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Science (New York, N.Y.) Jun 2009Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of...
Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; Pancreatic Neoplasms; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Stromal Cells; Veratrum Alkaloids; Zinc Finger Protein GLI1; Gemcitabine
PubMed: 19460966
DOI: 10.1126/science.1171362 -
Clinical Toxicology (Philadelphia, Pa.) Dec 2022The genus is composed of plants containing a diverse set of steroidal alkaloids. plant material has been utilized for centuries as herbal medicines, however the...
INTRODUCTION
The genus is composed of plants containing a diverse set of steroidal alkaloids. plant material has been utilized for centuries as herbal medicines, however the alkaloids have such a low therapeutic index that they are not used in modern medicine. Here we report an incident of inadvertent ingestion of by hikers in Georgia that allowed detection, and in several instances identification of alkaloids from the plant, and correlated their presence within patient blood and breast milk specimens.
CASE HISTORY
Eight patients, three male and five female, presented in the spring of 2020 and 2021 with symptoms requiring emergent medical attention after ingestion of All patients believed the plants to be a local native species of wild leek, , locally known as ramps. Plants were identified using photographs as well as fresh and cooked plant material provided by patients, in consultation with botanists at the University of Georgia Herbarium. Written consent was obtained from all patients for collection of blood and breast milk specimens for laboratory identification of alkaloids.
METHODS
plant material, and patient serum and breast milk were analyzed by high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF) to identify steroidal alkaloids.
RESULTS
The extract was confirmed to contain cyclopamine, veratramine, jervine, and muldamine. Two out of the eight patients had detectable concentrations of alkaloids. Of the alkaloids identified in the plant, cyclopamine and jervine were detected within patient serum, and cyclopamine and veratramine were observed to be present in breast milk.
DISCUSSION
Toxicity resulting from steroidal alkaloids has primarily been reported from and . This is the second report of poisoning. The present work reports for the first time the presence of muldamine and jervine within . This work provides the first instance of identification of alkaloids in breast milk. Thus, the findings presented herein add to literature record causative agents contributing to the toxicity of when ingested and potential for secondary poisoning through breastfeeding.
CONCLUSION
toxicity was observed to cause nausea, vomiting, hypotension, bradycardia, abdominal pain, light-headedness, blurred vision, and tingling in the arms. Patients experiencing mild symptoms improved with supportive care, IV fluids, and antiemetics, but hemodynamically unstable patients required atropine and vasopressors. This study demonstrated that more lipophilic alkaloids can be passed along in breast milk, which suggests additional precautions may be critical to limit further poisonings.
Topics: Female; Humans; Veratrum; Milk, Human; Veratrum Alkaloids; Alkaloids; Plant Poisoning
PubMed: 36301078
DOI: 10.1080/15563650.2022.2132166 -
Toxins Jul 2022Jervine, protoveratrine A (proA), and protoveratrine B (proB) are alkaloids that are presented in some remedies obtained from , such as . This paper reports on a...
Jervine, protoveratrine A (proA), and protoveratrine B (proB) are alkaloids that are presented in some remedies obtained from , such as . This paper reports on a single-center pilot cardiotoxic mechanism study of jervine, proA, and proB in case series. The molecular aspects were studied via molecular dynamic simulation, molecular docking with cardiac sodium channel Na1.5, and machine learning-based structure-activity relationship modeling. HPLC-MS/MS method in combination with clinical events were used to analyze alkaloid cardiotoxicity in patients. Jervine demonstrates the highest docking score (-10.8 kcal/mol), logP value (4.188), and p value (9.64) compared with proA and proB. Also, this compound is characterized by the lowest calculated IC. In general, all three analyzed alkaloids show the affinity to Na1.5 that highly likely results in cardiotoxic action. The clinical data of seven cases of intoxication by confirms the results of molecular modeling. Patients exhibited nausea, muscle weakness, bradycardia, and arterial hypotension. The association between alkaloid concentrations in blood and urine and severity of patient condition is described. These experiments, while primary, confirmed that jervine, proA, and proB contribute to cardiotoxicity by Na1.5 inhibition.
Topics: Alkaloids; Cardiotoxicity; Humans; Molecular Docking Simulation; Pilot Projects; Tandem Mass Spectrometry; Veratrum; Veratrum Alkaloids
PubMed: 35878228
DOI: 10.3390/toxins14070490 -
International Journal of Molecular... Oct 2021Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies.
METHODS
We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search.
RESULTS
Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit.
CONCLUSION
Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.
Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Dermatology; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Prognosis; Pyridines; Signal Transduction; Skin Neoplasms; Treatment Outcome; Veratrum Alkaloids
PubMed: 34639065
DOI: 10.3390/ijms221910725 -
Scientific Reports May 2023Veratrum (Melanthiaceae; Liliales) is a genus of perennial herbs known for the production of unique bioactive steroidal alkaloids. However, the biosynthesis of these...
Veratrum (Melanthiaceae; Liliales) is a genus of perennial herbs known for the production of unique bioactive steroidal alkaloids. However, the biosynthesis of these compounds is incompletely understood because many of the downstream enzymatic steps have yet to be resolved. RNA-Seq is a powerful method that can be used to identify candidate genes involved in metabolic pathways by comparing the transcriptomes of metabolically active tissues to controls lacking the pathway of interest. The root and leaf transcriptomes of wild Veratrum maackii and Veratrum nigrum plants were sequenced and 437,820 clean reads were assembled into 203,912 unigenes, 47.67% of which were annotated. We identified 235 differentially expressed unigenes potentially involved in the synthesis of steroidal alkaloids. Twenty unigenes, including new candidate cytochrome P450 monooxygenases and transcription factors, were selected for validation by quantitative real-time PCR. Most candidate genes were expressed at higher levels in roots than leaves but showed a consistent profile across both species. Among the 20 unigenes putatively involved in the synthesis of steroidal alkaloids, 14 were already known. We identified three new CYP450 candidates (CYP76A2, CYP76B6 and CYP76AH1) and three new transcription factor candidates (ERF1A, bHLH13 and bHLH66). We propose that ERF1A, CYP90G1-1 and CYP76AH1 are specifically involved in the key steps of steroidal alkaloid biosynthesis in V. maackii roots. Our data represent the first cross-species analysis of steroidal alkaloid biosynthesis in the genus Veratrum and indicate that the metabolic properties of V. maackii and V. nigrum are broadly conserved despite their distinct alkaloid profiles.
Topics: Veratrum; Transcriptome; Alkaloids; Gene Expression Profiling; Veratrum Alkaloids; Steroids; Cytochrome P-450 Enzyme System
PubMed: 37211560
DOI: 10.1038/s41598-023-35429-5 -
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 -
Zeitschrift Fur Naturforschung. C,... 2010Twelve steroidal alkaloids were isolated from four populations of Veratrum lobelianum Bernh. and Veratrum nigrum L. Full NMR data for veralosinine (1), and extensive 1H...
Twelve steroidal alkaloids were isolated from four populations of Veratrum lobelianum Bernh. and Veratrum nigrum L. Full NMR data for veralosinine (1), and extensive 1H NMR data for veralosine (3) and teinemine (5) are presented here for the first time. (+/-)-15-O-(2-Methylbutyroyl)germine (10) is undescribed up to now. The antiproliferative activities of veranigrine, veralosinine, and neogermitrine have shown that they are a perspective for further studies.
Topics: Animals; Bulgaria; Cell Division; Leukemia L5178; Magnetic Resonance Spectroscopy; Medicine, Traditional; Mice; Models, Molecular; Mongolia; Phytosterols; Veratrum; Veratrum Alkaloids
PubMed: 20469637
DOI: 10.1515/znc-2010-3-405 -
Computational and Mathematical Methods... 2022and record that Radix Veratri root is and the root of . According to () , Radix Veratri is a Liliaceae plant Veratrum taliense. Another literature pointed out that...
BACKGROUND
and record that Radix Veratri root is and the root of . According to () , Radix Veratri is a Liliaceae plant Veratrum taliense. Another literature pointed out that the aliases of Veratrum taliense and Veratrum angustifolia are both Radix Veratri, and their effects are basically the same. The main active ingredient of Veratrum is veratramine, of which veratramine and Jervine are higher in content, reaching 24.60% and 21.28% of the total alkaloids, respectively. Veratrum alkaloids are both toxic and effective ingredients. In addition to its good clinical efficacy, attention should also be paid to its pharmacokinetic characteristics in vivo. It is particularly important to study the pharmacokinetic characteristics of veratramine and Jervine in vivo.
OBJECTIVE
The goal of this study was to develop a simple and effective method for measuring veratramine and Jervine in rat plasma at the same time. This method was used to study the pharmacokinetic characteristics of veratramine and Jervine in the alcohol extract of Radix Veratri in rats, to provide a reasonable basis for the clinical use of Radix Veratri.
METHODS
Eighteen SD rats were randomly assigned into three groups, half male and half female, and were given 0.04 g/kg, 0.08g/kg, and 0.16 g/kg Radix Veratri alcohol extract, respectively. Blood samples were collected at different time points and were analyzed by LC-MS/MS after protein precipitation. Bullatine was set as the internal standard; the plasma samples were extracted with ethyl acetate. After the sample was processed, acetonitrile-10 mM ammonium acetate, whose pH was adjusted to 8.8 with ammonia water, was taken as the mobile phase. Veratramine quantitative ion pair was 410.1⟶295.1/, Jervine quantitative ion pair was 426.2⟶114.1/, and Bullatine B (IS) quantitative ion pair was 438.2⟶420.1/. In the positive ion mode, the multireaction monitoring (MRM) mode was used to determine the blood concentration of veratramine and Jervine. DAS 3.3.0 was used to calculate the relevant pharmacokinetic parameters.
RESULTS
Veratramine had a good linear relationship in the concentration range of 0.0745~18.2 ng/mL, and that of Jervine was 1.11~108 ng/mL. The correlation coefficient of three consecutive batches of the standard curve was greater than 0.995. Veratramine's lower quantification limit was 0.745 ng/mL, Jervine's was 1.11 ng/mL, and precision and accuracy were both less than 15%. The accuracy of veratramine was between 88.96% and 101.85%, and the accuracy of Jervine was between 92.96% and 104.50%. This method was adopted for the pharmacokinetic study of alcohol extracts of Radix Veratri. The results showed that only of veratramine female rats did not show linear kinetic characteristics in the dose range of Radix Veratri alcohol extract from 0.04 g/kg to 0.16 g/kg. For AUC and of veratramine and Jervine, it could not determine whether the Radix Veratri alcohol extract showed linear kinetic characteristics within the dosage range of 0.04 g/kg~0.16 g/kg. Veratramine and Jervine showed obvious gender differences in the absorption and elimination stages. The absorption rate of veratramine and Jervine by male mice was about 10 times higher than that of female mice, and the elimination rate of male mice is about 20 times lower than that of female mice. It was suggested that the clinical application of the steroidal alkaloids veratramine and Jervine in Radix Veratri required rational use of drugs based on gender.
CONCLUSION
An LC-MS/MS analysis method suitable for the pharmacokinetic study of veratramine and Jervine in Radix Veratri in SD rats was established to provide a basis for in vivo pharmacokinetic studies. The pharmacokinetic characteristics of veratramine and Jervine in the alcohol extract of Radix Veratri were significantly different in female and male rats. During the clinical use of Radix Veratri, it should pay close attention to the obvious gender differences that may occur after the medication.
Topics: Alkaloids; Animals; Chromatography, Liquid; Female; Humans; Male; Mice; Plant Extracts; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Veratrum; Veratrum Alkaloids
PubMed: 35785141
DOI: 10.1155/2022/8289548 -
British Journal of Pharmacology Nov 2003The endocannabinoids N-arachidonylethanolamine (AEA or anandamide) and 2-arachidonylglycerol (2-AG) are hypothesized to function in the brain as interneuronal signaling... (Review)
Review
The endocannabinoids N-arachidonylethanolamine (AEA or anandamide) and 2-arachidonylglycerol (2-AG) are hypothesized to function in the brain as interneuronal signaling molecules. Prevailing models of the actions of these molecules require that they traverse cellular plasma membranes twice; first, following cellular synthesis and second, prior to enzymatic hydrolysis. The transmembrane movement of AEA has been studied in multiple laboratories with a primary focus on its cellular accumulation following extracellular administration. Although there are areas of consensus among laboratories regarding AEA accumulation, several aspects are very unclear. In particular, there is a lack of consensus in the literature regarding the importance of AEA hydrolysis by fatty acid amide hydrolase in maintaining the driving force for accumulation. Furthermore, evidence for and against a transmembrane carrier protein has been published. We have reviewed the available literature and present a working model of the processes that are involved in the cellular accumulation of AEA. It is our hypothesis that transmembrane movement of AEA is regulated by concentration gradient between extracellular and intracellular free AEA. Furthermore, it is our view that a significant portion of the intracellular AEA in most cells is sequestered either by a protein or lipid compartment and that AEA sequestered in this manner does not equilibrate directly with the extracellular pool. Finally, we discuss the available data that have been presented in support of a transmembrane carrier protein for AEA.
Topics: Animals; Arachidonic Acids; Biological Transport; Cell Membrane; Endocannabinoids; Humans; Polyunsaturated Alkamides; Veratridine
PubMed: 12970089
DOI: 10.1038/sj.bjp.0705468 -
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