed into the plasma as prototype components. TIS alleviated LPS-induced neuroinflammation in mice, and its mechanism was related to inhibition of TLR4/NF-κB/NLRP3 signaling pathway. Copyright © 2024 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jep.2024.118807 PMID: 39245241 Conflict of interest statement: Declaration of competing interest We declare that there are no known conflicts of interest associated with this publication. 4. Microb Cell Fact. 2024 Jun 21;23(1):183. doi: 10.1186/s12934-024-02448-4. Metabolic engineering of Saccharomyces cerevisiae for chelerythrine biosynthesis. Zhu J(1), Zhang K(1), He Y(1), Zhang Q(1), Ran Y(1), Tan Z(1), Cui L(2), Feng Y(3). Author information: (1)State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai, 200240, China. (2)State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai, 200240, China. cuili@sjtu.edu.cn. (3)State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai, 200240, China. yfeng2009@sjtu.edu.cn. BACKGROUND: Chelerythrine is an important alkaloid used in agriculture and medicine. However, its structural complexity and low abundance in nature hampers either bulk chemical synthesis or extraction from plants. Here, we reconstructed and optimized the complete biosynthesis pathway for chelerythrine from (S)-reticuline in Saccharomyces cerevisiae using genetic reprogramming. RESULTS: The first-generation strain Z4 capable of producing chelerythrine was obtained via heterologous expression of seven plant-derived enzymes (McoBBE, TfSMT, AmTDC, EcTNMT, PsMSH, EcP6H, and PsCPR) in S. cerevisiae W303-1 A. When this strain was cultured in the synthetic complete (SC) medium supplemented with 100 µM of (S)-reticuline for 10 days, it produced up to 0.34 µg/L chelerythrine. Furthermore, efficient metabolic engineering was performed by integrating multiple-copy rate-limiting genes (TfSMT, AmTDC, EcTNMT, PsMSH, EcP6H, PsCPR, INO2, and AtATR1), tailoring the heme and NADPH engineering, and engineering product trafficking by heterologous expression of MtABCG10 to enhance the metabolic flux of chelerythrine biosynthesis, leading to a nearly 900-fold increase in chelerythrine production. Combined with the cultivation process, chelerythrine was obtained at a titer of 12.61 mg per liter in a 0.5 L bioreactor, which is over 37,000-fold higher than that of the first-generation recombinant strain. CONCLUSIONS: This is the first heterologous reconstruction of the plant-derived pathway to produce chelerythrine in a yeast cell factory. Applying a combinatorial engineering strategy has significantly improved the chelerythrine yield in yeast and is a promising approach for synthesizing functional products using a microbial cell factory. This achievement underscores the potential of metabolic engineering and synthetic biology in revolutionizing natural product biosynthesis. © 2024. The Author(s). DOI: 10.1186/s12934-024-02448-4 PMCID: PMC11191272 PMID: 38902758 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests. 5. Nat Commun. 2024 Jun 19;15(1):5238. doi: 10.1038/s41467-024-49554-w. Intein-mediated temperature control for complete biosynthesis of sanguinarine and its halogenated derivatives in yeast. Gou Y(1)(2), Li D(2), Zhao M(1)(2), Li M(1), Zhang J(2), Zhou Y(2), Xiao F(2), Liu G(2), Ding H(1)(2), Sun C(2), Ye C(1), Dong C(2), Gao J(2), Gao D(1), Bao Z(1)(2), Huang L(1)(2), Xu Z(1), Lian J(3)(4). Author information: (1)Key Laboratory of Biomass Chemical Engineering of Ministry of Education & National Key Laboratory of Biobased Transportation Fuel Technology, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China. (2)ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China. (3)Key Laboratory of Biomass Chemical Engineering of Ministry of Education & National Key Laboratory of Biobased Transportation Fuel Technology, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China. jzlian@zju.edu.cn. (4)ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China. jzlian@zju.edu.cn. While sanguinarine has gained recognition for antimicrobial and antineoplastic activities, its complex conjugated structure and low abundance in plants impede broad applications. Here, we demonstrate the complete biosynthesis of sanguinarine and halogenated derivatives using highly engineered yeast strains. To overcome sanguinarine cytotoxicity, we establish a splicing intein-mediated temperature-responsive gene expression system (SIMTeGES), a simple strategy that decouples cell growth from product synthesis without sacrificing protein activity. To debottleneck sanguinarine biosynthesis, we identify two reticuline oxidases and facilitated functional expression of flavoproteins and cytochrome P450 enzymes via protein molecular engineering. After comprehensive metabolic engineering, we report the production of sanguinarine at a titer of 448.64 mg L-1. Additionally, our engineered strain enables the biosynthesis of fluorinated sanguinarine, showcasing the biotransformation of halogenated derivatives through more than 15 biocatalytic steps. This work serves as a blueprint for utilizing yeast as a scalable platform for biomanufacturing diverse benzylisoquinoline alkaloids and derivatives. © 2024. The Author(s). DOI: 10.1038/s41467-024-49554-w PMCID: PMC11186835 PMID: 38898098 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.