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Nature Communications Jun 2024Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While...
Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While plant extraction of these compounds suffers from uncertain supply, efficient chemical synthesis approaches are in high demand. Here, we present concise, divergent, and scalable syntheses of veratramine and cyclopamine with 11% and 6.2% overall yield, respectively, from inexpensive dehydro-epi-androsterone. Our synthesis readily provides gram quantities of both target natural products by utilizing a biomimetic rearrangement to form the C-nor-D-homo steroid core and a stereoselective reductive coupling/(bis-)cyclization sequence to establish the (E)/F-ring moiety.
Topics: Veratrum Alkaloids; Stereoisomerism; Cyclization; Biological Products; Molecular Structure
PubMed: 38909052
DOI: 10.1038/s41467-024-49748-2 -
Phytochemical Analysis : PCA Jun 2024Veratrum alkaloids have gained attention due to their toxic effects and potential pharmaceutical applications, particularly in cancer and cardiology. Over 200 alkaloids...
INTRODUCTION
Veratrum alkaloids have gained attention due to their toxic effects and potential pharmaceutical applications, particularly in cancer and cardiology. Over 200 alkaloids are found in species of the Veratrum genus. The alkaloid composition and concentrations can greatly vary in plants depending on factors like species, plant part, location, season, weather, or nutrients.
OBJECTIVE
This study aims an analytical approach to analyze and quantify Veratrum alkaloids in different plant parts of Veratrum species. The purpose is to contribute essential alkaloid concentration data for future research on the pharmacological and toxicological aspects of Veratrum alkaloids.
METHODS
This study focuses on five Veratrum alkaloids (cevadine, jervine, protoveratrine A, veratramine, and veratridine) in three Veratrum species (Veratrum album L., Veratrum californicum Durand, and Veratrum nigrum L.) collected from four German botanical gardens (Dresden, Leipzig, Marburg, and Schellerhau). A liquid-liquid extraction method and a sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) method operating in multiple reaction monitoring (MRM) mode were applied for the alkaloid determination.
RESULTS
Quantification revealed varying alkaloid concentrations among plant parts and Veratrum species in the μg/g to mg/g range. Protoveratrine A exhibited the highest content, while veratramine concentrations were generally lower. Especially in fruit, roots and rootstock of Veratrum album L. alkaloid concentrations were significant high.
CONCLUSION
The developed HPLC-MS/MS method successfully determined Veratrum alkaloid concentrations in plant samples. The study contributes valuable data on Veratrum alkaloid distribution in different species and plant parts, crucial for understanding their potential medicinal and toxicological significance.
PubMed: 38863228
DOI: 10.1002/pca.3401 -
Glia Aug 2024Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells....
Activation of Shh/Smo is sufficient to maintain oligodendrocyte precursor cells in an undifferentiated state and is not necessary for myelin formation and (re)myelination.
Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-Cre (control), Smo/NG2-Cre (loss of function), and SmoM2/NG2-Cre (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.
Topics: Animals; Hedgehog Proteins; Oligodendrocyte Precursor Cells; Smoothened Receptor; Myelin Sheath; Mice, Transgenic; Cell Differentiation; Veratrum Alkaloids; Mice; Remyelination; Oligodendroglia; Mice, Inbred C57BL; Signal Transduction
PubMed: 38771121
DOI: 10.1002/glia.24540 -
Phytochemistry Aug 2024Eight previously undescribed cevanine-type steroidal alkaloids, cirrhosinones I-N and cirrhosinols A-B, along with five known analogs, were isolated from the bulbs of...
Eight previously undescribed cevanine-type steroidal alkaloids, cirrhosinones I-N and cirrhosinols A-B, along with five known analogs, were isolated from the bulbs of Fritillaria cirrhosa D. Don. Their structures were elucidated on the basis of comprehensive analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and single-crystal X-ray diffraction analyses. All compounds revealed weak NO inhibitory activities in the LPS-stimulated NR8383 cells at the concentration of 20 μM, with inhibition ratios ranging from 5.1% to 14.3%.
Topics: Fritillaria; Plant Roots; Molecular Structure; Alkaloids; Cevanes; Nitric Oxide; Lipopolysaccharides; Animals; Molecular Conformation; Crystallography, X-Ray; Cell Line; Rats; Steroids; Dose-Response Relationship, Drug; Structure-Activity Relationship; Models, Molecular
PubMed: 38750709
DOI: 10.1016/j.phytochem.2024.114140 -
Developmental Biology Aug 2024Understanding the developmental processes and signaling pathways involved in larval myogenesis and metamorphosis is crucial for comprehending the life history and...
Understanding the developmental processes and signaling pathways involved in larval myogenesis and metamorphosis is crucial for comprehending the life history and adaptive strategies of marine organisms. In this study, we investigated the temporal and spatial patterns of myogenesis in the mussel Mytilus coruscus (Mc), focusing on the emergence and transformation of major muscle groups during different larval stages. We also explored the role of the Hedgehog (Hh) signaling pathway in regulating myogenesis and larval metamorphosis. The results revealed distinct developmental stages characterized by the emergence of specific muscular components, such as velum retractor muscles and anterior adductor muscles, in D-veliger and umbo larvae, which are responsible for the planktonic stage. In the pediveliger stage, posterior ventral, posterior adductor, and foot muscles appeared. After larval metamorphosis, the velum structure and its corresponding retractor muscles degenerate, indicating the transition from planktonic to benthic life. We observed a conserved pattern of larval musculature development and revealed a high degree of conservation across bivalve species, with comparable emergence times during myogenesis. Furthermore, exposure to the Hh signaling inhibitor cyclopamine impaired larval muscle development, reduced larval swimming activity, and inhibited larval metamorphosis in M. coruscus. Cyclopamine-mediated inhibition of Hh signaling led to reduced expression of four key genes within the Hh signaling pathway (McHh, McPtc, McSmo, and McGli) and the striated myosin heavy chain gene (McMHC). It is hypothesised that the abnormal larval muscle development in cyclopamine-treated groups may be an indirect effect due to disrupted McMHC expression. We provide evidence for the first time that cyclopamine treatment inhibited larval metamorphosis in bivalves, highlighting the potential involvement of Hh signaling in mediating larval muscle development and metamorphosis in M. coruscus. The present study provides insights into the dynamic nature of myogenesis and the regulatory role of the Hh signaling pathway during larval development and metamorphosis in M. coruscus. The results obtained in this study contribute to a better understanding of the evolutionary significance of Hh signaling in bivalves and shed light on the mechanisms underlying larval muscle development and metamorphosis in marine invertebrates.
Topics: Animals; Hedgehog Proteins; Metamorphosis, Biological; Muscle Development; Larva; Mytilus; Signal Transduction; Gene Expression Regulation, Developmental; Veratrum Alkaloids; Muscles
PubMed: 38750688
DOI: 10.1016/j.ydbio.2024.05.007 -
Journal of Ethnopharmacology Sep 2024Veratrum nigrum L. (V. nigrum) is a well-known herb with a lengthy history of use in Asian and European countries. V. nigrum has been traditionally used to treat... (Review)
Review
ETHNOPHARMACOLOGICAL RELEVANCE
Veratrum nigrum L. (V. nigrum) is a well-known herb with a lengthy history of use in Asian and European countries. V. nigrum has been traditionally used to treat epilepsy, hypertension, malignant sores, and stroke, and it possesses emetic and insecticide properties.
AIM OF THE REVIEW
This review summarized the ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and metabolism, and toxicity of V. nigrum as well as its incompatibility with other herbs. Current challenges in the use of V. nigrum and possible future research directions were also discussed.
MATERIALS AND METHODS
Information on V. nigrum was collected from electronic databases such as PubMed, Google Scholar, Web of Science, CNKI, and WanFang DATA; Masterpieces of Traditional Chinese Medicine; local Chinese Materia Medica Standards; and relevant documents.
RESULTS
In ethnomedical practice, V. nigrum has been used as an emetic and insecticide. Approximately 137 compounds have been isolated from V. nigrum, including alkaloids, stilbenes, flavonoids, organic acids, and esters. Its crude extracts and compounds have shown various effects, including anticancer, hypotensive, insecticidal, and antimicrobial activities as well as the ability to improve hemorheological abnormalities. Pharmacokinetic studies have indicated that veratramine (VAM) and jervine have high bioavailability and possibly enterohepatic circulation. In addition, the sex-related pharmacokinetic differences in V. nigrum alkaloids warrant further attention. Toxicological studies have indicated that cevanine-type alkaloids and VAM may be the main toxic components of V. nigrum, and purine metabolism disorders may be related to V. nigrum toxicity. Furthermore, the neurotoxicity and embryotoxicity of V. nigrum have also been observed. The quality control of V. nigrum and the mechanism underlying its incompatibility with other herbs also deserve further research and refinement.
CONCLUSION
This review summarized the existing information on V. nigrum, laying the foundation for further studies on this herb and its safe use. Among the various compounds present in V. nigrum, steroid alkaloids are the most numerous and have high content; furthermore, they are closely related to the pharmacological effects of V. nigrum, but their toxicity can not also be ignored. Given that toxicity is a critical issue limiting the clinical application of V. nigrum, more toxicological studies on V. nigrum and its active ingredients, especially steroid alkaloids, should be conducted in the future to further explore its toxicity targets and the underlying mechanisms and to provide more evidence and recommendations to enhance the safety of its clinical application.
Topics: Humans; Ethnopharmacology; Animals; Phytochemicals; Veratrum; Plant Extracts; Phytotherapy
PubMed: 38663784
DOI: 10.1016/j.jep.2024.118219 -
Archives of Biochemistry and Biophysics Apr 2024Hedgehog (Hh) signaling plays a significant role in embryogenesis and several physiological processes, such as wound healing and organ homeostasis. In a pathological... (Review)
Review
Hedgehog (Hh) signaling plays a significant role in embryogenesis and several physiological processes, such as wound healing and organ homeostasis. In a pathological setting, it is associated with oncogenesis and is responsible for disease progression and poor clinical outcomes. Hedgehog signaling mediates downstream actions via Glioma Associated Oncogene Homolog (GLI) transcription factors. Inhibiting Hh signaling is an important oncological strategy in which inhibitors of the ligands SMO or GLI have been looked at. This review briefly narrates the Hh ligands, signal transduction, the target genes involved and comprehensively describes the numerous inhibitors that have been evaluated for use in various neoplastic settings.
Topics: Humans; Hedgehog Proteins; Signal Transduction; Veratrum Alkaloids; Neoplasms
PubMed: 38432565
DOI: 10.1016/j.abb.2024.109952 -
Biomedicine & Pharmacotherapy =... Apr 2024Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the...
Peiminine, the primary biologically active compound from Fritillaria thunbergii Miq., has demonstrated significant pharmacological activities. Doxorubicin is one of the most potent chemotherapeutic agents for breast cancer (BC). This study was designed to investigate the efficacy and underlying mechanisms of Peiminine combined with Doxorubicin in treating BC. Our results demonstrated that the combination of Peiminine and 1 mg/kg Doxorubicin exhibited more significant suppression of tumor growth compared with the monotherapy in MDA-MB-231 xenograft nude mice model, which is comparable to the effect of 3 mg/kg Doxorubicin in vivo. Notably, the 3 mg/kg Doxorubicin monotherapy resulted in organ toxicity, specifically in the liver and heart, whereas no toxicity was observed in the combination group. In vitro, this combined treatment exhibited a synergistic reduction on the viability of BC cells. Peiminine enhanced the cell cycle arrest and DNA damage induced by Doxorubicin. Furthermore, the combination treatment effectively blocked DNA repair by inhibiting the MAPKs signaling pathways. And ZEB1 knockdown attenuated the combined effect of Peiminine and Doxorubicin on cell viability and DNA damage. In conclusion, our study found that the combination of Peiminine and Doxorubicin showed synergistic inhibitory effects on BC both in vivo and in vitro through enhancing Doxorubicin-induced DNA damage. These findings support that their combination is a novel and promising therapeutic strategy for treating BC.
Topics: Mice; Animals; Humans; Female; Breast Neoplasms; Mice, Nude; Doxorubicin; DNA Adducts; Cell Line, Tumor; Apoptosis; Zinc Finger E-box-Binding Homeobox 1; Cevanes
PubMed: 38432128
DOI: 10.1016/j.biopha.2024.116353 -
Tissue & Cell Apr 2024Peiminine (PMI) is an active alkaloid sourced from Fritillaria thunbergii, which has been shown to suppress the development of a variety of tumors. Whereas, the roles...
BACKGROUND
Peiminine (PMI) is an active alkaloid sourced from Fritillaria thunbergii, which has been shown to suppress the development of a variety of tumors. Whereas, the roles and precise mechanism of PMI in breast cancer (BC) development remain not been clarified.
METHODS
The cytotoxic effect of PMI on MCF-10A and BC cell lines (MCF-7 and BT-549) were assessed by MTT and LDH release assay. Cell proliferation was evaluated by EdU staining. Levels of Malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH) activity and iron assay were measured by Enzyme linked immunosorbent assay (ELISA) kits, respectively. Transmission Electron Microscope was performed to observe mitochondrial morphological structure. Immunofluorescence, immunohistochemistry, and western blot were conducted to examine protein levels, respectively. Xenograft model was used to confirm cellular findings.
RESULTS
PMI treatment reduced the viability and enhanced LDH level of MCF-7 and BT-549 cells in a time- and concentration-dependent manner, and further suppressed cell proliferation in vitro and tumor growth in vivo. Subsequently, PMI administration resulted in significant increases of ROS, MDA and iron levels, reduction of GSH activity as well as mitochondrial shrinkage and GPX4 reduction, while all these phenomena could be rescued by ferrostatin-1. Mechanistically, PMI treatment led to promoted Nrf2 expression and its nuclear translocation, as well as it's downstream protein HO-1 and NQO1 expressions. Notably, ML-385, a Nrf2 specific inhibitor, greatly reversed the anti-tumor effects and pro-ferroptosis role of PMI in BC cells.
CONCLUSION
Taking these finding together, PMI could stimulate ferroptosis to inhibit BC tumor growth by activating Nrf2-HO-1 signaling pathway.
Topics: Humans; Female; Breast Neoplasms; NF-E2-Related Factor 2; Ferroptosis; Reactive Oxygen Species; Signal Transduction; Iron; Cevanes
PubMed: 38412577
DOI: 10.1016/j.tice.2024.102323 -
Plant Communications Jun 2024
Topics: Nicotiana; Veratrum Alkaloids; Antineoplastic Agents
PubMed: 38308438
DOI: 10.1016/j.xplc.2024.100831