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Chemical structure of verticine.
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Verticine is the major bioactive constituent of Fritillaria as a kind of Traditional Chinese Medicine. Pharmacological researches have reported various benefits of verticine, including anticancer, anti-inflammatory, protecting against acute lung injury, tracheobronchial relaxation, antitussive, expectorant, sedative, and analgesic activities, in ad...
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Background: Genus Fritillaria is one among the biggest genera of family Liliaceae comprising of around 130–165
species. Fritillaria is viewed as a signifcant genus and a source of signifcant pharmaceutically active compounds
utilized in conventional drugs by folklore. Fritillaria is utilized worldwide as medication and food. Diferent chemically...
Citations
... Professor Luo created Luo's Neiyi prescription, which contains Fritillaria thunbergii. Ma Kun and others believe that the long-term blood stasis syndrome can form cysts, and Fritillaria thunbergii Miq with oyster, litchi, forsythia and orange can promote the disappearance of cysts[22].In this work, fifteen active components of Fritillaria thunbergii Miq were obtained under screening conditions of DL>0.18, and there were 110 corresponding targets. There are 14 overlapping genes in Fritillaria thunbergii Miq and EMs. ...
Objective:
To explore the mechanism of Thunberg Fritillaria in treating endometriosis (EMs) based on network pharmacology and the effect of Peiminine on the MEK/ERK pathway.
Methods:
We applied Chinese medicine system pharmacology analysis platform (TCMSP) database and literature search to screen the main chemical components of Fritillaria thunbergii Miq and created a Vanny map from the databases of TCMSP, GENECARDS, Online Mendelian Inheritance in Man (OMIM), and some others. The STRING database was used to construct the protein interaction network of Fritillaria thunbergii Miq and EMs. The overlapping targets and enriched pathways were discovered using the cells of the innate immune annotation database (DAVID) and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. To test the mechanism of Peiminine, the active ingredients of Fritillaria thunbergii, in the therapy of EMs, we designed cell assays and animal research. EMs mouse models were treated with several therapies, including fibrosis inhibitor in Peiminine by utilizing Hematoxylin-eosin staining (HE staining), MASSON staining, Immunohistochemistry, Immunofluorescence, quantitative real-time PCR (qRT-PCR) experiment, and Western blotting test. We evaluated the anti-endometriotic effects of Peiminine using 12Z human endometriotic cells. Cell Counting Kit 8 was used to assess the vitality of 12z cells (CCK8). We evaluated the migration ability of 12z cells by cell scratch test.
Results:
The effective active ingredients of Fritillaria thunbergii Miq in the treatment of EMs are Pelargonidin, Beta-sitosterol syringaresinol, Peimisine Pelargonidin-3, 5-diglucoside Ziebeimine Zhebeiresinol Verticine Solatubin OSI-2040 Chaksine Peiminine Peiminoside Peiminoside_qt, and 6-Methoxyl-2-acetyl-3-methyl-1, 4-naphthoquinone-8-O-beta-D-glucopyranoside. The critical targets for Fritillaria thunbergii Miq treating EMs are NOS2/PTGS1/AR/PPARG/PTGS2/NCOA2/RXRA/PGR/NR3C1/NCOA1/SLC6A4/OPRM1/BCL2 and ESR1. The results of GO function and KEGG enrichment analysis showed that the role pathway was estrogen-related signaling and thyroid hormone-related signaling. The expression of E-cadherin was decreased in EMs while MEK1/2, P-ERK, N-cadherin and vimentin were all increased in MASSON, immunofluorescence, Real-time PCR and Western blotting. In epithelial 12Z cells, high concentrations of Peiminine can block cell activity and migration, which is directly related to blocking cell fibrosis.
Conclusion:
Overall, this study partially verified the network pharmacological prediction that Peiminine regulates the MAPK pathway in inhibiting 12Z cell proliferation and migration, and finally protects against EMs.
... It is worth noting that verticine is also known as peimine and verticinone is also known as peiminine. Modern pharmacological studies have shown that the alkaloids in BFC have significant antitussive, expectorant, anti-asthmatic, anti-inflammatory, anti-oxidant, antitumor, and angiotensin converting enzyme (ACE) inhibition activities and exhibit good curative effect on cough, sputum, tracheobronchial contraction, acute lung injury, inflammation, and lung cancer Wang et al., 2017b;Zhao et al., 2018b;Yin et al., 2019;Chen et al., 2020c). For example, imperialine is one of the essential steroidal alkaloids of BFC (Lin et al., 2013;Lin et al., 2015). ...
... Verticine was also reported to suppress human lung adenocarcinoma A549/DDP cell proliferation dosedependently and reverse multidrug resistance (MDR). The anti-lung cancer mechanisms of verticine were associated with apoptosis induction along with decreasing of lung resistance protein (LRP) and excision repair cross-complement 1 (ERCC1) mRNA expression (Yin et al., 2019). Imperialine, as quality control component (Ye and Wang, 2014), is one of the active compounds in alkaloids from BFC and is also the antiinflammatory agent. ...
Bulbus fritillariae cirrhosae (BFC) is one of the most used Chinese medicines for lung disease, and exerts antitussive, expectorant, anti-inflammatory, anti-asthmatic, and antioxidant effects, which is an ideal therapeutic drug for respiratory diseases such as ARDS, COPD, asthma, lung cancer, and pulmonary tuberculosis. Through this review, it is found that the therapeutic mechanism of BFC on respiratory diseases exhibits the characteristics of multi-components, multi-targets, and multi-signaling pathways. In particular, the therapeutic potential of BFC in terms of intervention of “cytokine storm”, STAT, NF-κB, and MAPK signaling pathways, as well as the renin-angiotensin system (RAS) that ACE is involved in. In the “cytokine storm” of SARS-CoV-2 infection there is an intense inflammatory response. ACE2 regulates the RAS by degradation of Ang II produced by ACE, which is associated with SARS-CoV-2. For COVID-19, may it be a potential drug? This review summarized the research progress of BFC in the respiratory diseases, discussed the development potentiality of BFC for the treatment of COVID-19, explained the chemical diversity and biological significance of the alkaloids in BFC, and clarified the material basis, molecular targets, and signaling pathways of BFC for the respiratory diseases. We hope this review can provide insights on the drug discovery of anti-COVID-19.
... Pm, also known as verticine, has been related to diverse therapeutic actions [8], including: (i) anti-inflammatory and analgesic, (ii) antitumor, inhibiting proliferation of human leukemia or lung cancer, (iii) expectorant, (iv) sedative, besides its analgesic action, (v) antihypertensive, (vi) a blocker of voltage-dependent ion channels, including both Na + and K + channels, and (vii) antimuscarinic, mainly acting on the M2 receptor subtype. Of note, Pm has a very low oral bioavailability, mainly because of its limited water solubility, and its intestinal absorption seems to take place through active transport, being pH-dependent [9]. ...
... Accordingly, a similar Pm bioavailability was reported after oral administration of Fritillaria thunbergii extracts in rats, with peak plasma concentrations of Pm of roughly 100 nM [31]. These Pm concentrations are several orders of magnitude lower than the IC50s reported for sodium or potassium channels (including hERG), muscarinic receptors, or acethylcholinesterase [8]. Interestingly, submicromolar Pm concentrations elicit a significant inhibition of nAChRs (roughly 20%; Figure 1) and therefore this family of LGIC might be relevant targets of its actions. ...
Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from Fritillaria, is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied if Pm affects nicotinic acetylcholine receptors (nAChRs), since they play broad functional roles, both in the nervous system and non-neuronal tissues. Muscle-type nAChRs were incorporated to Xenopus oocytes and the action of Pm on the membrane currents elicited by ACh (IAChs) was assessed. Functional studies were combined with virtual docking and molecular dynamics assays. Co-application of ACh and Pm reversibly blocked IACh, with an IC50 in the low micromolar range. Pm inhibited nAChR by: (i) open-channel blockade, evidenced by the voltage-dependent inhibition of IAch, (ii) enhancement of nAChR desensitization, revealed by both an accelerated IACh decay and a decelerated IACh deactivation, and (iii) resting-nAChR blockade, deduced from the IACh inhibition elicited by Pm when applied before ACh superfusion. In good concordance, virtual docking and molecular dynamics assays demonstrated that Pm binds to different sites at the nAChR, mostly at the transmembrane domain. Thus, Pm from Fritillaria bulbs, considered therapeutic herbs, targets nAChRs with high affinity, which might account for its anti-inflammatory actions.
... This anti-cancer property of sipeimine is largely due to anti-inflammation action affected by NF-κB inhibition, making it a potential drug candidate for treating cancer at early stages [18]. Recently, Yin and co-workers have reported several therapeutic properties of peimine, including anti-cancer, anti-inflammatory, antitussive, expectorant, and sedative [19]. A more recent study has also demonstrated cough relief by peimine by affecting the systemic network of proteins and pathways [20]. ...
Investigations were carried out to study the effects of light-emitting diode (LED) lights on growth and development of isosteroidal alkaloids in embryogenic calli of Fritillaria cirrhosa D. Don, an important traditional Chinese medicine herb. Calli were cultured in glass bottles, each containing 100 mL of Murashige and Skoog's basal medium supplemented with 2% sucrose and 0.4% gellan gum powder, a gelling agent. These bottles were incubated in a specially designed plant growth chamber equipped with eight different LED lights consisting of single or combinations of four different light spectra emitting blue (450 nm), green (525 nm), red (660 nm), and far-red (730 nm) light. After three months of incubation, morphological changes in embryogenic calli were recorded, and LC-MS/MS analysis of cultures was carried out for peimisine, sipeimine, peiminine, and peimine. The highest number of somatic embryos and the maximum fresh weight was recorded in calli incubated under red (9R), infrared (9IR), and a combination of red+blue+infrared (3R3B3IR), respectively, in decreasing order. The highest contents of peimisine, peiminine, and peimine were recorded under red (9R) and infrared (9IR) lights, respectively. Eight LED lights had significant effects on the morphogenesis of embryogenic calli of F. cirrhosa D. Don and contents of isosteroidal alkaloids.
... As a complementary and alternative medicine, Fritillariae Thunbergii Bulbus (FTB), listed in the Pharmacopeia of the People's Republic of China, has been widely used to suppress cough and resolve phlegm for thousands of years [12,13]. The alkaloid peimine (also called verticine) ( Figure 1A), is the major bioactive and characterized compound of FTB [13,14]. Our previous study used gas chromatography-mass spectrometry to show that peimine is abundant in the bulbs, flowers, leaves, and stems of FTB [15]. ...
... Our previous study used gas chromatography-mass spectrometry to show that peimine is abundant in the bulbs, flowers, leaves, and stems of FTB [15]. Peimine has several pharmacological benefits, including anticancer and antiinflammatory actions, protection against acute lung injury, and promotion of tracheobronchial relaxation as well as antitussive, expectorant, sedative, and analgesic activities [14]. However, most of the therapeutic targets and mechanisms of actions of peimine in relief from cough remain unclear, which impedes the discovery of novel drugs from natural products. ...
Peimine (also known as verticine) is the major bioactive and characterized compound of Fritillariae Thunbergii Bulbus, a traditional Chinese medicine that is most frequently used to relieve a cough. Nevertheless, its molecular targets and mechanisms of action for cough are still not clear. In the present study, potential targets of peimine for cough were identified using computational target fishing combined with manual database mining. In addition, protein-protein interaction (PPI), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using, GeneMANIA and Database for Annotation, Visualization and Integrated Discovery (DAVID) databases respectively. Finally, an interaction network of drug-targets-pathways was constructed using Cytoscape. The results identified 23 potential targets of peimine associated with cough, and suggested that MAPK1, AKT1 and PPKCB may be important targets of pemine for the treatment of cough. The functional annotations of protein targets were related to the regulation of immunological and neurological function through specific biological processes and related pathways. A visual representation of the multiple targets and pathways that form a network underlying the systematic actions of peimine was generated. In summary, peimine is predicted to exert its systemic pharmacological effects on cough by targeting a network composed of multiple proteins and pathways.
Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. Unlike acute pain, which is short-term and starts suddenly in response to an injury, neuropathic pain arises from somatosensory nervous system damage or disease, is usually chronic, and makes every day functioning difficult, substantially reducing quality of life. The main reason for the lack of effective pharmacotherapies for neuropathic pain is its diverse etiology and the complex, still poorly understood, pathophysiological mechanism of its progression. Numerous experimental studies, including ours, conducted over the last several decades have shown that the development of neuropathic pain is based on disturbances in cell activity, imbalances in the production of pronociceptive factors, and changes in signaling pathways such as p38MAPK, ERK, JNK, NF-κB, PI3K, and NRF2, which could become important targets for pharmacotherapy in the future. Despite the availability of many different analgesics, relieving neuropathic pain is still extremely difficult and requires a multidirectional, individual approach. We would like to point out that an increasing amount of data indicates that nonselective compounds directed at more than one molecular target exert promising analgesic effects. In our review, we characterize four substances (minocycline, astaxanthin, fisetin, and peimine) with analgesic properties that result from a wide spectrum of actions, including the modulation of MAPKs and other factors. We would like to draw attention to these selected substances since, in preclinical studies, they show suitable analgesic properties in models of neuropathy of various etiologies, and, importantly, some are already used as dietary supplements; for example, astaxanthin and fisetin protect against oxidative stress and have anti-inflammatory properties. It is worth emphasizing that the results of behavioral tests also indicate their usefulness when combined with opioids, the effectiveness of which decreases when neuropathy develops. Moreover, these substances appear to have additional, beneficial properties for the treatment of diseases that frequently co-occur with neuropathic pain. Therefore, these substances provide hope for the development of modern pharmacological tools to not only treat symptoms but also restore the proper functioning of the human body.
Since ancient times, natural products (NPs) have played a significant role in human health promotion and well-being. They serve as a broad spectrum of molecular diversity with unique molecular chemotypes and as better sources of therapeutics in the absence of viable synthetic leads. Rising health awareness, along with a large body of literature on the therapeutic advantages of phytochemicals, has resurrected the interest in plant-based bioactives in recent times. Plant-based NPs have also been used in ancient systems of medicine, including AYUSH (Ayurveda, Unani, Siddha, and homoeopathy). In the present chapter, recent scientific breakthroughs in the extraction, delivery, and discovery domains of phytochemical pharmacology (extraction methods, nanotechnology, and computational pharmaceutics) have been highlighted in the context of overcoming their major challenges. Further, various pharmaceutical activities and future possibilities for plant-derived compounds in drug development have also been discussed.
Fritillaria Cirrhosa Bulbus (known as chuanbeimu in Chinese, FCB) is one of the most used Chinese medicines for lung disease. However, a variety of substitutes have entered the market, with Fritillaria Pallidiflora Bulbus (FPB) being the most common. Due to their similarity in appearance, morphology, and chemical composition but a large price difference, the FCB has frequently been adulterated with the FPB, posing a serious challenge to the distinction and quality of the FCB. Therefore, we aimed to distinguish FCB and FPB based on their main nine isosteroidal alkaloid contents and test the potential of chemometrics as a discrimination approach for evaluating quality. The nine major isosteroidal alkaloids were measured using a liquid chromatography with tandem mass spectrometry (LC–MS/MS) approach in 41 batches of FCB and 17 batches of FPB. Additionally, they were categorized and distinguished using the methods of hierarchical cluster analysis (HCA) and principal component analysis (PCA). Quantitative analysis revealed that the nine alkaloids were present in different amounts in the two types of Fritillariae bulbus. In FCB, the highest amount was peimisine (17.92–123.53 μg/g) and the lowest was delavine (0.42–29.18 μg/g), while in FPB, imperialine was higher (78.05–344.09 μg/g), but verticinone and verticine were less than the other seven alkaloids. The FCB and FPB were successfully classified and distinguished by the HCA and PCA. Taken together, the method has a good linear relationship (R² > 0.9975). The LOD and LOQ of the nine alkaloids were in the range of 0.0651–0.6510 and 0.1953–1.9531 ng/mL, respectively. The intra- and inter-day precision were shown to be excellent, with relative standard deviations (RSDs) below 1.63% and 2.39%, respectively. The LC–MS/MS method in conjunction with HCA and PCA can effectively differentiate FCB and FPB. It may be a promising strategy for quality evaluation and control at the FCB.
Fritillaria Cirrhosa bulbus (BFC) is a Chinese herbal medicine. In the present study, subchronic toxicities of the ethanol extract from cultivated Fritillaria Cirrhosa bulbus (ECBFC) were performed by oral daily administration in Sprague-Dawley rats. The subchronic toxicity test of ECBFC was conducted at doses of 0.34, 0.68, and 2.04g/kg/day for 90 days (equivalent to the highest human clinical recommend dosage of 25, 50, and 150-fold) with a 4-week satellite group. No mortality or significant changes in behaviors, body weight and food consumption were observed during the experimental and recovery periods. According to the data from ematological analysis, biochemistry, organ coefficient and the results of histopathology, the ECBFC have toxicity to the spleen and liver at the highest (2.04g/kg), medium (0.68g/kg) dose and nephrotoxicity at the highest dose. Subchronic oral toxicity of ECBFC in SD rats (90 days) with NOAEL was 0.34 g/kg and LOAEL was 0.68 g/kg. In addition, the toxicity is gender neutral and reversible. The NOAEL value (0.34g/kg) is 25-fold of the highest human clinical recommend dosage thus the ECBFC could be long-term used as Chinese patent medicine or functional food.
