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The primary objective of this study is to evaluate the antitussive, expectorant and anti-inflammatory effects of alkaloids imperialine (I), chuanbeinone (II), verticinone (III), and verticine (IV), which were isolated from the Bulbus Fritillariae Cirrhosae (BFC) using phytochemical method. The results showed that all the alkaloids significantly inh...
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... from the BFC were identified based on spectral data ( 1 H-, 13 C-NMR, DEPT, and mass spectra, etc.). Their structures were determined by comparing the sample's spectral data with those reported in the literature [7][8][9][10]. After column chromatography, we obtained imperialine (I), chuanbeinone (II), verticinone (III), and verticine (IV) Fig. ...
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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...
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 f...
Bulbus Fritillaria Cirrhosae (BFC), known by the Chinese name "Chuan-Bei-Mu", is used as an antitussive, antiasthmatic and expectorant drug for more than 2000 years in China, and Bulbus of Fritillaria wabuensis S. Y. Tang & S. C. Yueh (BFW) was recorded in the 2010 edition of China Pharmacopoeia as one of sources for BFC. The primary objective of t...
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Citations
... Fritillariae Cirrhosae Bulbus belongs to the Fritillaria genus in the Liliaceae family and is mainly found in Southwestern China, is traditionally employed in Chinese medicine for treating diseases like asthma, inflammation, and tumors [18]. The principal active compounds of Fritillariae Cirrhosae Bulbus are alkaloids, manifesting diverse effects such as expectorant, cough suppressant, anti-inflammatory, analgesic, antioxidant, and anti-cancer properties [19,20]. Sipeimine (Sip, also known as imperialine), a steroidal alkaloid derived from Fritillariae Cirrhosae Bulbus, manifests various pharmacological benefits, encompassing anti-asthmatic activity [19], anti-hypotensive effects [21], anti-tumor properties [22], as well as anti-inflammatory and antibacterial activities [23]. ...
... The principal active compounds of Fritillariae Cirrhosae Bulbus are alkaloids, manifesting diverse effects such as expectorant, cough suppressant, anti-inflammatory, analgesic, antioxidant, and anti-cancer properties [19,20]. Sipeimine (Sip, also known as imperialine), a steroidal alkaloid derived from Fritillariae Cirrhosae Bulbus, manifests various pharmacological benefits, encompassing anti-asthmatic activity [19], anti-hypotensive effects [21], anti-tumor properties [22], as well as anti-inflammatory and antibacterial activities [23]. In RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS), Sip exhibited the inhibition of pro-inflammatory mediators, including NO, IL-1β, TNF-α, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), as well as NF-κB [24]. ...
Background
Osteoarthritis (OA) is a chronic and degenerative condition that persists and progresses over time. Sipeimine (Sip), a steroidal alkaloid derived from Fritillariae Cirrhosae Bulbus, has attracted considerable attention due to its exceptional anti-inflammatory, analgesic, antioxidant, and anti-cancer characteristics. However, Sip's effects on OA and its mechanism still need further research.
Methods
This study utilized network pharmacology to identify initial targets for Sip. Functional associations of Sip in OA were clarified through Gene Ontology (GO) enrichment analysis, bioinformatically analyzing a list of targets. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis assessed pathways linked to Sip's therapeutic efficacy in OA. Molecular docking techniques explored Sip's binding affinity with key targets. In vitro experiments assessed Sip's impact on lipopolysaccharide (LPS)-induced pro-inflammatory factors and its protective effects on collagen-II and aggrecan degradation within the extracellular matrix (ECM). Western blotting and fluorescence analyses were conducted to determine Sip-mediated signaling pathways. Moreover, in vivo experiments using a mouse OA model validated Sip's therapeutic efficacy.
Results
The results from network pharmacology revealed a total of 57 candidate targets for Sip in OA treatment. GO enrichment analysis demonstrated a robust correlation between Sip and inflammatory response, response to LPS and NF-κB-inducing kinase activity in OA. KEGG enrichment analysis highlighted the significance of NF-κB and PI3K-AKT pathways in Sip's therapeutic potential for OA. Furthermore, molecular docking results demonstrated Sip's robust binding affinity with p65 and PI3K. In vitro experiments demonstrated Sip's effectively suppressed the expression of pro-inflammatory factors induced by LPS, such as COX-2, iNOS, IL-1β, and IL-18. Besides, Sip counteracted the degradation of collagen-II and aggrecan within the ECM and the expression of MMP-13 and ADAMTS-5 mediated by LPS. The safeguarding effects of Sip were ascribed to its inhibition of PI3K/AKT/NF-κB pathway and NLRP3 inflammasome mediated pyroptosis. Additionally, in vivo experiments revealed that Sip could alleviate the subchondral remodeling, cartilage degeneration, synovitis as well as ECM degradation a mouse model of OA.
Conclusion
Sip exhibited potential in attenuating OA progression by suppressing the PI3K/AKT/NF-κB pathway, consequently inhibiting the activation of NLRP3 inflammasome and pyroptosis.
The translational potential statement
The translational potential of this articleThis study provides a biological rationale for the use of Sip as a potential candidate for OA treatment, provide a new concept for the cartilage targeted application of natural compounds.
... Peimisine, an alkaloid found in CBM, has expectorant and cough-relieving effects. 39 A study has shown that peimisine, a steroid alkaloid from CBM, reduces the expression of p-AKT and phosphorylated glycogen synthase kinase 3β (p-GSK3β), while increasing the expression of phosphorylated myosin light chain 2 (p-MLC2) to prevent the progression of COPD. 38 Meanwhile, peimisine can alleviate inflammation, acute lung injury, and oxidative stress. ...
Background
Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder in pulmonology. Chuanbeimu (CBM) is a traditional Chinese medicinal herb for treating COPD and has been widely utilized in clinical practice. However, the mechanism of CBM in the treatment of COPD remains incompletely understood. This study aims to investigate the underlying therapeutic mechanism of CBM for COPD using network pharmacology and experimental approaches.
Methods
Active ingredients and their targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database. COPD-associated targets were retrieved from the GeneCards database. The common targets for CBM and COPD were identified through Venn diagram analysis. Protein-protein interaction (PPI) networks and disease-herb-ingredient-target networks were constructed. Subsequently, the results of the network pharmacology were validated by molecular docking and in vitro experiments.
Results
Seven active ingredients and 32 potential targets for CBM were identified as closely associated with COPD. The results of the disease-herb-ingredient-target network and PPI network showed that peimisine emerged as the core ingredient, and SRC, ADRB2, MMP2, and NOS3 were the potential targets for CBM in treating COPD. Molecular docking analysis confirmed that peimisine exhibited high binding affinity with SRC, ADRB2, MMP2, and NOS3. In vitro experiments demonstrated that peimisine significantly upregulated the expression of ADRB2 and NOS3 and downregulated the expression of SRC and MMP2.
Conclusion
These findings indicate that CBM may modulate the expression of SRC, ADRB2, MMP2, and NOS3, thereby exerting a protective effect against COPD.
... Peimine, which is extracted from the respiratory Chinese medicine Fritillaria ussuriensis, exerts a variety of pharmacological properties such as antitussive [12], expectorant [13], antitumor [14], antimicrobial [12], anti-inflammation [15], and anti-ulcer [12]. Therefore, peimisine may have a potential anti-UC effect. ...
Objectives
Inflammatory cytokine secretion and gut microbiota dysbiosis play crucial roles in ulcerative colitis. In this research, the protective effects of peimisine on colitis mice were investigated.
Methods
The protective effects were evaluated by the disease activity index, colonic length, hematoxylin–eosin, and AB/PAS Staining. The protective mechanisms were analyzed by ELISA, Western-blot, immunohistochemistry staining, immunofluorescence staining, and 16S rRNA gene analysis.
Key findings
The results showed that peimisine treatment could reduce the disease activity index, prevent colonic shortening, and alleviate colon tissue damage. Peimisine treatment also decreased the levels of MCP-1, IL-1β, IL-6, IFN-γ, TNF-α and affected macrophage polarization and Th17/Treg cell balance by downregulating the expression of jak1/2, p-jak1/2, stat1/3, and p-stat1/3. Moreover, peimisine treatment significantly increased the abundances of beneficial microbes (e.g. Ruminococcaceae UCG-014 and Lachnospiraceae_NK4A136_group) and decreased the abundances of harmful microbes (e.g. Bacteroides and Escherichia).
Conclusions
Peimisine can ameliorate colitis by inhibiting Jak–Stat signaling pathway, reversing gut microbiota alterations, suppressing macrophage M1 polarization, maintaining the Th17/Treg cell balance, and reducing sustained inflammatory cytokines-related inflammatory injury.
... The anti-inflammation experiments were carried out as described previously. 16 Each group was administered once a day for 7 d of 20 mL/kg. An hour after the last administration, 0.05 mL xylene was applied to the anterior and posterior surfaces of the left ear evenly. ...
... Coughing and inflammatory processes have been involved in the pathogenesis of pneumonia. 16 In vivo activity analysis, QFDY showed a significant antiinflammatory effects in the xylene-induced ear edema in mice model. The swelling degree of mice in treatment groups were lower than that in control group, and presented a dose-effect relationship, while TNF-α and IL-6 decreased more significantly in the low dose groups. ...
... Sipeimine (5) has been shown to protect against lung damage induced by fine particulate matter [52,53], while peimisine (6), peimine (7), and peiminine (8) have exhibited anti-inflammatory effects in LPS-induced RAW264.7 cells [54,55]. Additionally, peimisine (6) and peimine (7) have been reported to have antitussive effects [56,57]. Further investigation is warranted to explore the ingredients that are associated with the factors that influence the UC, such as intestinal barrier integrity, ROS, inflammation, the physical barrier of the intestine, microbiota, and intestinal immunity. ...
The incidence of ulcerative colitis (UC), an inflammatory disorder of the gastrointestinal tract, has rapidly increased in Asian countries over several decades. To overcome the limitations of conventional drug therapies, including biologics for UC management, the development of herbal medicine-derived products has received continuous attention. In this study, we evaluated the beneficial effects of a hydroethanolic extract of Fritillariae thunbergii Bulbus (FTB) in a mouse model of DSS-induced UC. The DSS treatment successfully induced severe colonic inflammation and ulceration. However, the severity of colitis was reduced by the oral administration of FTB. Histopathological examination showed that FTB alleviated the infiltration of inflammatory cells (e.g., neutrophils and macrophages), damage to epithelial and goblet cells in the colonic mucosal layer, and fibrotic lesions. Additionally, FTB markedly reduced the gene expression of proinflammatory cytokines and extracellular matrix remodeling. Immunohistochemical analysis showed that FTB alleviated the decrease in occludin and zonula occludens-1 expression induced by DSS. In a Caco-2 monolayer system, FTB treatment improved intestinal barrier permeability in a dose-dependent manner and increased tight junction expression. Overall, FTB has potential as a therapeutic agent through the improvement of tissue damage and inflammation severity through the modulation of intestinal barrier integrity.
... Pneumonia is an acute inflammatory disease, which is characterized by acute onset and severe symptoms and leads to a great deal of infection-related deaths [43,44]. FTB is mainly used for airway inflammatory diseases, such as bronchitis and pneumonia [45]. However, the active compounds, Q-markers, and molecular mechanisms of FTB and its effects in the treatment of pneumonia remain unknown. ...
Fritillariae thunbergii bulbus (FTB) is a popular Chinese herbal medicine with various applications in respiratory diseases. The quality evaluation of FTB has been insufficient to date, as the active ingredients and mechanisms of action of FTB remain unclear. This study proposes a novel strategy for exploring the quality markers (Q-markers) of FTB based on UPLC-QTOF-MS analysis, network pharmacology, molecular docking, and molecular dynamics (MD) simulation. A total of 26 compounds in FTB were identified by UPLC-QTOF-MS. Ten of these compounds were screened as Q-markers based on network pharmacology for their anti-pneumonia effects, including imperialine, peimisine, peiminine, ebeiedinone, zhebeirine, puqiedine, 9-hydroxy-10,12-octadecadienoic acid, (9Z,12Z,15Z)-13-hydroxy-9,12,15-octadecatrienoic acid, 9,12,15-octadecatrienoic acid, and (2E,4Z,7Z,10Z,13Z,16Z,19Z)-2,4,7,10,13,16,19-docosaheptaenoic acid methyl ester (DAME). These Q-markers were predicted to act on multiple targets and pathways associated with pneumonia. Molecular docking results revealed that most of the Q-markers showed high affinity with at least one of the main targets of pneumonia, and the top ten complexes were confirmed with MD simulation. Network pharmacology indicated that FTB may act on the TNF signaling pathway, HIF-1 signaling pathway, JAK-STAT signaling pathway, etc. The results demonstrated that imperialine (P8), peimisine (P9), peiminine (P11), ebeiedine (P15), zhebeirine (P16), and puqiedine (P18) may be potential Q-markers of FTB, and AKT1, IL-6, VEGFA, TP53, EGFR, STAT3, PPARG, MMP9, and CASP3 may be promising therapeutic targets for pneumonia treatment that are worthy of further research.
Graphical abstract
... The copyright holder for this this version posted January 31, 2023. (Chen et al., 2020;Köfers, 2009;Lin et al., 2001;Wang et al., 2016;Wang et al., 2011;Zhou et al., 2010) ...
... Pathologic conditions caused by excessive exposure to environmental insults not only increase the number of solids present in airway mucus, but also change the compositions and ratio of the MUC5AC and MUC5B that is essential for airway homeostasis (Fahy et al., 1997;Rose & Voynow, 2006;Roy et al., 2014). Compounds of Fritillariae species, precisely imperialine, chuanbeinone, peimine and peiminine, have been shown to exhibit expectorant properties in mice measured by tracheal phenol red output (Wang et al., 2011). Similarly, imperialine-β-N-oxide, preprint (which was not certified by peer review) is the author/funder. ...
Bei Mu Gua Lou San (BMGLS) is an ancient formulation known for its moisturizing and expectorant properties, but the underlying mechanisms remain unknown. We investigated the dose-dependent effects of BMGLS on its rehydrating and mucus-modulating properties using an air-liquid-interface (ALI) cell culture model of the Calu-3 human bronchial epithelial cell line and primary normal human bronchial epithelial cells (NHBE) and specifically focused on quantity and composition of the two major mucosal proteins MUC5AC and MUC5B.
ALI cultures were treated with BMGLS at different concentrations over three weeks and evaluated by means of histology, immunostaining and electron microscopy. MUC5AC and MUC5B mRNA levels were assessed and quantified at the protein level using an automated image-based approach. Additionally, expression levels of the major mucus-stimulating enzyme 15-lipoxygenase (ALOX15) were evaluated.
BMGLS induced dose-dependent morphological changes in NHBE but not Calu-3 ALI cultures that resulted in increased surface area via the formation of herein termed intra-epithelial structures (IES). While cellular rates of proliferation, apoptosis or degeneration remained unaffected, BMGLS caused swelling of mucosal granules, increased the area of secreted mucus, decreased muco-glycoprotein density, and dispensed MUC5AC. Additionally, BMGLS reduced expression levels of MUC5AC, MUC5B and the mucus-stimulating enzyme 15-lipoxygenase (ALOX15).
Our studies suggest that BMGLS rehydrates airway mucus while stimulating mucus secretion by increasing surface areas and regulating goblet cell differentiation through modulating major mucus-stimulating pathways.
... It has been used to treat chronic respiratory disorders such as asthma, cough, lung cancer, and tuberculosis [3]. Modern pharmacological studies have indicated that the bulb of F. cirrhosa contained a variety of bioactive isosteroidal alkaloids (ISA) such as imperialine, verticinone, verticine, delavine, peimisine, etc., which are mainly responsible for the antiasthmatic, antioxidant, antitumor or anti-inflammatory action ascribed to them [4][5][6][7]. Imperialine is a vital ingredient of these F. cirrhosa ISA and is frequently utilized as a pharmacopoeia reference standard for the quality assessment of "Chuan-Bei-Mu" due to its significant pharmacological properties [8]. ...
Fritillaria cirrhosa D. Don (known as Chuan-Bei-Mu in Chinese) can synthesize isosteroidal alkaloids (ISA) with excellent medicinal value, and its bulb has become an indispensable ingredient in many patented drugs. Members of the cytochrome P450 (CYP450) gene superfamily have been shown to play essential roles in regulating steroidal alkaloids biosynthesis. However, little information is available on the P450s in F. cirrhosa. Here, we performed full-length transcriptome analysis and discovered 48 CYP450 genes belonging to 10 clans, 25 families, and 46 subfamilies. By combining phylogenetic trees, gene expression, and key F. cirrhosa ISA content analysis, we presumably identify seven FcCYP candidate genes, which may be hydroxylases active at the C-22, C-23, or C-26 positions in the late stages of ISA biosynthesis. The transcript expression levels of seven FcCYP candidate genes were positively correlated with the accumulation of three major alkaloids in bulbs of different ages. These data suggest that the candidate genes are most likely to be associated with ISA biosynthesis. Finally, the subcellular localization prediction of FcCYPs and transient expression analysis within Nicotiana benthamiana showed that the FcCYPs were mainly localized in the chloroplast. This study presents a systematic analysis of the CYP450 gene family in F. cirrhosa and provides a foundation for further functional characterization of the CYPs involved in ISA biosynthesis.
... At doses 200 and 400 mg/kg, the phenol-red secretion enhanced by 109.4 and 182.8%, respectively, which was better than that of ammonium chloride at the dose of 200 mg/kg. Several studies have reported the presence of saponins, alkaloids, and phenolic compounds in plants traditionally used to treat cough [32,46,65]. As evidenced by our results, quince seed mucilage's antitussive and expectorant activities can be attributed to the presence of these bioactive constituents. ...
Quince seed mucilage has been traditionally used as a cough remedy, but little has been reported about its extraction and biological activities. This study investigated the extraction of mucilage from quince seed through various methods. Single-step aqueous maceration, ultrasonic pretreatment followed by aqueous maceration, and microwave pretreatment followed by aqueous maceration were used for mucilage extraction, while Soxhlet was applied as a reference method. The antitussive and expectorant activity of the mucilage was evaluated using the ammonia-induced cough model and phenol red secretion model in mice, respectively. Results indicated that the highest mucilage (191.2±0.5 mg/g) and saponin (94.8±0.6 mg/g) extraction yields were obtained when 2 min microwave irradiation was used before aqueous maceration (70 o C, 2 h). At the 400 mg/kg dose, the mucilage significantly lengthened the cough incubation period and reduced the cough frequency in mice. Results also showed the considerable expectorant activity of the mucilage (p <0.01) at the dose of 400 mg/kg compared to the control and positive control groups. The mucilage showed significant antibacterial activity against Streptococcus pyogenes with MIC and MBC values of 62.5 and 125 µg/mL, respectively. The quince seed mucilage was curatively effective on coughing and expectoration, providing significant evidence for the traditional use of this mucilage as a cough remedy.
... On the other hand, the steroidal type of alkaloids can be sub-divided into two types: Verazine and Solanidine, depending on the nitrogen atom to be incorporated into an indolizidine ring or a piperidine ring ( Figure 1) [2,21]. The types of alkaloids Cevanine type with cis-configuration (8): imperialine, chuanbeinone, imperialine-β-N-oxide, delavine, 3β-acetylimperialine, delavinone, isodelavine, yibeinoside A [22][23][24][25]. Cevanine type with trans-configuration (6): peimine, peiminine, puqiedine, ebeiedinone, ebeiedine, isoforticine [22,23,25]. Jervine type (2): peimisine-3-O-β-D -glucopyranoside, peimisine [22,24]. ...
... The types of alkaloids Cevanine type with cis-configuration (8): imperialine, chuanbeinone, imperialine-β-N-oxide, delavine, 3β-acetylimperialine, delavinone, isodelavine, yibeinoside A [22][23][24][25]. Cevanine type with trans-configuration (6): peimine, peiminine, puqiedine, ebeiedinone, ebeiedine, isoforticine [22,23,25]. Jervine type (2): peimisine-3-O-β-D -glucopyranoside, peimisine [22,24]. ...
Fritillaria is a perennial herb with medicinal properties. There are 158 Fritillaria species worldwide, 33 of which have reported therapeutic efficacy. Alkaloids are the principal constituents in Fritillaria. Fritillaria species growing at 2700–4000 m are the sources of extract namely Chuan Beimu (the Pharmacopoeia of the People’s Republic of China, 2020 Edition), with low biomass, mainly containing more 5α-cevanine isosteroidal alkaloids with cis-configuration. In contrast, species growing below 1500 m are usually taller than 50 cm, and they mainly contain more trans-configuration isosteroidal alkaloids. There are two schemes of the biosynthetic pathways of steroidal alkaloids with different frameworks and catalytic reactions and combined high-throughput omics data. Based on the distributed elevations, Fritillaria species were divided into three major categories, which met classification features based on phylogenetic analysis or morphological features. Artificial or in vitro cultivations are effective strategies for balancing economical requirements and ecological protection. Fritillaria species growing at lower altitudes can be cultivated by bulb reproduction, but species growing at higher altitudes still rely mainly on gathering a large number of wild resources. Integration of asexual tissue culture and bulb reproduction with sexual artificial or imitated wild cultivation may create a very promising and effective way to maintain sustainable industrial development of Fritillaria.
