-
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 -
International Journal of Molecular... Aug 2023The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This...
The apical dendrite of a cortical projection neuron (CPN) is generated from the leading process of the migrating neuron as the neuron completes migration. This transformation occurs in the cortical marginal zone (MZ), a layer that contains the Cajal-Retzius neurons and their axonal projections. Cajal-Retzius neurons (CRNs) are well known for their critical role in secreting Reelin, a glycoprotein that controls dendritogenesis and cell positioning in many regions of the developing brain. In this study, we examine the possibility that CRNs in the MZ may provide additional signals to arriving CPNs, that may promote the maturation of CPNs and thus shape the development of the cortex. We use whole embryonic hemisphere explants and multiphoton microscopy to confirm that CRNs display intracellular calcium transients of <1-min duration and high amplitude during early corticogenesis. In contrast, developing CPNs do not show high-amplitude calcium transients, but instead show a steady increase in intracellular calcium that begins at the time of dendritic initiation, when the leading process of the migrating CPN is encountering the MZ. The possible existence of CRN to CPN communication was revealed by the application of veratridine, a sodium channel activator, which has been shown to preferentially stimulate more mature cells in the MZ at an early developmental time. Surprisingly, veratridine application also triggers large calcium transients in CPNs, which can be partially blocked by a cocktail of antagonists that block glutamate and glycine receptor activation. These findings outline a model in which CRN spontaneous activity triggers the release of glutamate and glycine, neurotransmitters that can trigger intracellular calcium elevations in CPNs. These elevations begin as CPNs initiate dendritogenesis and continue as waves in the post-migratory cells. Moreover, we show that the pharmacological blockade of glutamatergic signaling disrupts migration, while forced expression of a bacterial voltage-gated calcium channel (CavMr) in the migrating neurons promotes dendritic growth and migration arrest. The identification of CRN to CPN signaling during early development provides insight into the observation that many autism-linked genes encode synaptic proteins that, paradoxically, are expressed in the developing cortex well before the appearance of synapses and the establishment of functional circuits.
Topics: Calcium Signaling; Calcium; Veratridine; Neurons; Dendrites; Calcium, Dietary; Glutamic Acid
PubMed: 37629145
DOI: 10.3390/ijms241612965 -
Inflammopharmacology Feb 2024Ulcerative colitis is a chronic inflammatory disorder of the intestinal mucosa and a prevalent gastrointestinal condition in developed countries. Peiminine, derived from...
Ulcerative colitis is a chronic inflammatory disorder of the intestinal mucosa and a prevalent gastrointestinal condition in developed countries. Peiminine, derived from the Fritillaria imperialis plant, exhibits remarkable anti-inflammatory and anti-cancer properties. This study aims to investigate the anti-inflammatory effects of peiminine in an experimental model of ulcerative colitis. Ulcerative colitis was induced intra-rectally in all groups, except the negative control, using 100 μl of 4% acetic acid. Peiminine treatment was initiated after ulcerative colitis induction and symptom manifestation. After the final injection, mice were sacrificed on day 15 for assessment. Various parameters were evaluated, including disease activity index, myeloperoxidase activity, nitric oxide levels, production and expression of IL-1, IL-6, TNF-α cytokines, and expression of IL-1β, IL-6, TNF-α, iNOS, and COX2 genes. Microscopic pathological evaluation was performed on colon tissue. Peiminine treatment resulted in reduced levels of NO, MPO, IL-1β, IL-6, and TNF-α. Furthermore, the expression of IL-1β, IL-6, TNF-α genes, iNOS, and COX2 genes was decreased in response to peiminine treatment in these mice. This study demonstrates the effectiveness of peiminine in alleviating inflammatory manifestations and mitigating intestinal tissue damage in an experimental model of ulcerative colitis, probably by anti-inflammatory procedure. Peiminine holds potential as a therapeutic adjunct for the management of ulcerative colitis.
Topics: Animals; Mice; Acetic Acid; Colitis, Ulcerative; Cyclooxygenase 2; Interleukin-6; Tumor Necrosis Factor-alpha; Anti-Inflammatory Agents; Interleukin-1beta; Nitric Oxide; Cevanes
PubMed: 37855980
DOI: 10.1007/s10787-023-01360-4 -
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 -
Toxins Dec 2023The injudicious and excessive use of synthetic pesticides has deleterious effects on humans, ecosystems, and biodiversity. As an alternative to traditional...
The injudicious and excessive use of synthetic pesticides has deleterious effects on humans, ecosystems, and biodiversity. As an alternative to traditional crop-protection methods, botanical pesticides are gaining importance. In this research endeavor, we examined the contact toxicity, knockdown time, lethal time, and toxicity horizontal transmission of three natural pesticides from plants (azadirachtin, celangulin, and veratramine) on red imported fire ants (RIFA; ). Our research findings indicated that azadirachtin and celangulin exhibited relatively high toxicity, with median lethal dose (LD) values of 0.200 and 0.046 ng/ant, respectively, whereas veratramine exhibited an LD value of 544.610 ng/ant for large workers of at 24 h post-treatment. Upon treatment with 0.125 mg/L, the (median lethal time) LT values of azadirachtin and celangulin were determined to be 60.410 and 9.905 h, respectively. For veratramine, an LT value of 46.967 h was achieved after being tested with 200 mg/L. Remarkably, azadirachtin and celangulin were found to exhibit high horizontal transfer among RIFA, with high secondary mortality (100%) and tertiary mortalities (>61%) after 48 h of treatment with 250 mg/L, as well as with their dust formulations for 72 h. However, veratramine did not exhibit significant toxicity or horizontal transfer effects on RIFA, even at high concentrations. These findings suggest that azadirachtin and celangulin are likely to have a highly prominent potential in the management of .
Topics: Animals; Humans; Pesticides; Fire Ants; Ecosystem; Insecticides; Ants; Veratrum Alkaloids; Limonins
PubMed: 38276530
DOI: 10.3390/toxins16010006 -
International Journal of Molecular... Sep 2023Respiratory syncytial virus (RSV) RNA synthesis takes place in cytoplasmic viral factories also called inclusion bodies (IBs), which are membrane-less organelles...
Respiratory syncytial virus (RSV) RNA synthesis takes place in cytoplasmic viral factories also called inclusion bodies (IBs), which are membrane-less organelles concentrating the viral RNA polymerase complex. The assembly of IBs is driven by liquid-liquid phase separation promoted by interactions between the viral nucleoprotein N and the phosphoprotein P. We recently demonstrated that cyclopamine (CPM) inhibits RSV multiplication by disorganizing and hardening IBs. Although a single mutation in the viral transcription factor M2-1 induced resistance to CPM, the mechanism of action of CPM still remains to be characterized. Here, using FRAP experiments on reconstituted pseudo-IBs both in cellula and in vitro, we first demonstrated that CPM activity depends on the presence of M2-1 together with N and P. We showed that CPM impairs the competition between P and RNA binding to M2-1. As mutations on both P and M2-1 induced resistance against CPM activity, we suggest that CPM may affect the dynamics of the M2-1-P interaction, thereby affecting the relative mobility of the proteins contained in RSV IBs. Overall, our results reveal that stabilizing viral protein-protein interactions is an attractive new antiviral approach. They pave the way for the rational chemical optimization of new specific anti-RSV molecules.
Topics: RNA; Respiratory Syncytial Virus, Human; Veratrum Alkaloids; Inclusion Bodies
PubMed: 37762166
DOI: 10.3390/ijms241813862 -
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 -
Radiation Research May 2024The current geopolitical context has brought the radiological nuclear risk to the forefront of concerns. High-dose localized radiation exposure leads to the development... (Comparative Study)
Comparative Study
The current geopolitical context has brought the radiological nuclear risk to the forefront of concerns. High-dose localized radiation exposure leads to the development of a musculocutaneous radiation syndrome affecting the skin and subcutaneous muscles. Despite the implementation of a gold standard treatment based on an invasive surgical procedure coupled with autologous cell therapy, a muscular defect frequently persists. Targeting the modulation of the Hedgehog (Hh) signaling pathway appears to be a promising therapeutic approach. Activation of this pathway enhances cell survival and promotes proliferation after irradiation, while inhibition by Cyclopamine facilitates differentiation. In this study, we compared the effects of three antagonists of Hh, Cyclopamine (CA), Vismodegib (VDG) and Sonidegib (SDG) on differentiation. A stable cell line of murine myoblasts, C2C12, was exposed to X-ray radiation (5 Gy) and treated with CA, VDG or SDG. Analysis of proliferation, survival (apoptosis), morphology, myogenesis genes expression and proteins production were performed. According to the results, VDG does not have a significant impact on C2C12 cells. SDG increases the expression/production of differentiation markers to a similar extent as CA, while morphologically, SDG proves to be more effective than CA. To conclude, SDG can be used in the same way as CA but already has a marketing authorization with an indication against basal cell cancers, facilitating their use in vivo. This proof of concept demonstrates that SDG represents a promising alternative to CA to promotes differentiation of murine myoblasts. Future studies on isolated and cultured satellite cells and in vivo will test this proof of concept.
Topics: Animals; Mice; Hedgehog Proteins; Muscle, Skeletal; Signal Transduction; Cell Line; Regeneration; Pyridines; Veratrum Alkaloids; Anilides; Biphenyl Compounds; Cell Proliferation; Cell Differentiation; Cell Survival; Apoptosis; Muscle Development
PubMed: 38253061
DOI: 10.1667/RADE-23-00140.1 -
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 -
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