Magnolia kobus Extract Inhibits Periodontitis-Inducing Mediators in Porphyromonas gingivalis Lipopolysaccharide-Activated RAW 264.7 Cells.

Periodontitis, a disease caused by inflammation of oral bacteria, contributes to the loss of alveolar bone and destruction of connective tissues. Porphyromonas gingivalis, a Gram-negative bacterium, is known to possess important pathogenic factors for periodontal disease. In this study, we investigated the anti-periodontitis effects of Magnolia kobus extract (MKE) and magnolin as a component of Magnolia kobus (MK) in murine macrophage RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide (LPS). Effects of MKE and magnolin on the mechanism of RAW 264.7 cellular inflammation were determined by analyzing nitric oxide (NO) production and Western blot protein expression (n = 3). MKE/magnolin inhibited NO production without affecting cell survival. MKE/magnolin treatment inhibited LPS-induced pro-inflammatory cytokines, expression levels of matrix metalloproteinases (MMPs such as MMP-1, 3, 8, 9, and 13), and protein levels of inflammatory mediators (such as TNF-α, IL-1ß, and mPGES-1). MKE/magnolin also suppressed NF-κB activation by inhibiting the TLR4 signaling pathway. These findings suggest that MKE has a therapeutic effect on inflammatory periodontal disease caused by oral bacterium P. gingivalis and that magnolin is a major functional component in the anti-inflammatory effect of MKE.

Anticancer Potentials of the Lignan Magnolin: A Systematic Review.

Magnolin is a naturally occurring, multi-bioactive lignan molecule with inherent anticancer effects. This study aims to summarize the botanical origins and anticancer properties of magnolin. For this, a recent (as of March 2023) literature review was conducted using various academic search engines, including PubMed, Springer Link, Wiley Online, Web of Science, Science Direct, and Google Scholar. All the currently available information about this phytochemical and its role in various cancer types has been gathered and investigated. Magnolin is a compound found in many different plants. It has been demonstrated to have anticancer activity in numerous experimental models by inhibiting the cell cycle (G1 and G2/M phase); inducing apoptosis; and causing antiinvasion, antimetastasis, and antiproliferative effects via the modulation of several pathways. In conclusion, magnolin showed robust anticancer activity against many cancer cell lines by altering several cancer signaling pathways in various non- and pre-clinical experimental models, making it a promising plant-derived chemotherapeutic option for further clinical research.

Magnolin Inhibits Proliferation and Invasion of Breast Cancer MDA-MB-231 Cells by Targeting the ERK1/2 Signaling Pathway.

The aim of this study was to evaluate the effects of Magnolin (MGL) on inhibition of human breast cancer cells, and explore the underlying molecular mechanisms. The viability of the treated cells was assessed with the Cell Counting Kit-8 (CCK-8) assay, and the proliferation was analyzed in terms of EdU uptake, colony formation, and flow cytometry. The in vitro invasion and migration were determined by the transwell and wound healing assays respectively. The mRNA and protein levels of relevant factors was evaluated by quantitative real-time PCR and Western blotting respectively. MGL significantly decreased the viability and promoted apoptosis of MDA-MB-231 cells, along with reducing EdU incorporation rate as well as the colony forming capacity compared to the untreated control cells. In addition, the in vitro invasion and migration were also significantly inhibited by MGL. Furthermore, MGL suppressed the phosphorylation of MEK1/2, extracellular signal-regulated kinase (ERK)1/2 and significantly downregulated the expression of cyclin-dependent kinase 1 (CDK1), the anti-apoptotic B-cell lymphoma 2 (BCL2) and metastasis-associated matrix metalloproteases (MMPs) 2 & 9, and upregulated the cleaved caspases 3 and 9. After ERK was completely inhibited with the small interfering RNA (siRNA), MGL had no effect on these factors, indicating that ERK is essential for MGL action in breast cancer. In conclusion, MGL inhibits proliferation and invasion of and induces apoptosis in breast cancer cells through the ERK pathway.

Inhibitory Effects of Dimethyllirioresinol, Epimagnolin A, Eudesmin, Fargesin, and Magnolin on Cytochrome P450 Enzyme Activities in Human Liver Microsomes.

Magnolin, epimagnolin A, dimethyllirioresinol, eudesmin, and fargesin are pharmacologically active tetrahydrofurofuranoid lignans found in Flos Magnoliae. The inhibitory potentials of dimethyllirioresinol, epimagnolin A, eudesmin, fargesin, and magnolin on eight major human cytochrome P450 (CYP) enzyme activities in human liver microsomes were evaluated using liquid chromatography-tandem mass spectrometry to determine the inhibition mechanisms and inhibition potency. Fargesin inhibited CYP2C9-catalyzed diclofenac 4'-hydroxylation with a Ki value of 16.3 µM, and it exhibited mechanism-based inhibition of CYP2C19-catalyzed [S]-mephenytoin 4'-hydroxylation (Ki, 3.7 µM; kinact, 0.102 min-1), CYP2C8-catalyzed amodiaquine N-deethylation (Ki, 10.7 µM; kinact, 0.082 min-1), and CYP3A4-catalyzed midazolam 1'-hydroxylation (Ki, 23.0 µM; kinact, 0.050 min-1) in human liver microsomes. Fargesin negligibly inhibited CYP1A2-catalyzed phenacetin O-deethylation, CYP2A6-catalyzed coumarin 7-hydroxylation, CYP2B6-catalyzed bupropion hydroxylation, and CYP2D6-catalyzed bufuralol 1'-hydroxylation at 100 µM in human liver microsomes. Dimethyllirioresinol weakly inhibited CYP2C19 and CYP2C8 with IC50 values of 55.1 and 85.0 µM, respectively, without inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, and CYP3A4 activities at 100 µM. Epimagnolin A, eudesmin, and magnolin showed no the reversible and time-dependent inhibition of eight major CYP activities at 100 µM in human liver microsomes. These in vitro results suggest that it is necessary to investigate the potentials of in vivo fargesin-drug interaction with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 substrates.

Magnolin alleviated DSS-induced colitis by inhibiting ALOX5-mediated ferroptosis.

Inflammatory bowel disease (IBD) is a chronic and incurable disorder associated with higher cancer risk and currently faces unsatisfactory treatment outcomes. Ferroptotic cells secrete damage-associated molecular patterns (DAMPs) that recruit and activate immune cells, particularly macrophages. Magnolin has excellent antioxidant and anti-inflammatory properties, but its effect on IBD has not yet been clearly understood. This study aimed to investigate the therapeutic effects and mechanism of magnolin in IBD. For this purpose, in vivo and in vitro colitis models were established using dextran sulfate sodium (DSS), followed by optimization of magnolin concentration 2.5 µg/mL in vitro and 5 mg/kg in vivo. Bioinformatics analysis identified potential magnolin target sites and evaluated ferroptosis-associated gene expressions. Body weight, food intake, disease activity index (DAI), pathological changes, and inflammation levels were assessed. The effect of magnolin on ferroptosis and macrophages was evaluated using quantitative real time-polymerase chain reaction (qRT-PCR), immunofluorescent staining, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and western blotting. Results indicated that magnolin at a lower dose (5 mg/kg) alleviated DSS-induced colitis symptoms and reduced inflammation in mice. The bioinformatics analysis showed arachidonate 5-lipoxygenase (ALOX5) as a potential magnolin target. Furthermore, magnolin inhibited the expression of ALOX5 with no effect on GPX4. Moreover, magnolin regulated macrophage differentiation into the M2 phenotype and suppressed pro-inflammatory factors, that is, interleukin-6 and tumor necrosis factor-α (IL-6 and TNFα). These results suggested that magnolin possesses significant therapeutic potential in treating IBD by suppressing ALOX5-mediated ferroptosis, inhibiting M1 while promoting M2 macrophages, which is envisaged to provide novel strategies for treating IBD.

Magnolin inhibits intestinal epithelial cell apoptosis alleviating Crohn's disease-like colitis by suppressing the PI3K/AKT signalling pathway.

BACKGROUND AND AIMS: Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. METHODS: Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. RESULTS: The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. CONCLUSIONS: MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD.

Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation.

Magnolin (MGL), a compound derived from the magnolia plant, has inhibitory effects on tumor cell invasion and growth. His study aims to explore the antitumor effect and underlying molecular mechanism of MGL against human cervical cancer. We found that MGL inhibited the proliferation, migration, and invasiveness of cervical cancer cells in vitro and in vivo. The underlying mechanism was shown to involve MGL-induced inhibition of JNK/Sp1-mediated MMP15 transcription and translation. Overexpression of JNK/Sp1 resulted in significant restoration of MMP15 expression and the migration and invasion capabilities of MGL-treated cervical cancer cells. MGL modulated the cervical cancer microenvironment by inhibiting cell metastasis via targeting IL-10/IL-10 receptor B (IL-10RB) expression, thereby attenuating JNK/Sp1-mediated MMP15 expression. Analysis of the gut microbiota of mice fed MGL revealed a significant augmentation in Lachnospiraceae bacteria, known for their production of sodium butyrate. In vivo experiments also demonstrated synergistic inhibition of cervical cancer cell metastasis by MGL and sodium butyrate co-administration. Our study provides pioneering evidence of a novel mechanism by which MGL inhibits tumor growth and metastasis through the IL-10/IL-10RB targeting of the JNK/Sp1/MMP15 axis in human cervical cancer cells.

epi-Magnolin, a tetrahydrofurofuranoid lignan from the oleo-gum resin of Commiphora wightii, as inhibitor of pancreatic cancer cell proliferation, in-vitro and in-silico study.

Five known furofuran lignans, dia-sesamin (1), 5-methoxysesamin (2), epi-magnolin (3), kobusin (4) and yangambin (5) were isolated for the first-time from the oleo-gum resin of Commiphora wightii. This is the first report on the 13C NMR assignments for epi-magnolin (3). Each of the isolated compounds was evaluated for its ability to inhibit MIA PaCa-2 pancreatic cancer cell line. Among them, epi-magnolin (3) displayed potential activity (IC50 = 29 nM) compared to colchicine (IC50 = 56 nM). 3D-flexible alignment revealed that epi-magnolin (3) has great matching with the tubulin polymerization inhibitor, colchicine. Meanwhile, docking studies exhibited that compounds 1-5 displayed good binding free energies against colchicine binding site (CBS) of tubulin with binding modes that were highly comparable to that of colchicine. Compounds 2, 3, and 5 showed superior binding free energies than colchicine (-24.37 kcal/mol). epi-Magnolin (3) showed the highest binding score against CBS. MD simulation studies confirmed the stability of epi-magnolin (3) in the active site for 200 ns. Furthermore, four online servers (Swiss ADME, pkCSM pharmacokinetics, AdmetSAR, and ProTox-II) were utilized to predict the ADMET parameters. The in-silico pharmacokinetics predictions reveled that epi-magnolin (3) has significant oral bioavailability and drug-like capabilities.Communicated by Ramaswamy H. Sarma.

Magnolin Inhibits Paclitaxel-Induced Cold Allodynia and ERK1/2 Activation in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anti-cancer drugs. The main symptoms often include sensory disturbances and neuropathic pain, and currently there is no effective treatment for this condition. This study aimed to investigate the suppressive effects of magnolin, an extracellular signal-regulated kinase (ERK) inhibitor substance derived from a 95% EtOH extract of the seeds of Magnolia denudata, on the symptoms of CIPN. A taxol-based anti-cancer drug paclitaxel (PTX) was repeatedly injected (2 mg/kg/day, total 8 mg/kg) into mice to induce CIPN. A neuropathic pain symptom was assessed using a cold allodynia test that scores behaviors of licking and shaking paw after plantar administration of acetone drop. Magnolin was administered intraperitoneally (0.1, 1, or 10 mg/kg) and behavioral changes to acetone drop were measured. The effect of magnolin administration on ERK expression in the dorsal root ganglion (DRG) was investigated using western blot analysis. The results showed that the repeated injections of PTX induced cold allodynia in mice. Magnolin administration exerted an analgesic effect on the PTX-induced cold allodynia and inhibited the ERK phosphorylation in the DRG. These results suggest that magnolin could be developed as an alternative treatment to suppress paclitaxel-induced neuropathic pain symptoms.

Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A, Magnolin, and Yangambin Inhibit UDP-Glucuronosyltransferase 1A1 and 1A3 Activities in Human Liver Microsomes.

Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin are tetrahydrofurofuranoid lignans with various pharmacological activities found in Magnoliae Flos. The inhibition potencies of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on six major human uridine 5'-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes were evaluated using liquid chromatography-tandem mass spectrometry and cocktail substrates. Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin inhibited UGT1A1 and UGT1A3 activities, but showed negligible inhibition of UGT1A4, UGT16, UGT1A9, and UGT2B7 activities at 200 µM in pooled human liver microsomes. Moreover, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin noncompetitively inhibited UGT1A1-catalyzed SN38 glucuronidation with Ki values of 25.7, 25.3, 3.6, 26.0, and 17.1 µM, respectively, based on kinetic analysis of UGT1A1 inhibition in pooled human liver microsomes. Conversely, the aforementioned tetrahydrofurofuranoid lignans competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation with 39.8, 24.3, 15.1, 37.6, and 66.8 µM, respectively in pooled human liver microsomes. These in vitro results suggest the necessity of evaluating whether the five tetrahydrofurofuranoid lignans can cause drug-drug interactions with UGT1A1 and UGT1A3 substrates in vivo.

Magnolin inhibits IgE/Ag-induced allergy in vivo and in vitro.

Mast cells (MCs) play critical roles in allergic reactions and modulating the activation of MCs could be an effective strategy to treat allergic diseases, which cause a rapidly increasing threat to the public health. Herein, we described that Magnolin, a major component from Flos magnoliae could inhibit IgE-dependent MCs activation. We found Magnolin inhibited IgE/Ag-induced calcium mobilization, degranulation, and cytokines release in LAD2 cells. Magnolin was also found to attenuate IgE/Ag-induced mice paw swelling in a dose-dependent manner. Further mechanistic studies suggested a possible anti-allergic and anti-inflammatory effects of Magnolin in IgE/Ag-induced anaphylactic reactions. Thereby, Magnolin could be a potential therapeutic agent for preventing mast cell-related immediate and delayed allergic diseases.

Synergistic activity of magnolin combined with B-RAF inhibitor SB590885 in hepatocellular carcinoma cells via targeting PI3K-AKT/mTOR and ERK MAPK pathway.

The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains obscure. From a clinical point of view, the ERK MAPK pathway and the PI3K/AKT pathway are activated in the majority of liver cancer. In addition, long term used to single agent treatment of HCC, frequently results in reverse activation of the ERK MAPK pathway or the PI3K/AKT pathway, leading to drug resistance. Thus, it is important to research the mechanism of combination agents that could suppress different pathways to treat HCC. Here, we found that combination natural product magnolin with BRAF inhibitor SB590885 synergistically suppressed the proliferation, promoted cell cycle arrest and apoptosis in hepatocellular carcinoma cells Bel-7402 and SK-Hep1. Furthermore, we demonstrated that the magnolin and the SB590885 combination led to increased impaired proliferation via inhibition of the ERK MAPK pathway and the PI3K/AKT pathway. These findings highlight the important role of agent combination and provided the approaches of therapeutic improvement for patients with advanced HCC.

Magnolin inhibits prostate cancer cell growth in vitro and in vivo.

BACKGROUND: Magnolin is the most active ingredient in the herb Magnolia fargesii, which has been traditionally used in oriental medicine to treat headaches and nasal congestion. Recent researches demonstrate that Magnolin inhibits cancer cell migration and invasion. MATERIALS AND METHODS: This study used cell culture and the BALB/c nu/nu mouse xenograft model to investigate whether or not magnolin can inhibit the growth of PC3 and Du145 prostate cancer cells. MTT assay and flow cytometry were performed to estimate the proliferation, cycle, and apoptosis of the cells in vitro. Clone formation assay was also conducted. In the animal study, Ki-67 immunostaining and TUNEL assay were carried out to evaluate cell proliferation and apoptosis, respectively. To elucidate the possible mechanism by which magnolin attenuates prostate cancer cell growth, we estimated the expression levels of Akt/p-Akt, P53, P21, BCL-2, and cleaved Caspase3 by using Western blot 48h after magnolin-treatment of the cells. RESULTS: Magnolin inhibited the proliferation and viability of the tumor cells by triggering cell cycle arrest via P53/P21 activation and inducing apoptosis in vitro and in vivo. Magnolin downregulated the phosphorylation of Akt protein kinase and upregulated cleaved Caspase3 during anti-proliferation and pro-apoptosis. CONCLUSION: Magnolin may be a novel medicine for prostate cancer therapy.

Gu-Ben-Fang-Xiao decoction attenuates sustained airway inflammation by suppressing ER stress response in a murine asthma remission model of respiratory syncytial virus infection.

ETHNOPHARMACOLOGICAL RELEVANCE: In recent years, asthma has increased dramatically in prevalence with a considerable economic burden all over the world. Long-term remission should be regarded as the promising and meaningful therapeutic goal in asthma management. However, the precise definition criteria and rational therapies for asthma remission have not been well-established. In academia, there is a consensus that even in those who develop asymptomatic remission of asthma, persistent airway inflammation is ubiquitous. Gubenfangxiao decoction (GBFXD) has been widely used in treating asthma remission stage for decades in the Jiangsu Province Hospital of Chinese Medicine, China. We previously demonstrated that GBFXD could downregulate the asthma susceptibility gene ORMDL3, a trigger of Endoplasmic reticulum (ER) stress and unfolded protein response (UPR). AIM THIS STUDY: To investigate the involvement of ER stress and UPR in the anti-inflammatory effects of GBFXD in Respiratory Syncytial Virus (RSV)-OVA-induced asthma remission mice. MATERIALS AND METHODS: Mice were orally administered GBFXD at three doses for 30 days after an RSV-OVA challenge. The levels of inflammation mediators in serum were measured using a Luminex assay and the amount of IFN-γ in lung homogenates was detected using ELISA. The splenic CD4+ and CD8+ T lymphocytes were counted using flow cytometric analysis. The mRNA and protein levels of asthma susceptibility gene ORMDL3, ER stress markers (BIP, CHOP), and three canonical UPR branches (PERK-eIF2a-ATF4, IRE1α-XBP1/IRE1α-JNK-AP1 and ATF6-SERCA2b signal pathways) were detected using real-time RT-PCR and western blot. RESULTS: Histopathological analysis showed that the model group mice still exhibited a sustained airway inflammation even after suspending the OVA-challenge and RSV infections for 30 days. H&E staining results indicated that GBFXD could attenuate sustained airway inflammation. Decreased serum CXCL1 level and increased IFN-γ level in lung homogenate were observed after GBFXD treatment. Reductions in the number of splenic CD4+/CD8+ T lymphocytes were found after DEX treatment. We further confirmed the previous finding that GBFXD could downregulate the expression of ORMDL3. As a result of suppressed UPR, decreased ER stress markers and inhibited UPR branches (PERK and IRE1α signal pathway) were also observed through the significant reduction of signature mRNA and protein expressions after GBFXD treatment. CONCLUSION: GBFXD can significantly attenuate RSV-OVA-induced persistent airway inflammation in murine asthma remission model. These effects may be mediated, at least partially, by inhibiting the activation of ER stress responses.

Effects of add-on therapy with NDC-052, an extract from Magnoliae Flos, in adult asthmatic patients receiving inhaled corticosteroids.

BACKGROUND/AIMS: There is a need for new anti-asthmatic medications with fewer side effects. NDC-052, an extract of the medicinal herb Magnoliae flos, which has a long history of clinical use, was recently found to have anti-inflammatory effects. Herein, we evaluated the effects of NDC-052 as an add-on therapy in patients with mild to moderate asthma using inhaled corticosteroids (ICS). METHODS: In a non-comparative, multi-center trial, 148 patients taking ICS received NDC-052 for eight weeks. We evaluated their forced expiratory volume in one second (FEV1), morning and evening peak expiratory flow rate (AM and PM PEFR), AM/PM asthma symptom scores, visual analogue symptom (VAS) scores, night-time wakening, frequency of short-acting ß2-agonist usage, and adverse events. RESULTS: After eight weeks, both AM and PM PEFRs were significantly improved. Asthma symptom scores, VAS scores, the frequency of nights without awakening, and the frequency of ß2-agonist use were also reduced. Most of the adverse drug reactions were mild and resolved spontaneously. CONCLUSIONS: The addition of NDC-052 to ICS had a beneficial effect on asthma control in patients with mild to moderate asthma, with good tolerability and fewer side effects. Further studies are necessary to evaluate the effects of NDC-052 in patients with severe and/or refractory asthma.