Figure - available from: Frontiers in Endocrinology
This content is subject to copyright.
Peiminine dose-dependently inhibits osteoclastogenesis induced by RANKL and is not cytotoxic in vitro. (A) The molecular structure of peiminine. (B) Evaluation of the cytotoxicity of peiminine by the CCK-8 assay. n= 5, (C) TRAP staining of OCs treated with peiminine at every concentration. (D) Quantitative analysis of the TRAP-positive cells with more than 3 nuclei in each well of a 96-well plate. n= 5, *P < 0.05, ***P < 0.001. (E) Fluorescence staining images of OCs treated without or with peiminine at different concentrations (5 µmol/L and 10 µmol/L). The scale bar is 200 µm. (F) Analysis of the average number of OC nuclei (dots with blue fluorescence indicated by DAPI staining). n= 5, ***P < 0.001.
Source publication
Osteoclasts (OCs) play an important role in osteoporosis, a disease that is mainly characterized by bone loss. In our research, we aimed to identify novel approach for regulating osteoclastogenesis and thereby treating osteoporosis. Previous studies have set a precedent for screening traditional Chinese herbal extracts for effective inhibitors. Pei...
Citations
... Interestingly, NGF has been found to activate the NF-κB signaling pathway by binding to p75NTR [101]. The role of NF-κB in bone metabolism and bone formation is well documented [102][103][104] and its activation is a key mechanism in the development of HO [105]. Inhibition of the NF-κB signaling pathway can suppress the function and differentiation of osteoclasts, effectively ameliorating bone loss in OVX mice model [104]. ...
... The role of NF-κB in bone metabolism and bone formation is well documented [102][103][104] and its activation is a key mechanism in the development of HO [105]. Inhibition of the NF-κB signaling pathway can suppress the function and differentiation of osteoclasts, effectively ameliorating bone loss in OVX mice model [104]. NF-κB signaling pathway is involved in the regulation of growth plate cartilage formation and osteoblasts, there is an increase in osteoblast differentiation and BMP-2 activation when the NF-κB signaling pathway is blocked. ...
Heterotopic ossification (HO) is a pathological process characterized by the aberrant formation of bone in muscles and soft tissues. It is commonly triggered by traumatic brain injury, spinal cord injury, and burns. Despite a wide range of evidence underscoring the significance of neurogenic signals in proper bone remodeling, a clear understanding of HO induced by nerve injury remains rudimentary. Recent studies suggest that injury to the nervous system can activate various signaling pathways, such as TGF-β, leading to neurogenic HO through the release of neurotrophins. These pathophysiological changes lay a robust groundwork for the prevention and treatment of HO. In this review, we collected evidence to elucidate the mechanisms underlying the pathogenesis of HO related to nerve injury, aiming to enhance our understanding of how neurological repair processes can culminate in HO.
... Peiminine, a major component of Fritillaria, which is a herb from traditional Chinese medicine, has been studied for its anti-oxidant and anti-inflammatory effects [13]. Previous research has indicated that Fritillaria ussuriensis, which originates from the bulbs of various species of Fritillaria plants, inhibits the production of inflammatory cytokines and MAPKs in mast cells [14]. ...
... Peiminine is an alkaloid compound derived from the bulb of Fritillaria thunbergii Miq, a traditional herb in Chinese medicine [13]. The roots of F. thunbergii have various medicinal properties, such as cough relief, expectorant effects, and astringency [28]. ...
... The roots of F. thunbergii have various medicinal properties, such as cough relief, expectorant effects, and astringency [28]. Peiminine is known to have anti-inflammatory effects, influences cell apoptosis, and inhibits the proliferation of cancer cells [13,29]. The effect of peiminine is linked to the modulation of NF-κB activity and MAPK cascades. ...
Peiminine is the main natural alkaloid compound extracted from the Chinese herb Fritillaria. Although peiminine is known for its antioxidant and anti-inflammatory effects in conditions such as mastitis and arthritis, its impact on inflammation induced by Cutibacterisum acnes (C. acnes) has not been explored. The aim of this study was to investigate the effect of peiminine on C. acnes-induced inflammatory responses in the skin and to identify the underlying mechanism involved. We discovered that peiminine inhibits the C. acnes-induced expression of inflammatory mediators such as pro-interleukin-1β (pro-IL-1β), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in mouse bone marrow-derived macrophages (BMDMs). Peiminine suppressed the activation of nuclear factor-kappa B (NF-κB) without affecting the activation of mitogen-activated protein kinase (MAPK) pathways such as JNK, ERK, and p38 MAPK. In addition, we found that peiminine suppressed inflammatory cytokine expression and ameliorated histological symptoms in C. acnes-induced mouse skin. Our study is the first to provide evidence that peiminine has an inhibitory effect on acne, and it points toward the potential of incorporating peiminine into cosmetic and pharmaceutical formulations for acne treatment.
... Yu et al. (2021) highlighted its role in inducing cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells (Yu et al. 2021). Zhu et al. (2021) demonstrated its ability to suppress osteoclastogenesis by inhibiting NFATc1, ERK, and NF-κB signaling pathways (Zhu et al. 2021). Chen et al. (2022) reported its inhibition of myocardial injury and fibrosis after myocardial infarction through the mitogenactivated protein kinase pathway (Chen et al. 2022). ...
... Yu et al. (2021) highlighted its role in inducing cell cycle arrest, apoptosis, and autophagy in osteosarcoma cells (Yu et al. 2021). Zhu et al. (2021) demonstrated its ability to suppress osteoclastogenesis by inhibiting NFATc1, ERK, and NF-κB signaling pathways (Zhu et al. 2021). Chen et al. (2022) reported its inhibition of myocardial injury and fibrosis after myocardial infarction through the mitogenactivated protein kinase pathway (Chen et al. 2022). ...
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.
... To confirm the transduction of PKC-δ signaling, phosphorylated ERK (among the three major MAPKs) was found to be associated with the CV-mediated activation of PKC-δ ( Figure 4C). It is true that the MAPK pathway also plays an important role in OC-genesis and bone resorption by OCs [70,71]. The engagement of PKC-δ and ERK-MAPK in CV-elicited cell signaling indicates that CV may be a ligand for receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) [72]. ...
Elevated osteoclast (OC)-mediated bone resorption, a common pathological feature between periodontitis and rheumatoid arthritis (RA), implicates a possible mutually shared pathogenesis. The autoantibody to citrullinated vimentin (CV), a representative biomarker of RA, is reported to promote osteoclastogenesis (OC-genesis). However, its effect on OC-genesis in the context of periodontitis remains to be elucidated. In an in vitro experiment, the addition of exogenous CV upregulated the development of Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear OCs from mouse bone marrow cells and increased the formation of resorption pits. However, Cl-amidine, an irreversible pan-peptidyl arginine deiminase (PAD) inhibitor, suppressed the production and secretion of CV from RANKL-stimulated OC precursors, suggesting that the citrullination of vimentin occurs in OC precursors. On the other hand, the anti-vimentin neutralizing antibody suppressed in vitro Receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced OC-genesis. The CV-induced upregulation of OC-genesis was abrogated by the Protein kinase C (PKC)-δ inhibitor Rottlerin, accompanied by the downmodulation of OC-genesis-related genes, including Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP and Matrix Metallopeptidase 9 (MMP9) as well as extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. Elevated levels of soluble CV and vimentin-bearing mononuclear cells were found in the bone resorption lesions of periodontitis induced in mice in the absence of an anti-CV antibody. Finally, local injection of anti-vimentin neutralizing antibody suppressed the periodontal bone loss induced in mice. Collectively, these results indicated that the extracellular release of CV promoted OC-genesis and bone resorption in periodontitis.
... The alkaloid PMN derives from the bulbs of Fritillaria thunbergii Miq, and has several pharmacologic properties linked to antiinflammatory [42], anti-cancer [24,43] and antioxidant activity [44]. Therefore, in addition to the ability to hinder the interaction between HSD11B1L-181 and parkin, PMN also blocks the activation of inflammatory factors and cytokines [45]. Likewise, it reduces intracellular ROS production [44]. ...
Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we cloned and sequenced a splice variant of the hydroxysteroid 11-β dehydrogenase 1 like gene (HSD11B1L) and named it HSD11B1L-181. HSD11 B1L-181 was specifically expressed only in GBM cells. Overexpression of this variant can significantly promote the proliferation, migration and invasion of GBM cells. Knockdown of HSD11B1L-181 expression inhibited the oncogenic potential of GBM cells. Furthermore, we identified the direct interaction of parkin with HSD11B1L-181 by screening the GBM cDNA expression library via yeast two-hybrid. Parkin is an RBR E3 ubiquitin ligase whose mutations are associated with tumorigenesis. Small interfering RNA treatment of parkin enhanced the proliferative, migratory and invasive abilities of GBM. Finally, we found that the alkaloid peiminine from the bulbs of Fritillaria thunbergii Miq blocks the interaction between HSD11B1L-181 and parkin, thereby lessening carcinogenesis of GBM. We further confirmed the potential of peiminine to prevent GBM in cellular, ectopic and orthotopic xenograft mouse models. Taken together, these findings not only provide insight into GBM, but also present an opportunity for future GBM treatment.
... NF-κB pathway is considered a crucial downstream factor in the RANKL-induced differentiation of OC and is critical for NFATc1 activation [46,51]. RANKL can induce the phosphorylation of IκB, and phosphorylated p65 enters the nucleus to activate NFATc1 expression [52]. In the meantime, NF-κB mediates chondrocyte catabolism in response to IL-1β stimulation, which contributes to the increased expression of MMP13 and ADAMTS-5, resulting in ECM damage [53]. ...
... Our study showed that CDDO-Me inhibited the phosphorylation and nuclear translocation of p65, and osteoclast fusion and resorption genes, including CTSK, Integrinβ3 and DC-STAMP are under the transcriptional control of NFATc1 and were subsequently reduced by CDDO-Me, eventually, osteoclast formation was significantly inhibited. Similar results were obtained in a study by Zhu in which osteoclast formation was inhibited by inhibiting the NF-κB pathway [52]. Besides, CDDO-Me decreased the expression of MMP3, MMP13, ADAMTS5, and increased the expression of aggrecan and Sox9, in response to the IL-1β-induced inflammatory response. ...
Inflammation and oxidative damage are closely related to the development of osteoarthritis. Bardoxolone methyl (CDDO-Me), a semisynthetic oleanane triterpenoid, plays a strong anti-inflammatory and antioxidant role. The purpose of our research was to explore fundamental mechanisms of CDDO-Me in orthopaedics development. The results showed that CDDO-Me inhibited nuclear factor-κB ligand (RANKL)-induced osteoclast formation and extracellular matrix (ECM) degradation by activating the Nrf2/HO-1 signaling pathways and inhibiting NF-κB pathway activation and excess ROS production. In vivo, CDDO-Me significantly attenuated articular cartilage proteoglycan loss and the number of TRAP-positive osteoclasts in a destabilized medial meniscus (DMM) mouse model of OA. Taken together, these data demonstrate that CDDO-Me inhibits osteoclastogenesis and ECM degradation, underscoring its potential therapeutic value in treating OA.
... In addition, ZBM is frequently used as a heat-clearing and phlegm-resolving agent in TCM for the treatment of IPF [18][19][20]. However, since previous studies have emphasized the roles of single components and their targeted pathways, the overall mechanism underlying the therapeutic efects of ZBM on IPF requires elucidation [21,22]. ...
Idiopathic pulmonary fibrosis (IPF) is a long-term, distressing, and age-related interstitial lung disease characterized by a complicated etiology and irreversible progression. Fritillaria thunbergii Miq. (Zhe Beimu, ZBM) is frequently used for its heat-clearing and phlegm-resolving properties in herbal compounds for the treatment of IPF. However, the specific mechanisms underlying the effects of ZBM against IPF have not yet been reported. In this study, we applied a systematic analysis strategy based on network pharmacology to explore the probable core targets and major pathways of ZBM against IPF. In addition, molecular docking simulation and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to preliminarily investigate the possible mechanisms underlying the therapeutic effects of ZBM on IPF. We collected a total of 86 components of ZBM and used network pharmacology analysis to screen nine presumptive targets of ZBM against IPF. The molecular-docking results indicated that the components of ZBM exhibited good binding activity with presumptive targets. The qRT-PCR results also suggested that ZBM may partly alleviate IPF by regulating the expression of presumptive targets. This study laid the foundation for further clinical applications of ZBM and the development of IPF-related therapeutic products.
... Moreover, studies have shown that NF-κB and ERK1/2 signaling pathways are possible targets of peimine. Peimine was described to attenuate bone loss from an ovariectomized mouse by inhibiting the NFATc1, ERK, and NF-κB signaling pathways, thus suppressing the receptor activator of nuclear factor kappa-B ligand (RANKL), which is involved in osteoclastogenesis (Zhu et al., 2021). In vitro experiments have shown that FRT-derived verticinone has a hypoglycemic effect mediated by increased insulin secretion, glucose uptake, and inhibition of carbohydrate hydrolase activity (Boojar et al., 2020). ...
Fritillaria cirrhosa D. Don and F. thunbergii Miq. belong to the genus Fritillaria within the Liliaceae family. They are used in traditional Chinese medicines that are often administered in clinical settings as they have notable effects on cough, bronchitis, pneumonia, lung injury, cancer, and other diseases. In this review, we focus on the history, origin, similarities, and differences in efficacy, chemical composition, and pharmacological outcomes of the drugs obtained from F. cirrhosa (FRC) and F. thunbergii (FRT). We list various valuable pharmacological effects of FRC and FRT, including antitussive, expectorant, anti-inflammatory, antioxidant, and anticancer effects. Thus, this review offers a basis for the medical application of and further research into the pharmacological impacts of these two drugs. We believe that new drugs derived from the phytoconstituents of F. cirrhosa and F. thunbergii that have specific therapeutic properties can be developed in the future.
... BFT extracts exert antiviral effects against the influenza H1N1 virus [12], and the active compounds in BFT extracts function against influenza and influenza-associated diseases, mainly due to containing beta-sitosterol and pelargonidin [13]. BFT water extract was evaluated as a pharmacological candidate for reducing menopausal osteoporosis and menopause-related symptoms, such as fat accumulation [14], which result from the inhibitory effects of peiminine [15]. Therefore, no evidence has been presented in modern studies on pharmacological activities commom to BFT and FFT, other than antitussive and anticancer activities. ...
Both the bulbs and flowers of Fritillaria thunbergii Miq. (BFT and FFT) are widely applied as expectorants and antitussives in traditional Chinese medicine, but few studies have been conducted to compare the chemical compositions of these plant parts. In this study, 50% methanol extracts of BFT and FFT were analyzed via UHPLC-Q-Exactive Orbitrap MS/MS, and the feasibility of using non-targeted UHPLC-HRMS metabolomics and molecular networking to address the authentication of bulb and flower samples was evaluated. Principal component analysis (PCA), Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA), and heat map analysis showed there were dissimilar metabolites in BFT and FFT. As a result, 252 and 107 peaks in positive ion mode and negative mode, respectively, were considered to represent significant difference variables between BFT and FFT. Then, MS/MS-based molecular networking of BFT and FFT was constructed to perform an in-depth characterization of the peaks using different variables. A total of 31 alkaloids with significant differences were annotated in this paper, including seven cis-D/E-vevanine without C20-OH and one trans-D/E-cevanine with C20-OH, thirteen trans-D/E-cevanine without C20-OH, five cevanine N-oxide, and five veratramine. Among the 31 alkaloids, eight alkaloids had higher FFT than BFT contents, while all the flavonoids identified in our work had greater FFT than BFT contents. The influence of different ingredients on the pharmacological activities of BFT and FFT should be investigated in future studies.
... The activation of NF-κB and MAPK pathways plays key roles in osteoclastogenesis and bone resorption in inflammatory bone loss [40,41]. Recently, it was reported that peiminine suppresses OVX-induced bone loss by inhibiting osteoclastogenesis through the suppression of RANKL-induced NFATc1, ERK, and NF-κB signaling pathways [42]. In this study, we found that WEFT suppressed osteoclastogenesis by inhibiting NFATc1, MAPK (ERK and JNK), and NF-κB signaling pathways. ...
Fritillariae thunbergii bulbus has been widely used to treat symptoms of coughs and airway congestion in the chest due to pathological colds and damp phlegm in traditional Chinese medicine. Despite its long history of traditional use, its pharmacological activities on osteoclastogenesis and osteoporosis have not been evaluated. This study investigated the effects of the water extract of Fritillariae thunbergii bulbus (WEFT) on osteoclast differentiation in bone marrow-derived macrophage cells and on ovariectomy (OVX)-induced osteoporosis in mice. We found that WEFT significantly inhibited osteoclastogenesis by downregulating the receptor activator of the NF-κB ligand (RANKL) signaling-induced nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) expression. In an OVX-induced osteoporosis model, WEFT significantly prevented the OVX-induced trabecular loss of femurs, accompanied by a reduction in fat accumulation in the bone marrow and liver. In addition, WEFT significantly prevented weight gain and gonadal fat gain without recovering uterine atrophy. Using ultrahigh-performance liquid chromatography-tandem mass spectrometry, seven alkaloids (peimisine glucoside, yibeissine, peiminoside, sipeimine-glucoside, peimisine, peimine, and peiminine) were identified in WEFT. The results of this study suggest that WEFT can be a potential pharmacological candidate to reduce menopausal osteoporosis and menopause-related symptoms, such as fat accumulation.
