Yanan Sun
Lu Xu
Qihan Cai
Mengmeng Wang2- 1College of Traditional Chinese Medicine, Hebei University, Baoding, China
- 2School of Basic Medical Science, Hebei University, Baoding, China
- 3Affiliated Hospital of Hebei University, Baoding, China
- 4Clinical Medical College, Hebei University, Baoding, China
- 5Hebei Collaborative Innovation Center of Tumor Microecological Metabolism Regulation, Baoding, China
Matrine possesses anti-cancer properties, as well as the prevention and treatment of allergic asthma, and protection against cerebral ischemia-reperfusion injury. Its mechanism of action may be (1) regulation of cancer cell invasion, migration, proliferation, and cell cycle to inhibit tumor growth; (2) reduction of oxidized low-density lipoprotein and advanced glycation end products from the source by exerting anti-inflammatory and antioxidant effects; (3) protection of brain damage and cortical neurons by regulating apoptosis; (4) restoration of the intestinal barrier and regulation of the intestinal microbiota. This article aims to explore matrine’s therapeutic potential by summarizing comprehensive information on matrine’s pharmacology, toxicity, and bioavailability.
Introduction
The dry roots of Leguminosae, Sophora herbs or subshrubs, Sophora flavescens Alt., and Sophora tonkinensis. They are widely used in clinical practice due to their ability to treat various damp-heat syndromes, carbuncle sores, and other heat-toxic syndromes and skin itching (Li et al., 2021). Matrine structure (MT) is shown in Figure 1, it is the main bioactive component of Sophora flavescens Alt. and Sophora tonkinensis roots (Gu et al., 2019; You et al., 2019), it can easily penetrate the biofilm barrier and produces a wide range of pharmacological effects (Table 1), including anti-cancer, anti-inflammatory, antioxidant, neuroprotective, etc., (You et al., 2020). However, the toxicity and bioavailability of MT in clinical usage remain unclear, and its absorption, distribution, metabolism, and excretion in vivo can affect its future development and application. Therefore, it is urgent to clarify the mechanism of MT as well as its toxicity and pharmacokinetics. This article explores matrine’s therapeutic potential by summarizing recent advances in the pharmacology, toxicology, and pharmacokinetics of MT, with an emphasis on its mechanism of action. Finally, the prospect of MT has been discussed.
Figure 1. Chemical structure of matrine.
Table 1. Pharmacology of matrine.
Pharmacological effects of matrine
Anticancer effects
The treatment of cancer is a growing problem in much of the world and is becoming increasingly urgent. Cancer is characterized by uncontrolled tumor cell proliferation caused by the abnormal activity of various cyclins; therefore, cell cycle regulators are considered attractive targets in cancer therapy (Otto and Sicinski, 2017). MT can induce a G0/G1 cycle arrest in human non-small cell lung cancer cells by downregulating the activity of the epidermal growth factor receptor (EGFR)-Akt signaling pathway and inhibiting the growth of human non-small cell lung cancer cells; MT can inhibit tumor volume in vivo and weight, with inhibition rates of tumor transplanted mice were 16.29 and 35.35%, respectively (Li et al., 2018). MT inhibits gastric cancer cell proliferation in a dose-dependent manner by arresting cells in the G1 phase; it significantly inhibits gastric cancer cell migration and invasion by inhibiting EGFR phosphorylation (Guo et al., 2015). As can be shown, EGFR is an important anti-tumor target of MT. The viability and single-cell proliferation of breast cancer cells was significantly inhibited after MT treatment in a time- and concentration-dependent manner; additionally, the cell cycle of MT-treated breast cancer cells was arrested in the S phase and induced mitochondrial-mediated apoptosis, indicating that MT plays an important role in inhibiting breast cancer cell carcinogenesis (Wu et al., 2017b).
Matrix metalloproteinase(MMP)-2 and -9 are two related zinc-dependent endopeptidases that are critical in cancer cell invasion and migration, and MMP-2 and -9 are expressed at high levels in cancer tissues and invasive cell lines (Chang et al., 2015). The study found that intraperitoneal injection of MT could significantly inhibit tumor growth after transplanting cervical cancer cells into nude mice; it reduces the expression and activity of extracellular matrix factor, MMP-2, and MMP-9 by inhibiting the p38 signaling pathway, and inhibits the growth and metastasis of cervical cancer (Wu et al., 2017c). MT inhibits the proliferation of human non-small cell lung cancer cells, which induces apoptosis by altering miRNA expression profiles (Liu et al., 2014). In addition to the cancers listed above, it inhibits colorectal cancer (Ge et al., 2016), neuroblastoma (Mallepalli et al., 2019), etc.
Anti-inflammatory effect
Oxidized LDL increases macrophage inflammatory response by activating reactive oxygen species (ROS)-mediated MKKs/p38 MAPK signaling pathway; MT can significantly reduce intracellular ROS production and further inhibit the activation of the MKKs/p38 MAPK signaling pathway to suppress oxidized low-density lipoprotein-induced inflammation (Zhou et al., 2019). In vivo experiments, BALB/c mice sensitized to ovalbumin-induced allergic asthma. Human tracheal epithelial cells were pretreated with MT and then cultured with TNF-α in vitro; it was found that MT can significantly reduce airway hyperresponsiveness in asthmatic mice, inhibit goblet cell hyperplasia, eosinophil infiltration, and inflammatory response in mice lung tissue; and can reduce the production of pro-inflammatory cytokines in human tracheal epithelial cells (Huang et al., 2014). Mouse mastitis was induced by lipopolysaccharide and MT was intraperitoneally injected before and after lipopolysaccharide induction, which could inhibit NF-κB signal path NF-κB p65 and I κ The phosphorylation of B decreased the phosphorylation of p38, ERK and JNK of mitogen activated protein kinases (MAPKs) signal pathway, and significantly reduced the damage of LPS to mammary gland (Yang et al., 2014). Similarly, MT treatment of BV2 microglia reduced inflammatory mediator levels following LPS stimulation by inhibiting NF-κB, ERK 1/2, p38MAPK, and JNK activation in activated microglia. This finding suggests that MT may provide a beneficial role in the treatment of inflammatory brain injury (Dong et al., 2013). Intraperitoneal injection of MT into traumatic brain injury rats found that MT can inhibit the Toll-like receptor 4/NF-κB-dependent inflammatory response, reducing neuronal apoptosis after traumatic brain injury (Dong et al., 2011). A similar finding was obtained by the treatment of MT in the brain neuroinflammation model established by injecting lipopolysaccharide into the hippocampus of rats, indicating that MT may effectively treat neuroinflammation in the brain (Mao et al., 2012). Extracellular release of heat shock protein 60 (HSP60) increases other pro-inflammatory effects by binding to Toll-like receptor 4 (TLR-4) and stimulating neuronal cell death generation factors (Zhang et al., 2012; Cheng et al., 2014). By inhibiting the HSP60 signaling pathway, MT can prevent microglia activation (Zhang et al., 2017).
Antioxidant effect
Renal ischemia-reperfusion produces excess ROS, such as superoxide radicals, hydrogen peroxide, and hydroxyl radicals, and down-regulates the expression of some endogenous antioxidant enzymes, resulting in oxidative stress in the kidney, which MT can significantly reverse. Reperfusion-induced decrease in superoxide dismutase (SOD) activity and increase in malondialdehyde (MDA) levels suggest that MT can alleviate oxidative stress by enhancing endogenous antioxidant capacity and reducing lipid peroxidation (Jiang et al., 2015a). MT can inhibit As2O3-induced liver pathology and reduce liver ROS and MDA levels in a dose-dependent manner, which protects As2O3-induced oxidative damage via the Nrf2/HO-1 signaling pathway (Li et al., 2017). By promoting the translocation of Nrf2 to the nucleus and thereby up-regulating the expression of antioxidant enzymes and improving antioxidant activity, MT can effectively prevent the transformation of high-fructose diet-induced hepatic steatosis into non-alcoholic steatohepatitis in rats (Zhang et al., 2013a). MT can also increase glutathione (GSH), catalase (CAT), and glutathione mercaptotransferase (GST) levels in the prefrontal cortex and hippocampus of mice, while reducing MDA and nitrite levels, reducing the oxidative stress induced by CCl4 (Khan et al., 2019). Both in vivo and in vitro, advanced glycation end-products can lead to excessive production of ROS, induce apoptosis of vascular endothelial cells, and inhibit the antioxidant signal transduction of p38MAPK/Nrf2/ARE; it was found that the use of matrine alkaloids could restore the activity of p38MAPK/Nrf2/ARE, and p38MAPK kinase MKK3/6 can be considered as the molecular target of matrine alkaloids. Matrine alkaloids exert a protective effect on ROS-mediated apoptosis induced by advanced glycation end-products by targeting MKK3/6 and enhancing its phosphorylation (Liu et al., 2017b).
Neuroprotective effect
The pharmacological mechanism of MT was studied by detecting the pharmacological properties of MT against focal cerebral ischemia in vivo and the neurotoxicity induced by N-methyl-D-aspartic acid (NMDA) in vitro. It was found that MT could regulate NMDA receptors (NMDARs) through the Bcl-2 and Bax families to over-activate NR2B and cause apoptosis, thereby protecting brain injury in vivo and cortical neurons in vitro (Zhang et al., 2013b). Some studies have reported that MT exhibits an analgesic effect on the vincristine-induced neuropathic pain mouse model that is mediated by regulating endogenous antioxidant defense mechanism and pro-inflammatory cytokines (Linglu et al., 2014; Gong et al., 2016). In addition, the anti-inflammatory and antioxidant effects of MT can significantly improve the learning and memory function of diabetic rats (Wang and Jia, 2014). Another study found that MT reduces cognitive impairment in diabetic mice by inhibiting endoplasmic reticulum stress and regulating the PK2/PKRs pathway (Zhang et al., 2022). By inhibiting apoptosis and oxidative stress, MT has a potential neuroprotective effect on cerebral ischemia-hypoxia injury in rats, and its mechanism may be related to Akt and GSK3β and the regulation of the Nrf-2/HO-1 signaling pathway (Ge et al., 2018). MT can also play a role in cerebral ischemia-reperfusion injury in rats, significantly reducing infarction and edema, and improving neural function after cerebral ischemia-reperfusion (Li et al., 2011). Similarly, MT pretreatment could significantly reduce infarct size and improve neurological function scores; it can also reduce the percentage of apoptotic neurons and morphological damage of neurons (Zhao et al., 2015). Burned mice exhibit anxiety- and depression-like behaviors, whereas MT exerts significant anxiolytic and antidepressant effects by inhibiting JNK-mediated apoptosis/inflammatory signaling, oxidative stress, and reversing burn-induced hippocampal BDNF/VEGF downregulation (Khan et al., 2020).
Matrine structure can restore Th17/Treg cytokine balance and alleviate cognitive impairment in Alzheimer’s disease rats in a dose-dependent manner (Zhang et al., 2015); MT can improve scopolamine-induced amnesia by inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities (Sun et al., 2019a). Meng et al. (2017) demonstrated that MT has a neuroprotective effect against MPTP-induced Parkinson’s disease. MT has an analgesic effect on neuropathic pain caused by chronic contractile injury; however, its mechanism requires more molecular and cellular research (Haiyan et al., 2013). MT can effectively suppress the severity of experimental autoimmune encephalomyelitis (EAE), increase myelin protein production in the central nervous system, and activate the corpus callosum P13K/Akt/mTOR signaling pathway (Liu et al., 2017a). In addition, MT can protect stressed oligodendrocytes by inhibiting apoptosis and enhancing mitochondrial autophagy, so achieving the purpose of effective treatment of EAE (Wang et al., 2019). In the CNS of EAE, MT inhibits A1 production and promotes neuroprotective A2 production; MT also downregulates the expression of vascular endothelial growth factor-A and upregulates the expression of the tight junction proteins Claudin 5 and Occludin, thereby protecting the BBB from damage caused by CNS inflammation (Jing et al., 2021).
In addition to the above findings, MT can increase synaptic density and promote the remodeling and reconnection of neural circuits (Tanabe et al., 2019). Kan et al. (2017) discovered that MT significantly induced the expression of camp and PKA in cells and promoted axonal regeneration; and cAMP blockade significantly reduced MT-induced PKA expression and production of BDNF, which is an effective neurotrophic factor for nerve regeneration, indicating that MT can directly promote regeneration of the injured central nervous system.
Effects on the gut and gut microbes
Glucagon-like peptide-1 (GLP-1) released from intestinal endocrine cells, controls dietary-related blood glucose fluctuations by increasing insulin and inhibiting glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, maximizes nutrient absorption, and limits weight gain (Drucker, 2018). MT can act as a calcium-sensing receptor (CaSR) agonist and stimulate GLP-1 intestinal secretion (Guo et al., 2021). Through NF-κB-mediated signaling, MT can reverse CCl4-induced histological changes and restore intestinal barrier integrity (Wen et al., 2014). MT was also found to improve gut barrier integrity in mice with dextran sulfate-induced ulcerative colitis; it also altered gut microbiota composition and function, such as increased human Pasteurella enterica abundance and reduced Helicobacter gammanii abundance, to achieve the purpose of improving colitis (Yao et al., 2021). LPS-induced intestinal inflammation and oxidative balance were improved by MT, as was the expression of the intestinal chemokine receptor 7 (CCR7), and CCR7 siRNA transfection inhibited MT’s protective effect (Wu et al., 2017a).
Biofilm formation is linked to bacteria’s perception of their surroundings and bacterial density (Kai, 2018), and quorum-sensing systems are lacking in bacterial biofilms (Kumar et al., 2016). MT has a biofilm inhibitory effect, diminishing E. coli resistance in terms of inter-community communication, and drug-resistant strains treated with MT showed reduced adhesion, reducing E. coli pathogenicity (Sun et al., 2019b). Different administration routes of MT can cause differences in the intestinal flora. MT delivered intraperitoneally is more favorable to improving the structure and function of intestinal flora than MT administered via gavage. Intraperitoneal MT injection can significantly change the structure of Kunming mice’s intestinal flora, increase the colonization of beneficial bacteria Lactobacillus acidophilus in the intestinal tract, and cause differences in metabolic pathways such as glycan biosynthesis and metabolism, transport, and catabolism. The identification of the mechanism by which MT exerts its pharmacodynamic effect laid the foundation. MT does not affect the structure of the intestinal flora in mice, unlike the steady decline in the diversity and richness of the intestinal flora in mice induced by the overuse of antibiotics such as amoxicillin. However, amoxicillin changes the composition and structure of the microbial community by increasing the ratio of pathogenic bacteria to beneficial bacteria, whereas MT increases the number of beneficial bacteria, and provides a rationale for developing antibiotic alternatives to reduce bacterial resistance and gut flora imbalance (Wu et al., 2021).
In other animal models, such as mice, trinitrobenzene sulfonic acid can induce intestinal inflammation, colon damage, and intestinal microbiota dysbiosis, and MT significantly improves the intestinal microbiota community and protects intestinal tissue (Li et al., 2019).
Toxicity of matrine
Matrine structure has a wide spectrum of pharmacological effects; however, its toxic effects limit its clinical application (Table 2).
Table 2. Toxicity of matrine.
Aside from dosage, it is unreasonable to discuss the toxicity of any drug, and MT is no exception. A low concentration of matrine (7, 14, and 21 mg/L) enhances ethoxycoumarin-O-demethylation (ECOD) activity and reduces cytokine-induced NO2- levels in human hepatocytes. For 72 h, a moderate dosage of matrine (140 mg/L) induced the expression of CYP2A6, CYP2B6, and CYP3A4 proteins, indicating that it can regulate the CYP450 enzyme system to protect hepatocytes. In addition, high concentrations of matrine (250, 500, and 1,000 mg/L) reduced the levels of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST), and cytotoxicity to hepatocytes, resulting in decreased cell viability and total protein content (Gong et al., 2015). Increased taurine in urine is a biomarker for liver injury caused by several drugs (Wang et al., 2013; Li et al., 2014). Thus, elevated taurine levels in rat urine suggest that high-dose MT induces liver dysfunction and damage (Li et al., 2015). At hepatotoxic doses, MT caused centrilobular hypertrophy of the mouse liver; in addition, other matrine alkaloids were more toxic in combination with MT than MT alone (Gu et al., 2019). Caspase-3 and caspase-9 activation was observed in normal mouse hepatocytes treated with MT; after intraperitoneal injection of MT into healthy mice, vacuolar degeneration was found in the cytoplasm of mouse liver tissue. Furthermore, high concentrations of matrine (500 and 1,000 mg/L) were shown to induce ROS production and inhibit mitochondrial membrane potential and ATP level, which may be related to matrine toxicity to hepatocytes (Liu et al., 2020). It can be seen that changing the concentration of matrine has an opposite effect on antioxidation. The effects of endoplasmic reticulum stress and ROS-mediated JNK phosphorylation are linked to MT-induced cellular injury in human normal hepatocytes. Antioxidants, JNK phosphorylation inhibitors, and endoplasmic reticulum stress inhibitors may be potential antidotes to MT and Chinese medicine containing MT-induced liver damage (Gu et al., 2018). Past studies have demonstrated that the hepatotoxic effect of MT is exerted by inhibiting the Nrf2 pathway, activating the ROS-mediated mitochondrial apoptosis pathway, and arresting the cell cycle in the S phase (You et al., 2019). However, the antioxidant N-acetylcysteine reverses MT-induced hepatotoxicity and ROS production (Liu et al., 2020).
In addition to being hepatotoxic, MT has also been shown to be developmental and neurotoxic to zebrafish embryos, as well as teratogenic and lethal (Lu et al., 2014). MT depresses the central nervous system and impairs balance and coordination in ICR mice when administered at doses of 10 and 40 mg/kg/day for 60 days.
Pharmacokinetics of matrine
In addition to being hepatotoxic, the bioavailability of MT is not ideal and has a short in vivo half-life (Jiang et al., 2015b). The pharmacokinetics of MT in rats were studied using the UPLC-MS/MS method, and it was found that at the dose of 2 mg/kg, its absolute oral bioavailability was 17.1 ± 5.4% (Yang et al., 2010). Human organic cation transporters (hOCTs; SLC22) are highly expressed in the intestine, liver, kidney, heart, brain, and other organs, and are primarily responsible for the absorption, distribution, and elimination of endogenous and exogenous substances. When the inhibitory effect of MT on the functions of hOCT1 (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3) at 100-fold excess, it was found that MT did not significantly inhibit hOCT1, hOCT2, and hOCT3. At 6 mM, MT, on the other hand, exhibited an 88% inhibitory effect on hOCT3-mediated substrate uptake. These data suggest that drug interactions may occur during hOCT3-mediated intestinal absorption (Pan et al., 2014). The protein binding rate of MT in plasma is very low (5.10–10.55%), causing the drug to metabolize quickly and be eliminated from the body (Tang et al., 2013). AUC, Cmax, and Tmax are the key parameters of pharmacokinetics, the former reflects the degree of drug absorption, and the latter two comprehensively reflect the absorption, distribution, metabolism, and excretion of drugs. The pharmacokinetics of MT in organs and tissues such as liver, blood, and skin were studied after intravenous injection (40 mg/kg) or transdermal administration (6 mg/cm2, 5 cm2) in rats. AUC (0-t) values in the liver, Micro dialysate, and plasma after intravenous administration were 395.91 ± 74.48, 848.86 ± 146.35, and 1304.07 ± 305.92 min mg/l respectively; after transdermal administration (Tang et al., 2017). The difference in AUC indicates that the blood concentration of MT will be affected by different administration methods. These data allow us to better understand the transdermal pharmacokinetics of MT, which will contribute to further clinical and laboratory studies.
Conclusion and future prospects
Matrine structure can regulate the secretion of a variety of inflammatory factors and regulate the activation of multiple signaling pathways, indicating that MT’s mechanism of action is complex and has multiple targets. This article reviews the pharmacological effects and toxicities of MT and provides a reference for the treatment of related diseases. The main function of the matrine is to affect the intestinal tract and intestinal microorganisms. Matrine, as a calcium-sensitive receptor agonist, can activate intestinal tissue and restore the integrity of the intestinal barrier via the NF-κB-mediated signal pathway. In addition, it will also affect the composition and function of intestinal microbiota.
The brain-gut axis is a regulatory system for two-way signal communication between the nervous system and the gastrointestinal tract, and the digestive tract’s microbial community is an important participant in the brain-gut axis. Changes in intestinal information will be transmitted to the central nervous system through the vagus nerve, sympathetic nerve, etc. Matrine, as a result, has a therapeutic effect on central nervous system diseases.
To prevent inflammation, the intestinal flora stimulates the afferent neurons of the intestinal nervous system. Therefore, Matrine’s effect on intestinal flora contributes to its anti-inflammatory effect.
Increased proinflammatory cytokines production causes increased oxidative and nitrosative brain damage. Matrine’s anti-inflammatory effect also enables it to play as an antioxidant.
Finally, the pharmacological effect of matrine cannot be exerted without considering its impact on the intestine and intestinal microorganisms (Figure 2).
Figure 2. Pharmacological activities of matrine.
These pharmacological effects suggest that MT may have potential application value in psychiatric diseases such as depression. However, from the standpoint of the brain-gut axis, the current treatment of MT for depression has not been elucidated. Therefore, further exploring whether MT can improve depression through the brain-gut axis may have important significance for the clinical application of MT and the intervention of depression.
Author contributions
YS contributed to the overall organization of this review and the preparation of figures and tables. YS, LX, QC, MW, and XW contributed to writing. All authors contributed to the article and approved the submitted version.
Funding
This study was supported by Natural Science Foundation of Hebei Province, Hebei Province, China (H2021201043), the Training Program for Outstanding Clinical Medical Talents, Hebei Province, China (No. 2020), and the Outstanding Youth Scientific Research and Innovation Team (Science and Technology) Project of Hebei University, Hebei Province, China (No. 2020-8).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
Chang, W.-L., Yu, C.-C., Chen, C.-S., and Guh, J.-H. (2015). Tubulin-binding agents down-regulate matrix metalloproteinase-2 and -9 in human hormone-refractory prostate cancer cells – a critical role of Cdk1 in mitotic entry. Biochem. Pharmacol. 94, 12–21. doi: 10.1016/j.bcp.2015.01.005
Cheng, W., Li, Y., Hou, X., Zhang, N., Ma, J., Ding, F., et al. (2014). HSP60 is involved in the neuroprotective effects of naloxone. Mol. Med. Rep. 10, 2172–2176. doi: 10.3892/mmr.2014.2411
Dong, X.-Q., Du, Q., Yu, W.-H., Zhang, Z.-Y., Zhu, Q., Che, Z.-H., et al. (2013). Anti-inflammatory Effects of Oxymatrine Through Inhibition of Nuclear Factor-kappa B and Mitogen-activated Protein Kinase Activation in Lipopolysaccharide-induced BV2 Microglia Cells. Iran. J. Pharm. Res. 12, 165–174.
Dong, X.-Q., Yu, W.-H., Hu, Y.-Y., Zhang, Z.-Y., and Huang, M. (2011). Oxymatrine reduces neuronal cell apoptosis by inhibiting Toll-like receptor 4/nuclear factor kappa-B-dependent inflammatory responses in traumatic rat brain injury. Inflamm. Res. 60, 533–539. doi: 10.1007/s00011-010-0300-7
Drucker, D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 27, 740–756. doi: 10.1016/j.cmet.2018.03.001
Ge, L., Wang, Y. F., Tian, J. H., Mao, L., Zhang, J., Zhang, J. H., et al. (2016). Network meta-analysis of Chinese herb injections combined with FOLFOX chemotherapy in the treatment of advanced colorectal cancer. J. Clin. Pharm. Ther. 41, 383–391. doi: 10.1111/jcpt.12410
Ge, X.-H., Shao, L., and Zhu, G.-J. (2018). Oxymatrine attenuates brain hypoxic-ischemic injury from apoptosis and oxidative stress: Role of p-Akt/GSK3β/HO-1/Nrf-2 signaling pathway. Metab. Brain Dis. 33, 1869–1875. doi: 10.1007/s11011-018-0293-4
Gong, S.-S., Li, Y.-X., Zhang, M.-T., Du, J., Ma, P.-S., Yao, W.-X., et al. (2016). Neuroprotective Effect of Matrine in Mouse Model of Vincristine-Induced Neuropathic Pain. Neurochem. Res. 41, 3147–3159. doi: 10.1007/s11064-016-2040-8
Gong, X., Gao, Y., Guo, G., Vondran, F. W. R., Schwartlander, R., Efimova, E., et al. (2015). Effect of matrine on primary human hepatocytes in vitro. Cytotechnology 67, 255–265. doi: 10.1007/s10616-013-9680-1
Gu, L.-L., Shen, Z.-L., Li, Y.-L., Bao, Y.-Q., and Lu, H. (2018). Oxymatrine Causes Hepatotoxicity by Promoting the Phosphorylation of JNK and Induction of Endoplasmic Reticulum Stress Mediated by ROS in LO2 Cells. Mol. Cells 41, 401–412. doi: 10.14348/molcells.2018.2180
Gu, Y., Lu, J., Sun, W., Jin, R., Ohira, T., Zhang, Z., et al. (2019). Oxymatrine and its metabolite matrine contribute to the hepatotoxicity induced by radix Sophorae tonkinensis in mice. Exp. Ther. Med. 17, 2519–2528. doi: 10.3892/etm.2019.7237
Guo, B., Zhang, T., Su, J., Wang, K., and Li, X. (2015). Oxymatrine targets EGFR(p-Tyr845) and inhibits EGFR-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells. Cancer Chemother. Pharmacol. 75, 353–363. doi: 10.1007/s00280-014-2651-1
Guo, S., Yan, T., Shi, L., Liu, A., Zhang, T., Xu, Y., et al. (2021). Matrine, as a CaSR agonist promotes intestinal GLP-1 secretion and improves insulin resistance in diabetes mellitus. Phytomedicine 84:153507. doi: 10.1016/j.phymed.2021.153507
Haiyan, W., Yuxiang, L., Linglu, D., Tingting, X., Yinju, H., Hongyan, L., et al. (2013). Antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury. Pharm. Biol. 51, 844–850. doi: 10.3109/13880209.2013.767363
Huang, W.-C., Chan, C.-C., Wu, S.-J., Chen, L.-C., Shen, J.-J., Kuo, M.-L., et al. (2014). Matrine attenuates allergic airway inflammation and eosinophil infiltration by suppressing eotaxin and Th2 cytokine production in asthmatic mice. J. Ethnopharmacol. 151, 470–477. doi: 10.1016/j.jep.2013.10.065
Jiang, G., Liu, X., Wang, M., Chen, H., Chen, Z., and Qiu, T. (2015a). Oxymatrine ameliorates renal ischemia-reperfusion injury from oxidative stress through Nrf2/HO-1 pathway. Acta Cir. Bras. 30, 422–429. doi: 10.1590/S0102-865020150060000008
Jiang, M., Wang, L., Jiang, W., and Huang, S. (2015b). Simultaneous determination of 14-thienyl methylene matrine and matrine in rat plasma by high-performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 974, 126–130. doi: 10.1016/j.jchromb.2014.10.041
Jing, Y., Ma, R., Chu, Y., Dou, M., Wang, M., Li, X., et al. (2021). Matrine treatment induced an A2 astrocyte phenotype and protected the blood-brain barrier in CNS autoimmunity. J. Chem. Neuroanat. 117:102004. doi: 10.1016/j.jchemneu.2021.102004
Kai, K. (2018). Bacterial quorum sensing in symbiotic and pathogenic relationships with hosts. Biosci. Biotechnol. Biochem. 82, 363–371. doi: 10.1080/09168451.2018.1433992
Kan, Q.-C., Zhang, H.-J., Zhang, Y., Li, X., Xu, Y.-M., Thome, R., et al. (2017). Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis. Mol. Neurobiol. 54, 8404–8418. doi: 10.1007/s12035-016-0333-1
Khan, A., Shal, B., Naveed, M., Nasir, B., Irshad, N., Ali, H., et al. (2020). Matrine alleviates neurobehavioral alterations via modulation of JNK-mediated caspase-3 and BDNF/VEGF signaling in a mouse model of burn injury. Psychopharmacology 237, 2327–2343. doi: 10.1007/s00213-020-05537-5
Khan, A., Shal, B., Naveed, M., Shah, F. A., Atiq, A., Khan, N. U., et al. (2019). Matrine ameliorates anxiety and depression-like behaviour by targeting hyperammonemia-induced neuroinflammation and oxidative stress in CCl4 model of liver injury. Neurotoxicology 72, 38–50. doi: 10.1016/j.neuro.2019.02.002
Kumar, J. S., Umesha, S., Prasad, K. S., and Niranjana, P. (2016). Detection of Quorum Sensing Molecules and Biofilm Formation in Ralstonia solanacearum. Curr. Microbiol. 72, 297–305. doi: 10.1007/s00284-015-0953-0
Li, L., Liu, Q., Fan, L., Xiao, W., Zhao, L., Wang, Y., et al. (2017). Protective effects of oxymatrine against arsenic trioxide-induced liver injury. Oncotarget 8, 12792–12799. doi: 10.18632/oncotarget.12478
Li, M., Zhang, X., Cui, L., Yang, R., Wang, L., Liu, L., et al. (2011). The neuroprotection of oxymatrine in cerebral ischemia/reperfusion is related to nuclear factor erythroid 2-related factor 2 (nrf2)-mediated antioxidant response: Role of nrf2 and hemeoxygenase-1 expression. Biol. Pharm. Bull. 34, 595–601. doi: 10.1248/bpb.34.595
Li, P., Lei, J., Hu, G., Chen, X., Liu, Z., and Yang, J. (2019). Matrine Mediates Inflammatory Response via Gut Microbiota in TNBS-Induced Murine Colitis. Front. Physiol. 10:28. doi: 10.3389/fphys.2019.00028
Li, W., Yu, X., Tan, S., Liu, W., Zhou, L., and Liu, H. (2018). Oxymatrine inhibits non-small cell lung cancer via suppression of EGFR signaling pathway. Cancer Med. 7, 208–218. doi: 10.1002/cam4.1269
Li, X., Tang, Z., Wen, L., Jiang, C., and Feng, Q. (2021). Matrine: A review of its pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches. J. Ethnopharmacol. 269:113682. doi: 10.1016/j.jep.2020.113682
Li, X., Zhang, F., Wang, D., Li, Z., Qin, X., and Du, G. (2014). NMR-based metabonomic and quantitative real-time PCR in the profiling of metabolic changes in carbon tetrachloride-induced rat liver injury. J. Pharm. Biomed. Anal. 89, 42–49. doi: 10.1016/j.jpba.2013.10.023
Li, Z., Zheng, L., Shi, J., Zhang, G., Lu, L., Zhu, L., et al. (2015). Toxic Markers of Matrine Determined Using (1) H-NMR-Based Metabolomics in Cultured Cells In Vitro and Rats In Vivo. Evid Based Complement. Alternat. Med. 2015:598412. doi: 10.1155/2015/598412
Linglu, D., Yuxiang, L., Yaqiong, X., Ru, Z., Lin, M., Shaoju, J., et al. (2014). Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice. Neurol. Sci. 35, 815–821. doi: 10.1007/s10072-013-1603-6
Liu, J., Zhao, Y., Xia, J., and Qiu, M. (2020). Matrine induces toxicity in mouse liver cells through an ROS-dependent mechanism. Res. Vet. Sci. 132, 308–311. doi: 10.1016/j.rvsc.2020.07.006
Liu, S.-Q., Zhang, M.-L., Zhang, H.-J., Liu, F.-Z., Chu, R.-J., Zhang, G.-X., et al. (2017a). Matrine promotes oligodendrocyte development in CNS autoimmunity through the PI3K/Akt signaling pathway. Life Sci. 180, 36–41. doi: 10.1016/j.lfs.2017.05.010
Liu, Z., Lv, Y., Zhang, Y., Liu, F., Zhu, L., Pan, S., et al. (2017b). Matrine-Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species-Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling. J. Am. Heart Assoc. 6:e007441. doi: 10.1161/JAHA.117.007441
Liu, Y.-Q., Li, Y., Qin, J., Wang, Q., She, Y.-L., Luo, Y.-L., et al. (2014). Matrine reduces proliferation of human lung cancer cells by inducing apoptosis and changing miRNA expression profiles. Asian Pac. J. Cancer Prev. 15, 2169–2177. doi: 10.7314/apjcp.2014.15.5.2169
Lu, Z.-G., Li, M.-H., Wang, J.-S., Wei, D.-D., Liu, Q.-W., and Kong, L.-Y. (2014). Developmental toxicity and neurotoxicity of two matrine-type alkaloids, matrine and sophocarpine, in zebrafish (Danio rerio) embryos/larvae. Reprod. Toxicol. 47, 33–41. doi: 10.1016/j.reprotox.2014.05.015
Mallepalli, S., Gupta, M. K., and Vadde, R. (2019). Neuroblastoma: An Updated Review on Biology and Treatment. Curr. Drug Metab. 20, 1014–1022. doi: 10.2174/1389200221666191226102231
Mao, J., Hu, Y., Zhou, A., Zheng, B., Liu, Y., Du, Y., et al. (2012). Oxymatrine reduces neuroinflammation in rat brain: A signaling pathway. Neural Regen. Res. 7, 2333–2339. doi: 10.3969/j.issn.1673-5374.2012.30.002
Meng, F., Wang, J., Ding, F., Xie, Y., Zhang, Y., and Zhu, J. (2017). Neuroprotective effect of matrine on MPTP-induced Parkinson’s disease and on Nrf2 expression. Oncol. Lett. 13, 296–300. doi: 10.3892/ol.2016.5383
Otto, T., and Sicinski, P. (2017). Cell cycle proteins as promising targets in cancer therapy. Nat. Rev. Cancer 17, 93–115. doi: 10.1038/nrc.2016.138
Pan, X., Wang, L., Gründemann, D., and Sweet, D. H. (2014). Inhibition of human organic cation transporters by the alkaloids matrine and oxymatrine. Fitoterapia 92, 206–210. doi: 10.1016/j.fitote.2013.11.009
Sun, K., Bai, Y., Zhao, R., Guo, Z., Su, X., Li, P., et al. (2019a). Neuroprotective effects of matrine on scopolamine-induced amnesia via inhibition of AChE/BuChE and oxidative stress. Metab. Brain Dis. 34, 173–181. doi: 10.1007/s11011-018-0335-y
Sun, T., Li, X.-D., Hong, J., Liu, C., Zhang, X.-L., Zheng, J.-P., et al. (2019b). Inhibitory Effect of Two Traditional Chinese Medicine Monomers, Berberine and Matrine, on the Quorum Sensing System of Antimicrobial-Resistant. Front. Microbiol. 10:2584. doi: 10.3389/fmicb.2019.02584
Tanabe, N., Kuboyama, T., and Tohda, C. (2019). Matrine promotes neural circuit remodeling to regulate motor function in a mouse model of chronic spinal cord injury. Neural Regen. Res. 14, 1961–1967. doi: 10.4103/1673-5374.259625
Tang, L., Dong, L.-N., Peng, X.-J., Li, Y., Shi, J., Zhou, F.-Y., et al. (2013). Pharmacokinetic characterization of oxymatrine and matrine in rats after oral administration of radix Sophorae tonkinensis extract and oxymatrine by sensitive and robust UPLC-MS/MS method. J. Pharm. Biomed. Anal. 83, 179–185. doi: 10.1016/j.jpba.2013.05.003
Tang, Z., Wang, Q., He, Z., Yin, L., Zhang, Y., and Wang, S. (2017). Liver, blood microdialysate and plasma pharmacokinetics of matrine following transdermal or intravenous administration. Pharmazie 72, 167–170. doi: 10.1691/ph.2017.6101
Wang, H., Bai, J., Chen, G., Li, W., Xiang, R., Su, G., et al. (2013). A metabolic profiling analysis of the acute hepatotoxicity and nephrotoxicity of Zhusha Anshen Wan compared with cinnabar in rats using (1)H NMR spectroscopy. J. Ethnopharmacol. 146, 572–580. doi: 10.1016/j.jep.2013.01.026
Wang, M.-R., Zhang, X.-J., Liu, H.-C., Ma, W.-D., Zhang, M.-L., Zhang, Y., et al. (2019). Matrine protects oligodendrocytes by inhibiting their apoptosis and enhancing mitochondrial autophagy. Brain Res. Bull. 153, 30–38. doi: 10.1016/j.brainresbull.2019.08.006
Wang, S.-B., and Jia, J.-P. (2014). Oxymatrine attenuates diabetes-associated cognitive deficits in rats. Acta Pharmacol. Sin. 35, 331–338. doi: 10.1038/aps.2013.158
Wen, J.-B., Zhu, F.-Q., Chen, W.-G., Jiang, L.-P., Chen, J., Hu, Z.-P., et al. (2014). Oxymatrine improves intestinal epithelial barrier function involving NF-κB-mediated signaling pathway in CCl4-induced cirrhotic rats. PLoS One. 9:e106082. doi: 10.1371/journal.pone.0106082
Wu, J., Cai, Y., Li, M., Zhang, Y., Li, H., and Tan, Z. (2017b). Oxymatrine Promotes S-Phase Arrest and Inhibits Cell Proliferation of Human Breast Cancer Cells in Vitro through Mitochondria-Mediated Apoptosis. Biol. Pharm. Bull. 40, 1232–1239. doi: 10.1248/bpb.b17-00010
Wu, G., Zhou, W., Zhao, J., Pan, X., Sun, Y., Xu, H., et al. (2017a). Matrine alleviates lipopolysaccharide-induced intestinal inflammation and oxidative stress via CCR7 signal. Oncotarget 8, 11621–11628. doi: 10.18632/oncotarget.14598
Wu, X., Zhou, J., Cai, D., and Li, M. (2017c). Matrine inhibits the metastatic properties of human cervical cancer cells via downregulating the p38 signaling pathway. Oncol. Rep. 38, 1312–1320. doi: 10.3892/or.2017.5787
Wu, H., Chen, Q., Liu, J., Chen, X., Luo, H., Ye, Z., et al. (2021). Microbiome analysis reveals gut microbiota alteration in mice with the effect of matrine. Microb. Pathog. 156:104926. doi: 10.1016/j.micpath.2021.104926
Yang, Z., Gao, S., Yin, T., Kulkarni, K. H., Teng, Y., You, M., et al. (2010). Biopharmaceutical and pharmacokinetic characterization of matrine as determined by a sensitive and robust UPLC-MS/MS method. J. Pharm. Biomed. Anal. 51, 1120–1127. doi: 10.1016/j.jpba.2009.11.020
Yang, Z., Yin, R., Cong, Y., Yang, Z., Zhou, E., Wei, Z., et al. (2014). Oxymatrine lightened the inflammatory response of LPS-induced mastitis in mice through affecting NF-κB and MAPKs signaling pathways. Inflammation. 37, 2047–2055. doi: 10.1007/s10753-014-9937-7
Yao, H., Shi, Y., Yuan, J., Sa, R., Chen, W., and Wan, X. (2021). Matrine protects against DSS-induced murine colitis by improving gut barrier integrity, inhibiting the PPAR-α signaling pathway, and modulating gut microbiota. Int. Immunopharmacol. 100:108091. doi: 10.1016/j.intimp.2021.108091
You, L., Yang, C., Du, Y., Liu, Y., Chen, G., Sai, N., et al. (2019). Matrine Exerts Hepatotoxic Effects via the ROS-Dependent Mitochondrial Apoptosis Pathway and Inhibition of Nrf2-Mediated Antioxidant Response. Oxid. Med. Cell. Longev. 2019:1045345. doi: 10.1155/2019/1045345
You, L., Yang, C., Du, Y., Wang, W., Sun, M., Liu, J., et al. (2020). A Systematic Review of the Pharmacology, Toxicology and Pharmacokinetics of Matrine. Front. Pharmacol. 11:01067. doi: 10.3389/fphar.2020.01067
Zhang, D., Sun, L., Zhu, H., Wang, L., Wu, W., Xie, J., et al. (2012). Microglial LOX-1 reacts with extracellular HSP60 to bridge neuroinflammation and neurotoxicity. Neurochem. Int. 61, 1021–1035. doi: 10.1016/j.neuint.2012.07.019
Zhang, H.-F., Shi, L.-J., Song, G.-Y., Cai, Z.-G., Wang, C., and An, R.-J. (2013a). Protective effects of matrine against progression of high-fructose diet-induced steatohepatitis by enhancing antioxidant and anti-inflammatory defences involving Nrf2 translocation. Food Chem. Toxicol. 55, 70–77. doi: 10.1016/j.fct.2012.12.043
Zhang, K., Li, Y.-J., Yang, Q., Gerile, O., Yang, L., Li, X.-B., et al. (2013b). Neuroprotective effects of oxymatrine against excitotoxicity partially through down-regulation of NR2B-containing NMDA receptors. Phytomedicine 20, 343–350. doi: 10.1016/j.phymed.2012.10.018
Zhang, R., Li, Y., Hou, X., Miao, Z., and Wang, Y. (2017). Neuroprotective effect of heat shock protein 60 on matrine-suppressed microglial activation. Exp. Ther. Med. 14, 1832–1836. doi: 10.3892/etm.2017.4691
Zhang, R., Liao, W., Wu, K., Hua, L., Wu, M., Li, C., et al. (2022). Matrine alleviates spatial learning and memory impairment in diabetic mice by inhibiting endoplasmic reticulum stress and through modulation of PK2/PKRs pathway. Neurochem. Int. 154:105289. doi: 10.1016/j.neuint.2022.105289
Zhang, Y., Liu, M., Sun, H., and Yin, K. (2015). Matrine improves cognitive impairment and modulates the balance of Th17/Treg cytokines in a rat model of Aβ1-42-induced Alzheimer’s disease. Cent. Eur. J. Immunol. 40, 411–419. doi: 10.5114/ceji.2015.56961
Zhao, P., Zhou, R., Zhu, X.-Y., Hao, Y.-J., Li, N., Wang, J., et al. (2015). Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice. Int. J. Mol. Med. 36, 633–644. doi: 10.3892/ijmm.2015.2260
Keywords: matrine, pharmacological action, toxicology, pharmacokinetics, gut and gut microbes
Citation: Sun Y, Xu L, Cai Q, Wang M, Wang X, Wang S and Ni Z (2022) Research progress on the pharmacological effects of matrine. Front. Neurosci. 16:977374. doi: 10.3389/fnins.2022.977374
Received: 24 June 2022; Accepted: 05 August 2022;
Published: 23 August 2022.
Edited by:
Li Li, University of Texas Southwestern Medical Center, United StatesReviewed by:
Zhenglong Liu, Mayo Clinic, United StatesBaijie Xu, UT Southwestern Medical Center, United States
Copyright © 2022 Sun, Xu, Cai, Wang, Wang, Wang and Ni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Siming Wang, d2FuZ3NpbWluZzE5ODgwODA1QDEyNi5jb20=; Zhiyu Ni, OTQ5MTkyMDk4QHFxLmNvbQ==