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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 -
Plant Communications Jun 2024
Topics: Nicotiana; Veratrum Alkaloids; Antineoplastic Agents
PubMed: 38308438
DOI: 10.1016/j.xplc.2024.100831 -
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 -
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 -
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 -
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 -
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 -
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 -
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