Magnolia officinalis Rehd is derived from Magnolia officinalis Rehd. et Wils. or Magnolia officinalis M. officinalis Rehd. et Wils. var. biloba Rehd. The dry bark, root bark and branch bark of et Wils., according to the theory of traditional Chinese medicine, Magnolia officinalis has the effect of drying dampness and eliminating phlegm, and removing the fullness of lower qi, and is mainly used to treat dampness and stagnation, vomiting and diarrhea, food accumulation and qi stagnation, abdominal distension and constipation, phlegm and cough. Magnokiol and honokiol are the main active components of Magnolia officinalis, and their content has become an important indicator to identify the quality of Magnolia officinalis. The pharmacological effects of Magnolia officinalis extract and its active ingredients Magnokiol and Honokiol have been reviewed [1-2]. This article reviews the respiratory pharmacological effects and mechanisms of Magnolia officinalis extract and its active ingredients in the treatment of respiratory diseases, in order to confirm the theory of traditional Chinese medicine, and also to provide a reference for R&D enterprises to develop Magnolia officinalis as a new preparation for the treatment of respiratory diseases and the rational clinical application of Magnolia officinalis and its active ingredients in the treatment of respiratory diseases.
1 Respiratory pharmacological effects of crude extract of magnolia officinalis
Jiang Juan [3] reported that giving 6 g·kg-1 of Ig Magnolia officinalis decoction to mice could significantly prolong the incubation period of ammonia-induced cough in mice, the incubation period was extended from an average of 42.63 s to 156.10 s in the model control group, and the number of coughs was reduced from 24.13 times to 0.80 times, which could also significantly increase the amount of tracheal phenol red excretion in mice, showing the cough and expectorant effect of Magnolia officinalis decoction. The compatibility of Magnolia officinalis and Yuanzhi can resist the effect of Magnolia officinalis in prolonging the incubation period of cough and reducing the number of coughs, and it cannot enhance Magnolia officinalis to promote the excretion of tracheal phenol red.
Ma Xiao et al. [4] reported that giving 20 g·kg-1 of Ig Magnolia officinalis decoction to mice could significantly prolong the incubation period of cough induced by ammonia (from 42.79 s to 65.00 s), and the number of coughs decreased from 19.71 to 12.00 times, which could also increase the excretion of tracheal phenol red, but could not significantly enhance the cough and expectorant effect of Yuanzhi.
Chen Si [5] gave mice 7.5 and 15 g·kg-1 per day at the extraction site of Ig Magnolia officinalis n-butanol or ginger magnolia officinalis n-butanol extraction site for 3 consecutive days, and the incubation period of ammonia-induced cough in mice was extended from 40.00 s in the control group to 52.87, 45.27, 63.38, and 84.83 s, respectively, and the number of coughs increased from 27.85 times in the control group to 16.48, 30.28, 10.04, and 7.20 times, respectively. The cough suppressant effect of the low-dose group was better than that of the high-dose group, and the cough suppressant effect of the n-butanol extraction site after ginger brozing was dose-related. However, the ethyl acetate extraction site of Magnolia officinalis and the ethyl acetate extraction site of ginger burn magnolia officinalis could only prolong the incubation period of cough, but did not reduce the number of coughs, and ginger burn could enhance the effect of magnolia officinalis in prolonging the incubation period of cough [6].
Zhu et al. [7] reported that the concentrations of total alkaloids in the water-soluble parts of Magnolia officinalis were 0.01, 0.05, 0.1, 0.2 g· L-1 does not affect the tension of guinea pig in isolated tracheal smooth muscle balance, but can inhibit the contraction caused by acetylcholine. However, the oil-soluble part of the total alkaloids of Magnolia officinalis was found at a low concentration (≤0.05 g· L-1), but at a high concentration (≥0.1 g· L-1) had a relaxing effect on the tracheal smooth muscle at equilibrium, and the oil-soluble alkaloids of Magnolia officinalis were effective in 0.1 g· L-1 could inhibit the tracheal constriction caused by acetylcholine, but at 0.2 g· L-1 does not inhibit the tracheal constriction caused by acetylcholine, suggesting that there are complex components in the oil-soluble alkaloids of Magnolia officinalis that oppose each other's effects on tracheal smooth muscle.
2 Respiratory pharmacological effects of honokiol
2.1 Prevention and treatment of asthma
Huang et al. [8] sensitized mice to ovalbumin for 21 consecutive days with 12.5, 25, and 50 mg·kg-1 of ig honokiol per day could dose-correlated reduce airway resistance and improve lung compliance in mice with variant asthma, that is, they could improve the lung function of asthma mice. It can also dose-correlated inhibit the infiltration of leukocytes, lymphocytes, monocytes, eosinophils, and neutrophils into bronchoalveolar lavage fluid, and reduce the level of ovalbumin-specific immunoglobulin (IgE) in bronchoalveolar lavage fluid and serum; It also dose-related reduces the levels of interleukin (IL)-4, IL-5 and IL-13 in bronchoalveolar lavage fluid, and the levels of Th17 cytokines IL-6 and IL-17, and increases the level of interferon-γ, which can restore the balance of Th1/Th2 cytokines, and can also reduce the number of Th17 cells in bronchoalveolar lavage fluid and spleen in dose-related. It can also dose-correlated restore the lung structure after ovalbumin attack, reduce inflammation, inhibit the infiltration of eosinophils and neutrophils into lung tissue, and it is believed that honokiol produces anti-inflammatory effects by downregulating Janus kinase (JAK)/signaling and transcriptional activator protein (STAT)/Notch signaling, thereby reducing the hypersensitivity reactivity of the airways, and finally producing the pharmacological effect of prevention and treatment of asthma.
Luo et al. [9] used an ovalbumin-sensitized mouse model to significantly reduce the number of inflammatory cell infiltrations in the bronchial mucosal epithelium by using an ovalbumin-sensitized mouse model with 20 mg·kg-1 of IP honokiol per day for 7 consecutive days before ovalbumin challenge, thereby reducing airway inflammation. Significantly reduce collagen deposition in lung tissue, intracytoplasmic mucus components and goblet cell count of lung epithelial cells, and alleviate pneumonia and mucus secretion; Network pharmacology studies have found that arginase-1, matrix metalloproteinase (MMP)-12, signal transducer and activator of transcription -1 (STAT1) and phosphodiesterase-4B genes are potential targets of honokiol in the treatment of asthma, and these four genes are related to immune response and cytokine response during asthma. Magnokiol significantly reduced the number of eosinophils in ovalbumin asthma mice, significantly increased the levels of memory B cells, plasma cells and activated CD4 T cells, and the responses of γ-interferon and α-interferon, and it was believed that honokiol prevented and treated asthma by increasing the mechanism of STAT1 and down-regulating the expression of arginase-1, phosphodiesterase-4B and MMP-12 in asthma mice.
Magnokiol has significant anti-inflammatory and antiallergic effects [10]. Magnokiol concentrations correlated inhibition of calcium ionophore A23187 to stimulate the release of leukotriene-B4 and leukotriene-C4 from human polymorphonuclear leukocytes with an IC50 of 0.7 μmol· L-1［11］。 Magnolol 0.01~
10 µmol· L-1 can inhibit the release of leukotriene-B4 and leukotriene-C4 from polymorphonuclear leukocytes in normal and bronchial asthma patients with A23187 concentration-correlatedly, and the effect of honokiol on the release of leukotrien-C4 from polymorphonuclear leukocytes in patients with asthma is significantly stronger than that of polymorphonuclear leukocytes in normal people [12].
Wang et al. [13] studied that honokiol inhibited oxygen consumption in isolated rat neutrophils, and its inhibitory reactive oxygen species (ROS) generation with an IC50 of 15.4 μmol· L-1, it can also inhibit the sudden respiration of rat neutrophils induced by chemotripeptides, and the IC50 of 24.0 μmol· L-1 and induced phosphorylation of mitogen-activated protein kinase (MAPK) p42/44 with an IC50 of 28.5 μmol· L-1, it is believed that honokiol mainly inhibits the occurrence of sudden neutrophil respiration by inhibiting chemotactic tripeptide-induced protein tyrosine phosphorylation and MAPK phosphorylation. Taniguchi et al. [14] reported that giving ig honokiol 100 mg·kg-1 to mice could significantly inhibit ear swelling caused by 2,4,6 trinitrochlorobenzene with an inhibition rate of 23.6%, and because honokiol could inhibit the concentration-related inhibition of concanavalin A to induce human lymphocyte blastization, it was believed that honokiol could produce antiasthmatic effect by inhibiting type IV allergic reactions.
Ko et al. [15] reported that magnolol 0.1~100 μmol· L-1 can inhibit the contraction of porcine tracheal smooth muscle caused by high potassium or carbacholine in a concentration-related manner, but does not affect its basal tension, and the inhibitory effect is still present after washing away the drug, indicating that the inhibitory effect of honokiol is irreversible. Honokiol can also inhibit Ca2+-dependent tracheal smooth muscle contraction caused by high-potassium depolarization. Calcium channel blockers can attenuate the contraction caused by carbachol by 30%, but cannot further enhance the inhibition of contraction effect of honokiol, if the pretreated calcium channel blocker is washed away, it can partially restore the contractile response caused by carbachol's inhibition of carbachol; Because honokiol does not affect the contraction of porcine tracheal smooth muscle caused by caffeine, it is thought that honokiol may release calcium ions by blocking voltage-gated Ca2+ channels, rather than intracellular calcium pools, that is, by blocking Ca2+ influx, it relaxes tracheal smooth muscle and produces asthmatic effect.
Wu et al. [16] used whole-cell patch clamping technique to find that honokiol reversibly increased the amplitude of K+ outward current in manifolia smooth muscle cells, while conospiroxin peptide or muscarcopsin could increase the amplitude of K+ outward current against magnolol, but glibenclamide could not. Magnokiol can also enhance the activity of large conductance Ca2+ to activate K+ channels, and can correlate the opening rate of these channels with a half effective concentration (EC50) of 1.5 μmol· L-1, and the channel opening rate was not related to the concentration of calcium ions in smooth muscle cells, and it was believed that honokiol could change the kinetic behavior of large conductance Ca2+ to activate K+ channels by increasing the dissociation and gating constants, and directly improve the activity of large conductance Ca2+ to activate K+ channels, resulting in antiasthmatic effect. In conclusion, honokiol produces an antiasthmatic effect through anti-inflammatory, anti-allergic mechanisms and mechanisms for relaxing bronchial smooth muscle.
2.2 Prevention and treatment of lung injury
Duan Jinqi et al. [17] reported that the daily ip of honokiol 4 and 8 mg·kg-1 for 3 consecutive days in rats had a protective effect on sepsis-induced acute lung injury prepared by cecal ligation and perforation, so that the alveolar structure of sepsis rats was intact and only a small amount of inflammatory cells were infiltrated. The pathological score of lung histopathology decreased from 18.52 points in the control group to 12.43 and 5.26 points, respectively, and the expression levels of phosphonuclear factor-κB (NF-κB) p65 and phosphorylated NF-κB inhibitory protein (IκBα), tumor necrosis factor-α (TNF-α), IL-1β, IL-6, intercellular adhesion molecule-1, macrophage inflammatory protein-2, malondialdehyde (MDA) content and xanthine oxidase activity were down-regulated. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were up-regulated, and it was believed that honokiol inhibited acute lung injury in sepsis rats through antioxidant and anti-inflammatory mechanisms.
Kong et al. [18] significantly improved the survival rate of sepsis rats when the pretreatment dose reached 1 μg·kg-1, and when honokiol was given 6 h after sepsis, the dose needed to reach 10 μg·kg-1 before or after sepsis was administered, indicating that the effect of pre-administration was stronger than that of therapeutic administration. Magnokiol can also dose-correlated alleviate lipid peroxidation in plasma, liver and lung of sepsis rats, indicating that honokiol can improve the survival rate of sepsis rats through antioxidant effect. Magnokiol can also significantly reduce TNF-α levels and lung permeability in plasma and lung tissues of sepsis rats, and it is believed that honokiol can also improve the survival rate of sepsis rats through anti-inflammatory effects [19].
Lipopolysaccharide (LPS), or bacterial endotoxin, is the main bacterial toxin that causes perforated sepsis in cecal ligation. Wang Xuebing [20] used ip LPS instead of cecal ligation and perforation to establish a model of acute lung injury of sepsis, and found that 30 min before modeling, ip honokiol 4 and 8 μg·kg-1 could significantly improve the pathological changes of lung tissue in sepsis rats, and the pathological morphological score decreased from the average of 11.8 points in the model control group to 7.9 and 5.6 points, respectively, and down-regulated the serum TNF-α and IL-1β contents. Moss et al. [21] gave mice pre-IG honokiol 50 mg·kg-1 for 7 days for 7 days, which significantly inhibited the overexpression of inflammatory cytokines and systemic inflammatory response caused by ip LPS.
Fu Yunhe [22] injected LPS into the nasal cavity 1 h before making an acute pneumonia model, and the ip honokiol was 5, 10, and 20 mg·kg-1, and the results showed that the total number of inflammatory cells, neutrophils, macrophages, and the levels of TNF-α, IL-1β, and IL-6 in alveolar lavage fluid were dose-correlated, and the wet/dry mass ratio and myeloperoxidase activity of lung tissue in mice were reduced, and the inflammatory cell infiltration and alveolar wall thickening of lung tissue were reduced. LPS was used to stimulate macrophage RAW264.7 to make a cell inflammation model, and it was found that 15, 30 and 60 mg· L-1 can inhibit the expression of TNF-α, IL-1β and IL-6 genes and proteins, and the protein expression of receptor-4 (TLR-4), NF-κB and MAKP γ induced by LPS in RAW264.7 cells. produces anti-pneumonia effect.
Studies have shown that honokiol concentration correlates against LPS-induced inflammatory response in mouse RAW264.7 cells, and inhibits the expression of inflammatory cytokines (such as inducible nitric oxide synthase, cyclooxygenase-2, NF-κB, IL-1, IL-6, etc.), and it is believed that honokiol and honokiol are inhibited by blocking phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated kinase (ERK)/ MAPK and the activation of the nuclear factor erythrocyte line-associated factor-2 (Nrf2)/heme oxygenase (HO-1) antioxidant pathway inhibit the expression of inflammatory cytokines in phagocytic cells and block the synthesis and release of inflammatory mediators [10].
Li Zhenmao et al. [23] prepared a rat model of necrotizing pancreatitis by retrograde biliary duct injection of sodium bozocholate, and at 5 min after modeling, iv honokiol 2 mg·kg-1 significantly resisted the gene expression and amylase levels of NF-κB and TNF-α in lung tissues induced by sodium bozolocholate α, but did not affect the overexpression of IL-10 in lung tissue, and alleviated acute lung injury complicated by necrotizing pancreatitis [24].
Wang et al. [25] changed the therapeutic administration to prophylactic administration, and 15 min before modeling in pancreatitis rats, iv honokiol 200 μg·kg-1 also increased the levels of IL-1β, IL-8, diamine oxidase, D-lactate, high-mobility protein B1 (HMGB1) and advanced glycation end product receptor (RAGE) in serum and lymphatic fluid, as well as the levels of IL-1β, IL-8, TNF-α, HMGB1 and RAGE in lung and intestinal tissues. Inhibiting the overexpression of TLR4 in lymphatic fluid, it is believed that honokiol blocks the damage of inflammatory cytokines in intestinal lymph to the intestinal mucosal barrier by inhibiting the HMGB1-TLR4/NF-κB signal transduction pathway, reduces the expression of inflammatory cytokines in lung tissue, and alleviates lung tissue congestion, edema, hemorrhage and inflammatory cell infiltration in rats with acute pancreatitis, so that the lung histopathological score is reduced from an average of 2.67 points in the control group to 1.50 points, which plays a protective role in lung injury.
Zhou et al. [26] reported that the establishment of a mouse viral pneumonia model with influenza virus H1N1 nasal challenge and the simultaneous use of ig honokiol 96, 192, and 384 mg·kg-1 twice a day for 7 consecutive days could reduce the lung index of pneumonia mice by 22.5%, 34.1%, and 38.9%, respectively. By down-regulating the expression of TLR-7, intracellular myeloid differentiation factor-88, TNF-α and NF-κB in lung tissues of pneumonia mice, the inflammatory cell infiltration, alveolar structure destruction and alveolar wall thickening of lung tissues were alleviated, and the effect of prevention and treatment of viral pneumonia was produced.
Liu Bo et al. [27] used intratracheal injection of bleomycin to make a rat pulmonary fibrosis model, and the IP of honokiol 50 mg·kg-1 per day for 28 consecutive days began on the second day of modeling, and the results showed that the lung index, alveolitis score, and hydroxyproline content of lung tissue in pulmonary fibrosis rats decreased significantly from 22.05 g·kg-1, 2.33 points, and 1.20 μg·mg-1 in the model control group to 8.46 g·kg-1, 1.16 points, and 1.02 μg·mg-1, respectively. The alveolar wall in the lung tissue of rats with pulmonary fibrosis was not significantly damaged, the pulmonary septum was significantly narrowed, and the inflammatory cell infiltration, myofibrillar cell proliferation and fibroblast production were significantly reduced. The above-mentioned anti-pulmonary fibrotic effects of honokiol began to manifest themselves on the 7th day of administration.
Li Haibo[28] reported that the effect of honokiol in 1~20 μmol· Low concentrations of L-1 promoted DNA synthesis and cell growth in lung H460 cells, but at ≥40 μmol· L-1 is inhibitive; Magnolol 1~20 μmol· L-1 can protect lung H460 cells from oxidative stress induced by tert-butyl hydrogen peroxide and improve cell viability, and the protective effect on cells is significantly stronger than that of N-acetylcysteine. Therefore, it is believed that honokiol protects lung cells by down-regulating p53 phosphorylation and the expression of PTEN, as well as up-regulating the phosphorylation of Akt, against tert-butyl hydrogen peroxide-induced single-stranded DNA destruction and lipid peroxidation.
Wang et al. [29] gave 10 and 30 mg·kg-1 of the animal IP honokiol 30 min before intrapleural injection of calcium ionophore A23187 to make a mouse pleurisy model, which could reduce the pleurisy inflammation of model mice and reduce the leakage of protein, leukocytes and polymorphonuclear leukocytes into the pleural cavity, and the number of polymorphonuclear leukocytes in the pleural cavity was reduced by 62.1% and 88.6%, respectively. The 30 mg·kg-1 group of honokiol also reduced the levels of prostaglandin-E2 and leukotriene-B4 in the pleural fluid of pleurisy mice, but the 10 mg·kg-1 group did not have this effect.
After 2 days of administration, the lung injury model of IV trioleate could be used to resist the loss of inflammatory exudation and structural damage to the exfoliated epithelium and cilia loss caused by inflammatory exudation and structural damage in the alveolar cavity caused by glyceryl IV trioleate for 2 days, and the expression of α-smooth muscle actin and collagen fiber deposition in the alveolar septum, blood vessel wall and bronchi were significantly increased. The number of CD68-positive macrophages in lung tissue was significantly increased, and honokiol is thought to protect the lungs from trioleate damage through anti-inflammatory, antioxidant, and antifibrotic effects [30].
Due to the low solubility of honokiol, Tsai et al. [31] made honokiol into PK3 particles loaded with honokiol polyketone, and PK3 particles administered to a low dose of honokiol (0.5 mg·kg-1) in the trachea could significantly inhibit the pneumonia response caused by LPS in rats.
3 and the respiratory pharmacological effects of honokiol
3.1 Prevention and treatment of asthma
Teng et al. [32] reported that the asthma model was made by ovalbumin and aluminum hydroxide sensitization, and that 0.02 mg of Ig and honokiol in the model mice was given 0.5 h before each asthma stimulation with ovalbumin could significantly reduce the area of common bronchial casts, inner wall and smooth muscle from 25.3, 20.6 and 5.8 μm2 in the control group to 20.2, 16.9 and 3.8 μm2, respectively, with a slight inflammatory response and a decrease in mucus secretion. Serum vascular endothelial growth factor decreased from 5.76 ng·mL-1 in the control group to 2.81 ng·mL-1, suggesting that honokiol delayed the occurrence of airway remodeling by inhibiting the expression of vascular endothelial growth factor, resulting in antiasthmatic effect.
Qin Chao et al. [33] used the experimental method of Teng Hong et al. [32] to change Ig to IP and honokiol 150 μg·kg-1, and lung histopathological morphological examination found that honokiol could alleviate bronchial lumen stenosis, bronchial wall thickening, smooth muscle layer thickening, airway epithelial cell necrosis and sloughing, and airway and perivascular inflammatory cell infiltration. It can also reduce the number of neutrophils, eosinophils and total inflammatory cells in bronchoalveolar lavage fluid, the levels of IL-4, IL-6 and IL-17 in serum, the protein expression of MDA and DNA double-strand break markers γH2Ax, caspase-3, NF-κB and phosphorylated JNK in lung tissue, and improve the activity of SOD, GSH-Px and Bcl-2 protein expression levels in lung tissue. It reduces oxidative stress inflammatory response, reduces tracheal epithelial cell apoptosis, alleviates lung tissue damage and inflammatory response in asthma mice, and produces antiasthmatic effects. Liu et al. [34] also suggested that honokiol can inhibit the PI3K/Akt signaling pathway and produce asthmatic effects by downregulating the overexpression of TLR-2 and TLR-4 genes and proteins in lung tissue.
Xu Jiali et al. [35], Han Feng et al. [36], and Fu et al. [37] reported that PM2.5 particles can aggravate asthma symptoms and lung tissue damage caused by ovalbumin-induced mice in mice, respectively. For example, at the beginning of asthma with ovalbumin, ig and honokiol 8 μg·kg-1 can alleviate PM2.5 aggravated inflammatory symptoms, reduce lung tissue damage, lung interstitial thickening, alveolar and bronchial lumen space enlargement, and inflammatory cell infiltration. Reducing the number of neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage fluid, reducing the level of inflammatory cytokine IL-17, and increasing the level of IL-10 can down-regulate the expression of IL-17, TLR4, NF-κB and retinoin-related orphan nuclear receptor-γ (RORγt) and the proportion of T helper cells-17 (Th17), and up-regulate the proportion of regulatory T cells (Treg cells) and IL-10, The expression of forkhead transcription protein-3 (Foxp3) is thought to inhibit the inflammatory response mediated by the TLR-4/NF-κB signaling pathway by upregulating the expression of Foxp3, and can also produce antiallergic asthma effects by balancing Th17 cells/Treg cells.
Nan Li Gang et al. [38] used rats to conduct experiments, and gave ovalbumin-sensitized rats to inhale ovalbumin once every other day for 8 consecutive weeks to stimulate asthma, and 1 h before each asthma stimulation, IP and honokiol 5 mg·kg-1 or dexamethasone 0.5 mg·kg-1 could alleviate the positive reactions of wheezing, increased respiratory rate, faltering, irritability, and abdominal muscle spasm during ovalbumin attack. Alleviate the thickening of the bronchial wall and smooth muscle layer of the lung tissue, the shedding and necrosis of airway epithelial cells, the narrowing of the bronchial lumen, and the infiltration of a large number of inflammatory cells around the airways and blood vessels seen during ovalbumin attack; Reducing the total number of inflammatory cells, eosinophils, neutrophils, inflammatory cytokines IL-4, IL-6, IL-17 levels and YAP protein levels in serum and bronchoalveolar lavage fluid in serum and bronchoalveolar lavage fluid after challenge, and the above effects of honokiol are similar to those of dexamethasone.
Ko et al. [15] reported that 0.1~100 μmol· L-1 can inhibit the contraction of porcine tracheal smooth muscle caused by high potassium or carbacholine in concentration, but does not affect its basal tension, and the inhibitory effect is still present after washing away the drug, indicating that the inhibitory effect of honokiol is irreversible. and honokiol also inhibited Ca2+-dependent tracheal smooth muscle contraction caused by hyperpotassium depolarization; Calcium channel blockers can weaken the contraction caused by carbachol by 30%, but can not further enhance the inhibition of contraction caused by honokiol, if the pretreated calcium channel blocker is washed off, it can partially restore and magnokiol inhibits the contraction response caused by carbachol; Because honokiol does not affect the contraction of porcine-induced tracheal smooth muscle in pigs, it is believed that honokiol may release calcium ions by blocking voltage-gated Ca2+ channels instead of intracellular calcium pools, that is, by blocking Ca2+ influx, it relaxes tracheal smooth muscle and produces an antiasthmatic effect.
3.2 Prevention and treatment of lung injury
Wang et al. [39-40] used LPS to make a mouse model of acute lung injury, and ip and honokiol 10 and 50 μg·kg-1 reduced the lung wet-to-dry mass ratio from 6.85 in the model control group to 5.93 and 4.82, respectively, and increased the alveolar fluid clearance rate from 18% to 37% and 76%, respectively. Dose-related reductions in neutrophil count, albumin concentration, and Evans blue concentration in bronchoalveolar lavage fluid can reduce alveolar permeability in lung injury mice; It increased the partial pressure of oxygen and pH of blood, down-regulated the overexpressed TNF-α and IL-1β in serum, the activity of myeloperoxidase in lung tissue, the content of lipid peroxide MDA, ROS, protein carbonyl content, MMP-9 and NF-κB, and up-regulated the activities of antioxidant enzymes SOD, catalase, reduced GSH-Px, glutathione-S-transferase and reduced glutathione levels in lung tissue, and believed that honokiol inhibited oxidative stress inflammatory response through antioxidant effect. Mitigate LPS-induced acute lung injury.
Wang Guizuo et al. [41] gave ip and magnokiol 5 mg·kg-1 to mice 1 h before LPS induced acute lung injury, which could resist the destruction of alveolar wall structure and inflammatory cell infiltration caused by intratracheal instillation of LPS. The total number of cells and neutrophils in the anti-bronchoalveolar lavage fluid increased, the levels of inflammatory cytokines IL-1β and IL-6 increased, and the expression of IL-10 and HO-1 in lung tissue was further up-regulated. Giving mice pre-ip and honokiol 10 and 50 μg·kg-1 can also fight against acute lung injury caused by LPS: dose-related reduction of bronchoalveolar lavage fluid protein and cell content and myeloperoxidase activity, increase the level of antioxidant enzymes SOD, catalase, reduced glutathione and reduce MDA levels in lung tissue, and also counter LPS activation of MMP-9, that is, honokiol can also improve the endogenous antioxidant system and inhibit MMP activity. Combating LPS-induced acute lung injury [42].
Intratracheal injection of LPS into rats with 1.25, 2.5 and 5 mg·kg-1 of ip and honokiol every 0.5 hours can be dose-related to counter LPS-induced acute lung injury in rats: reduce the pathological score and inflammatory cell number of acute lung injury, reduce alveolar hemorrhage, pulmonary interstitial edema, and lung wet-to-dry mass ratio; Anti-LPS increased myeloperoxidase activity and MDA level in bronchoalveolar lavage fluid, and reduced SOD level; and honokiol can also increase the gene and protein expression of Nrf2 and HO-1 in lung tissue; Anti-LPS increased the gene and protein expression of NLRP3, ASC, CASP1 and GSDMD in lung tissue, and the levels of lactate dehydrogenase, IL-18 and IL-1β in bronchoalveolar lavage fluid, i.e., honokiol inhibited the occurrence of pyroptosis by blocking the activation of NLRP3 inflammasome; The Nrf2 inhibitor ML385 can resist the above-mentioned anti-LPS effects of honokiol.
In vitro experiments showed that 12.5, 25, and 50 μmol· L-1 concentration correlated to decrease LPS+ATP, increase the number of PI-stained positive cells of normal human bronchial epithelial cells BEAS-2B, and the lactate dehydrogenase level of supernatant in culture medium. It reduces the gene and protein expression of NLRP3 and NLRP3 inflammasome markers ASC, CASP1, and GSDMD, inhibits the production of IL-18, IL-1β, and MDA, and upregulates the gene and protein expression of Nrf2 and HO-1 and SOD levels, which is consistent with the overall experimental results, that is, honokiol inhibits oxidative stress by activating Nrf2, thereby blocking NLRP3 inflammasome-mediated pyroptosis, and alleviating LPS-induced acute lung injury [43].
Chen Lan et al. [44-45] used 1.25, 2.5, and 5 μmol· L-1 pretreatment could improve the survival rate of LPS-stimulated human lung microvascular endothelial cells, inhibit LPS-induced apoptosis, and maintain the normal physiological function of mitochondria. Inhibition of deacetylase-3 (SIRT3) with nicotinamide or inhibition of adenylate-activated protein kinase (AMPK) with complex C can partially block and the protective effect of honokiol on pulmonary vascular endothelial cells; The results of dose-related dose-related reduction of inflammatory response in lung tissue, up-regulation of SIRT3 gene and protein expression, inhibition of angiopoietin-2 expression, alleviation of pulmonary vascular endothelial cell injury, reduction of pulmonary microvascular permeability, alleviation of pulmonary edema, and improvement of survival rate of model mice.
It is believed that honokiol may inhibit the expression of angiopoietin-2, up-regulate the expression of vascular endothelial cadherin and β-catenin, down-regulate the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, protect the vascular endothelial barrier, and alleviate the acute respiratory distress syndrome caused by LPS by activating the SIRT3/AMPK signaling pathway.
Nie Jia et al. [46] instilled Pseudomonas aeruginosa into the trachea of mice to establish a pneumonia model, and started Ig and honokiol 96, 192, and 384 mg·kg-1 for 4 consecutive weeks 2 h after modeling, and the results showed that the lung index of pneumonia mice was dose-correlated, from 1.85% in the model control group to 1.57%, 1.31%, and 1.09%, respectively, and reduced inflammatory cell infiltration, edema, interstitial congestion, and alveolar wall thickening in lung tissue. It can also dose-correlate the gene and protein expressions of TLR4, myeloid differentiation factor-88 (MyD88) and NF-κB in serum IL-6, IL-1β, TNF-α, lung tissue of pneumonia mice, and it is believed that honokiol is the treatment of bacterial pneumonia by inhibiting the TLR4/MyD88/NF-κB signaling pathway.
Li Bin et al. [47] gave cigarette smoke-induced chronic obstructive pulmonary disease (COPD) model mice an alternate day with IP and 10 mg·kg-1 of magnokiol for 30 days, which reduced the distal terminal bronchioles airspace expansion, space narrowing, alveolar cavity dilation, alveolar wall rupture, reduced inflammatory cell infiltration, and increased alveolar number. In terms of lung function, it can improve the low peak inspiratory flow rate and peak expiratory flow rate of mice with chronic obstructive pulmonary disease; Increasing the levels of IL-4 and IL-10 in the serum of model mice, reducing the levels of IL-17 and TNF-α, the percentage of Th1, the ratio of Th1/Th2, the percentage of Th17 and the ratio of Th17/Treg of T cell subsets can correct the immune imbalance, because honokiol can significantly reduce the protein expression of Notch 1, Notch 2, Notch 3, Hes 1, Hes 5 and Hey 1 in the spleen T cells of model mice. It is thought that honokiol may correct the immune imbalance of T cells and improve lung function by inhibiting the activation of the Notch signaling pathway.
Xiao Lei et al. [48] placed neonatal rats in a hyperoxic environment, and 10, 25, and 50 μg·kg-1 of IP and honokiol per day for 14 consecutive days for 14 days could dose-correlate against hyperoxia-induced bronchial and pulmonary dysplasia: reducing pulmonary edema, punctate hemorrhage, alveolar wall thickening, and alveolar number reduction; The wet-to-dry mass ratio of the lungs decreased from 7.97 in the model control group to 7.18, 6.47 and 5.78, the Holfbauer score decreased from 3.36 to 2.81, 2.07 and 1.02, and the radial alveolar count increased from 5.79 to 6.47, 7.29 and 8.11, respectively. It is believed that honokiol can promote alveolar regeneration by inhibiting the Hippo signaling pathway and up-regulating the expression of YAP, thereby promoting alveolar regeneration and preventing bronchopulmonary dysplasia caused by hyperoxia.
4 Conclusion
Magnolia officinalis has cough and expectorant effects, and has a biphasic effect of contraction and relaxation on tracheal smooth muscle. Magnokiol and honokiol are isomers of hydrophobic allyl biphenol structure, and are also the main active components of Magnolia officinalis to produce respiratory pharmacological effects. Both honokiol and honokiol have the effect of relaxing tracheal smooth muscle and flattening, and both have lung protection and anti-lung damage caused by various pathological factors. Magnokiol and honokiol also exhibit broad-spectrum antiviral, antibacterial, and cytoprotective effects [2,49-55]. Therefore, the author recommends honokiol and honokiol as drug candidates for the prevention and treatment of viral pneumonia for further research and development.
The lung protective effect of honokiol and honokiol is mainly due to their antioxidant stress inflammatory response, and their antioxidant activity is manifested by direct scavenging of free radicals and increasing the activity of antioxidant enzymes in the body to indirectly quench free radicals [56]. In recent years, it has been discovered that honokiol can also activate the activity of antioxidant enzymes in the body by upregulating the expression of various deacetylases (SIRTs), indirectly reducing free radicals in the body, and producing cytoprotective effects [44-45,53]. Unfortunately, there is no literature on the upregulation of SIRT expression by honokiol, and it is hoped that experimental studies in this area will be carried out in the future.
and honokiol and honokiol inhibit SIRT expression when anti-tumor cells [57]. It has been reported in the literature that the concentration of honokiol in ≤20 μmol· L-1 protected human lung cancer H460 cells through antioxidant effect, and when the concentration was ≥40 μmol· L-1, but the authors did not investigate whether honokiol is anti-cancer by enhancing oxidative stress [28]. Zhang Ning [58] also reported that the concentration of honokiol was less than 15 μmol· L-1 promoted the growth of pancreatic cancer PANC-1 cells and Miapaca cells, and the concentration was higher than 15 μmol· L-1 can inhibit the proliferation of these two pancreatic cancer cells in a concentration-correlated manner. However, the high concentration of honokiol (5~15 mg· L-1) induced apoptosis in colorectal cancer RKO cells and rapidly increased ROS production, which was lower than the induced apoptosis concentration (0.1~5 mg· L-1) inhibited ROS production [59].
The authors speculate that honokiol and honokiol are reducing agents and SIRT expression promoters at low concentrations, and exhibit antioxidant effects under oxidative stress. At high concentrations, it is an oxidant and an inhibitor of SIRT expression, which can cause oxidative stress damage to cells. It is hoped that the investigators will demonstrate this hypothesis, because it is the theoretical basis to guide the dose selection for clinical use in cell protection or anti-tumor, and it is also an important basis for the development of new drugs.
Source: Zhang Mingfa, Shen Yaqin. Research Progress on Respiratory Pharmacological Effects of Magnolia Officinalis Extract and Its Active Ingredients [J]. Drug Evaluation Research, 2024, 47(4): 904-913.