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Journal of the American Chemical Society Sep 2023The alkaloids are highly complex steroidal alkaloids characterized by their intricate structural and stereochemical features and exhibit a diverse range of...
The alkaloids are highly complex steroidal alkaloids characterized by their intricate structural and stereochemical features and exhibit a diverse range of pharmacological activities. A new synthetic pathway has been developed to access this family of natural products, which enabled the first total synthesis of (-)-zygadenine. This synthetic route entails the construction of a hexacyclic carbon skeleton through a stereoselective intramolecular Diels-Alder reaction, followed by a radical cyclization. Subsequently, a meticulously designed sequence of redox manipulations was optimized to achieve the synthesis of this highly oxidized alkaloid.
Topics: Stereoisomerism; Cyclization; Biological Products; Carbon; Cycloaddition Reaction
PubMed: 37683183
DOI: 10.1021/jacs.3c08039 -
Phytomedicine : International Journal... Nov 2023Hypertension is a serious global public health issue. Blood pressure (BP) is still not effectively controlled in about 20 - 30% of hypertensive patients. Therefore, it...
BACKGROUND
Hypertension is a serious global public health issue. Blood pressure (BP) is still not effectively controlled in about 20 - 30% of hypertensive patients. Therefore, it is imperative to develop new treatments for hypertension. Veratrum alkaloids were once used for the clinical treatment of hypertension, the mechanism of which is still unclear. It was gradually phased out due to adverse reactions.
PURPOSE
This study aimed to investigate the short-term and long-term hypotensive profiles of different components of Veratrum alkaloids in spontaneously hypertensive rats (SHRs) to unveil their mechanisms of action.
RESULTS
Total Veratrum alkaloid (V), component A (A), and veratramine (M) quickly decreased BP within 30 min of treatment, reduced renal and cardiovascular damage, and improved relevant biochemical indicators (nitric oxide [NO], endothelin-1 [ET-1], angiotensin II [Ang II)], noradrenaline [NE], etc) in SHRs to delay stroke occurrence. Thereinto, A exhibited excellent protective effects in cardiovascular disease. The metabolomic profiles of SHRs treated with V, A, and M were significantly different from those of SHRs treated with vehicle. Thirteen metabolites were identified as potential pharmacodynamic biomarkers. Through Kyoto Encyclopedia of Genes and Genomes analysis, V, A, and M-induced hypotension was mainly related to alterations in nicotinate and nicotinamide metabolism, GABAergic synapses, linoleic acid metabolism, ketone body synthesis and degradation, arginine and proline metabolism, and urea cycle, of which nicotinate and nicotinamide metabolism was the key metabolic pathway to relieve hypertension.
CONCLUSION
This work shows that A is an effective and promising antihypertensive agent for hypertension treatment to reduce BP and hypertensive target organ damage, which is mainly mediated through modulating nicotinate and nicotinamide metabolism, RAS, and NO-ET homeostasis.
Topics: Humans; Animals; Rats; Antihypertensive Agents; Niacin; Veratrum Alkaloids; Hypertension; Data Analysis; Niacinamide
PubMed: 37647672
DOI: 10.1016/j.phymed.2023.155033 -
Journal of the American Chemical Society Oct 2023A concise and enantioselective total synthesis of the alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS)...
A concise and enantioselective total synthesis of the alkaloid cyclopamine is disclosed. This highly convergent synthesis with a 16-step longest linear sequence (LLS) was enabled by a synthesis of the -6,5-heterobicycle via a strain-inducing halocyclization process, a key Tsuji-Trost cyclization to construct the fully substituted, spirocyclic THF motif with exquisite diastereocontrol, and a late-stage ring-closing metathesis (RCM) reaction to forge the central tetrasubstituted olefin.
Topics: Cyclization; Alkenes; Veratrum Alkaloids; Stereoisomerism
PubMed: 37782691
DOI: 10.1021/jacs.3c09085 -
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 -
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 -
Pharmaceuticals (Basel, Switzerland) Jan 2024contains steroidal alkaloids that function as inhibitors of hedgehog (Hh) signaling, a pathway involved in the growth and differentiation of cells and normal tissue...
contains steroidal alkaloids that function as inhibitors of hedgehog (Hh) signaling, a pathway involved in the growth and differentiation of cells and normal tissue development. This same Hh pathway is abnormally active for cell proliferation in more than 20 types of cancer. In this current study, alkaloids have been extracted from the root and rhizome of , followed by their separation into five fractions using high performance liquid chromatography. Mass spectrometry was used to identify the presence of twenty-five alkaloids, nine more than are commonly cited in literature reports, and the Bruker Compass Data Analysis software was used to predict the molecular formula for every detected alkaloid. The Gli activity of the raw extract and each fraction were compared to 0.1 µM cyclopamine, and fractions 1, 2, and 4 showed increased bioactivity through suppression of the Hh signaling pathway. Fractions 2 and 4 had enhanced bioactivity, but fraction 1 was most effective in inhibiting Hh signaling. The composition of fraction 1 consisted of veratrosine, cycloposine, and potential isomers of each.
PubMed: 38256956
DOI: 10.3390/ph17010123 -
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 -
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 -
Molecules (Basel, Switzerland) Oct 2023The phytochemical investigation of Loes. roots resulted in the isolation and characterization of two novel, namely Mengtzeanines A (), Mengtzeanines B (), and eight...
The phytochemical investigation of Loes. roots resulted in the isolation and characterization of two novel, namely Mengtzeanines A (), Mengtzeanines B (), and eight known steroidal alkaloids (-). Their structural properties were assessed though extensive spectroscopic techniques. All constituents - were analyzed for suppression of NO formation in LPS-induced RAW264.7 macrophages. Among them, constituent (Verazine) showed inhibition against LPS-induced NO production (IC = 20.41 μM). Additionally, compound could inhibit the secretion of IL1β, IL6, and TNFα, and downregulate the productions of iNOS and COX2 in LPS-induced RAW264.7 macrophages. Further experiments revealed that exhibited a potent anti-inflammatory level in LPS-stimulated RAW264.7 macrophages via inhibiting NF-κB, and triggering of Keap1/Nrf2/HO-1 axis, implying that compound may be a promising candidate for treating inflammatory disorders.
Topics: Animals; Mice; Veratrum; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; NF-E2-Related Factor 2; Anti-Inflammatory Agents; Alkaloids; NF-kappa B; RAW 264.7 Cells; Nitric Oxide
PubMed: 37894597
DOI: 10.3390/molecules28207116 -
Virus Research Jan 2024Porcine epidemic diarrhea (PED) is a contagious intestinal disease caused by α-coronavirus porcine epidemic diarrhea virus (PEDV). At present, no effective vaccine is...
Porcine epidemic diarrhea (PED) is a contagious intestinal disease caused by α-coronavirus porcine epidemic diarrhea virus (PEDV). At present, no effective vaccine is available to prevent the disease. Therefore, research for novel antivirals is important. This study aimed to identify the antiviral mechanism of Veratramine (VAM), which actively inhibits PEDV replication with a 50 % inhibitory concentration (IC) of ∼5 µM. Upon VAM treatment, both PEDV-nucleocapsid (N) protein level and virus titer decreased significantly. The time-of-addition assay results showed that VAM could inhibit PEDV replication by blocking viral entry. Importantly, VAM could inhibit PEDV-induced phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) activity and further suppress micropinocytosis, which is required for PEDV entry. In addition, PI3K inhibitor LY294002 showed anti-PEDV activity by blocking viral entry as well. Taken together, VAM possessed anti-PEDV properties against the entry stage of PEDV by inhibiting the macropinocytosis pathway by suppressing the PI3K/Akt pathway. VAM could be considered as a lead compound for the development of anti-PEDV drugs and may be used during the viral entry stage of PEDV infection.
Topics: Animals; Chlorocebus aethiops; Coronavirus Infections; Phosphatidylinositol 3-Kinases; Porcine epidemic diarrhea virus; Proto-Oncogene Proteins c-akt; Swine; Swine Diseases; Veratrum Alkaloids; Vero Cells; Virus Internalization
PubMed: 37923169
DOI: 10.1016/j.virusres.2023.199260