QSAR prediction, synthesis, anticancer evaluation, and mechanistic investigations of novel sophoridine derivatives as topoisomerase I inhibitors.

Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.

Sophoridine exerts anti-arthritic effects on fibroblast-like synoviocytes and collagen-induced arthritis in rats.

The discovery of alternative medicines with fewer adverse effects is urgently needed for rheumatoid arthritis (RA). Sophoridine (SR), the naturally occurring quinolizidine alkaloid isolated from the leguminous sophora species, has been demonstrated to possess a wide range of pharmacological activities. However, the effect of SR on RA remains unknown. In this study, the collagen-induced arthritis (CIA) rat model and tumor necrosis factor alpha (TNFα)-induced fibroblast-like synoviocytes (FLSs) were utilized to investigate the inhibitory effect of SR on RA. The anti-arthritic effect of SR was evaluated using the CIA rat model in vivo and TNFα-stimulated FLSs in vitro. Mechanistically, potential therapeutic targets and pathways of SR in RA were analyzed through drug target databases and disease databases, and validation was carried out through immunofluorescence, immunohistochemistry, and Western blot. The in vivo results revealed that SR treatment effectively ameliorated synovial inflammation and bone erosion in rats with CIA. The in vitro studies showed that SR could significantly suppress the proliferation and migration in TNFα-induced arthritic FLSs. Mechanistically, SR treatment efficiently inhibited the activation of MAPKs (JNK and p38) and NF-κB pathways in TNFα-induced arthritic FLSs. These findings were further substantiated by Immunohistochemistry results in the CIA rat. SR exerts an anti-arthritic effect in CIA rats through inhibition of the pathogenic characteristic of arthritic FLSs via suppressing NF-κB and MAPKs (JNK and p38) signaling pathways. SR may have a great potential for development as a novel therapeutic agent for RA treatment.

Matrine reduced intestinal stem cell damage in eimeria necatrix-infected chicks via blocking hyperactivation of Wnt signaling.

BACKGROUND: Coccidiosis is a rapidly spreading and acute parasitic disease that seriously threatening the intestinal health of poultry. Matrine from leguminous plants has anthelmintic and anti-inflammatory properties. PURPOSE: This assay was conducted to explore the protective effects of Matrine and the AntiC (a Matrine compound) on Eimeria necatrix (EN)-infected chick small intestines and to provide a nutritional intervention strategy for EN injury. STUDY DESIGN: The in vivo (chick) experiment: A total of 392 one-day-old yellow-feathered broilers were randomly assigned to six groups in a 21-day study: control group, 350 mg/kg Matrine group, 500 mg/kg AntiC group, EN group, and EN + 350 mg/kg Matrine group, EN + 500 mg/kg AntiC group. The in vitro (chick intestinal organoids, IOs): The IOs were treated with PBS, Matrine, AntiC, 3 µM CHIR99021, EN (15,000 EN sporozoites), EN + Matrine, EN + AntiC, EN + Matrine + CHIR99021, EN + AntiC + CHIR99021. METHODS: The structural integrity of chicks jejunal crypt-villus axis was evaluated by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). And the activity of intestinal stem cells (ISCs) located in crypts was assessed by in vitro expansion advantages of a primary in IOs model. Then, the changes of Wnt/ß-catenin signaling in jejunal tissues and IOs were detected by Real-Time qPCR,Western blotting and immunohistochemistry. RESULTS: The results showed that dietary supplementation with Matrine or AntiC rescued the jejunal injury caused by EN, as indicated by increased villus height, reduced crypt hyperplasia, and enhanced expression of tight junction proteins. Moreover, there was less budding efficiency of the IOs expanded from jejunal crypts of chicks in the EN group than that in the Matrine and AntiC group, respectively. Further investigation showed that AntiC and Matrine inhibited EN-stimulated Wnt/ß-catenin signaling. The fact that Wnt/ß-catenin activation via CHIR99021 led to the failure of Matrine and AntiC to rescue damaged ISCs confirmed the dominance of this signaling. CONCLUSION: Our results suggest that Matrine and AntiC inhibit ISC proliferation and promote ISC differentiation into absorptive cells by preventing the hyperactivation of Wnt/ß-catenin signaling, thereby standardizing the function of ISC proliferation and differentiation, which provides new insights into mitigating EN injury by Matrine and AntiC.

Alkaloids from the roots of Sophora flavescens and their anti-tumor activity.

Sophora flavescens belongs to Sophora genus of Leguminosae. Its roots are used as a traditional Chinese medicine. In our study on Sophora flavescens roots, 3 new and 19 known alkaloids have been found, including 8 aloperine-type and 14 matrine-type alkaloids. The planar configurations of these compounds were determined by the spectral data, and the absolute configurations of new compounds 1, 2 and 4 were determined by pyridine solvent effect, ECD and snatzke methods, respectively. All compounds were tested for their inhibitory activity on MCF-7 cell growth, and compound 12 exhibited certain inhibitory effects on the growth of MCF-7 cells after 24 h of treatment at a concentration of 20 µM, with inhibition rates of 31.28%. Through target screening and molecular docking, human Rho GTPase activating protein 5 variant and human arachidonate 12-lipoxygenase (12S-type) might be important targets for compound 12 to exert anti-tumor activity.

Sophflarine A, a novel matrine-derived alkaloid from Sophora flavescens with therapeutic potential for non-small cell lung cancer through ROS-mediated pyroptosis and autophagy.

BACKGROUND: Novel compounds and more efficient treatment options are urgently needed for the treatment of non-small cell lung cancer (NSCLC). The decoction of Sophora flavescens has been used to treat NSCLC in the clinic, and matrine-type alkaloids are generally considered to be the key pharmacodynamic material basis. But the previous study showed that common matrine-type alkaloids exhibit significant cytotoxicity only when at concentrations close to the millimolar (mM) level. The key antitumor alkaloids in S. flavescens seem to have not yet been revealed. PURPOSE: The aim of this study was to screen water-soluble matrine alkaloid with novel skeleton and enhanced activity from S. flavescens, and to reveal the pharmacological mechanism of its therapeutic effect on NSCLC. METHODS: Alkaloid was obtained from S. flavescens by chromatographic separation methods. The structure of alkaloid was determined by spectroscopic methods, and single-crystal X-ray diffraction. The mechanism of anti-NSCLC in vitro with cellular models was evaluated by MTT assay, western blotting, cell migration and invasion assay, plate colony-formation assay, tube formation assay, immunohistochemistry assay, hematoxylin and eosin staining. The antitumor efficacy in vivo was test in NSCLC xenograft models. RESULTS: A novel water-soluble matrine-derived alkaloid incorporating 6/8/6/6 tetracyclic ring system, named sophflarine A (SFA), was isolated from the roots of S. flavescens. SFA had significantly enhanced cytotoxicity compared with the common matrine-type alkaloids, having an IC50 value of 11.3 µM in A549 and 11.5 µM in H820 cells at 48 h. Mechanistically, SFA promoted NSCLC cell death by inducing pyroptosis via activating the NLRP3/caspase-1/GSDMD signaling pathway, and inhibited cancer cell proliferation by increasing the ROS production to activate autophagy via blocking the PI3K/AKT/mTOR signaling pathway. Additionally, SFA also inhibited NSCLC cell migration and invasion by suppressing EMT pathway, and inhibited cancer cell colony formation and human umbilical vein endothelial cell angiogenesis. In concordance with the above results, SFA treatment blocked tumor growth in an A549 cell-bearing orthotopic mouse model. CONCLUSION: This study revealed a potential therapeutic mechanism of a novel matrine-derived alkaloid, which not only described a rational explanation for the clinical utilization of S. flavescens, but also provided a potential candidate compound for NSCLC treatment.

Oxymatrine: A current overview of its health benefits.

Oxymatrine (OMT), was identified as a quinolizidine alkaloid, which was one of the major matrine-type alkaloids extracted from Sophora medicinal plants. Growing studies revealed that OMT has a wide range of beneficial pharmacological values, consisting of anticancer, antidiabetic, antivirus, and antiinflammtion, as well as the protective activities to the brain, liver, heart, lung, vascular, gastrointestinal, bone, kidney, and skin organs. Various in vitro and in vivo models of pharmacological actions were recorded in regard to the usage of alkaloidal OMT. Mechanisms underlying anticancer activity of this compound may have been possibly involved anti-proliferation, invasion, migration, angiogenesis, epithelial-mesenchymal transition of cells, autophagy, especially apoptotic cell deaths. OMT could reduce hyperglycemia and hyperlipemia in a high-fat diet and streptozotocin-stimulated diabetic mice by improving insulin secretion and sensitivity. OMT suppressed gastric ulcer via gastric inflammatory and oxidative inhibitions, and pro-apoptotic actions. It turns out that OMT is relatively safe for cell and animal experiments. In this study, we offer a systematic review of natural occurrence, pharmacological potentials, possible mechanisms of action, pharmacokinetics, and bioavailability. Clinical research with OMT is needed to extensively elucidate its health potential benefits.

[Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives].

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

[Effect of apigenin in combination with oxymatrine on non-small cell lung cancer and mechanism].

This study explores the effect of apigenin(APG), oxymatrine(OMT), and APG+OMT on the proliferation of non-small cell lung cancer cell lines and the underlying mechanisms. Cell counting kit-8(CCK-8) assay was used to detect the vitality of A549 and NCI-H1975 cells, and colony formation assay to evaluate the colony formation ability of the cells. EdU assay was employed to examine the proliferation of NCI-H1975 cells. RT-qPCR and Western blot were performed to detect the mRNA and protein expression of PLOD2. Molecular docking was carried out to explore the direct action ability and action sites between APG/OMT and PLOD2/EGFR. Western blot was used to study the expression of related proteins in EGFR pathway. The viability of A549 and NCI-H1975 cells was inhibited by APG and APG+OMT at 20, 40, and 80 µmol·L~(-1) in a dose-dependent manner. The colony formation ability of NCI-H1975 cells was significantly suppressed by APG and APG+OMT. The mRNA and protein expression of PLOD2 was significantly inhibited by APG and APG+OMT. In addition, APG and OMT had strong binding activity with PLOD2 and EGFR. In APG and APG+OMT groups, the expression of EGFR and proteins in its downstream signaling pathways was significantly down-regulated. It is concluded that APG in combination with OMT could inhibit non-small lung cancer, and the mechanism may be related to EGFR and its downstream signaling pathways. This study lays a new theoretical basis for the clinical treatment of non-small cell lung cancer with APG in combination with OMT and provides a reference for further research on the anti-tumor mechanism of APG in combination with OMT.

Effect of matrine in MAC-T cells and their transcriptome analysis: A basic study.

Matrine, an alkaloid derived from herbal medicine, has a wide range of biological activities, including antibacterial. Matrine was toxic to multiple cells at high concentrations. Bovine mammary epithelial cells (MAC-T) could be used as model cells for cow breast. Matrine was a feasible option to replace antibiotics in the prevention or treatment of mastitis against the background of prohibiting antibiotics, but the safe concentration of matrine on MAC-T cells and the mechanism of action for matrine at different concentrations were still unclear. In this study, different concentrations of matrine (0.5, 1, 1.5, 2, 2.5 and 3 mg/mL) were used to treat MAC-T cells for various time periods (4, 8, 12, 16 and 24 h) and measure their lactic dehydrogenase (LDH). And then the optimal doses (2 mg/mL) were chosen to detect the apoptosis at various time periods by flow cytometry and transcriptome analysis was performed between the control and 2 mg/mL matrine-treated MAC-T cells for 8 hours. The results showed that matrine was not cytotoxic at 0.5 mg/mL, but it was cytotoxic at 1~3 mg/mL. In addition, matrine induced apoptosis in MAC-T cells at 2 mg/mL and the proportion of apoptosis cells increases with time by flow cytometry. RNA-seq analysis identified 1645 DEGs, 676 of which were expressed up-regulated and 969 were expressed down-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated the following pathways were linked to matrine-induced toxicity and apoptosis, including cytokine-cytokine receptor interaction pathway, viral protein interaction with cytokine and cytokine receptor, P53 and PPAR pathway. We found 7 DEGs associated with matrine toxicity and apoptosis. This study would provide a basis for the safety of matrine in the prevention or treatment of mastitis.

Systematic elucidation of the bioactive alkaloids and potential mechanism from Sophora flavescens for the treatment of eczema via network pharmacology.

ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens is a frequently used traditional Chinese medicine (TCM) for the treatment of skin disorders, diarrhea, vaginal itching and inflammatory diseases. In particular, the root of S. flavescens combination with other herbs mainly treat eczema ailment in the clinical applications. However, a holistic network pharmacology approach to understanding the mechanism by which alkaloids in S. flavescens treat eczema has not been pursued. AIM OF THE STUDY: To examine the network pharmacological potential effect of S. flavescens on eczema, we studied the alkaloids, performed protein targets prediction and investigated interacting signal pathways. Furthermore, animal experiment was carried out to evaluate its efficacy and real-time quantitative polymerase chain reactions (RT-qPCR) analysis was explored the mechanism of action. MATERIALS AND METHODS: The detail information on alkaloids from S. flavescens were obtained from a handful of public databases on the basis of oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Then, correlations between compounds and protein targets were linked using the STRING database, and targets associated with eczema were gathered by the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis. Particularly, matrine, the crucial alkaloid from S. flavescens, was estimated using a 2,4-dinitrochlorobenzene (DNCB)-induced eczema Kunming (KM) mice model, administered (50 mg/kg and 10 mg/kg) to mice for 22 days. On the last day, the activities of serum tumor necrosis factor α (TNF-α), interleukin-4 (IL-4) and histopathologic examinations were determined. For further to elucidate the mechanisms, the mRNA levels of TNF-α, STAT3, TP53, AKT1, IL-6, JUN and EGFR in dorsal skin tissues were also tested. RESULTS: Network analysis collected and identified 35 alkaloids from S. flavescens. Among them, in total 10 dominating alkaloids, including matrine, oxymatrine, sophoridine, sophocarpine, oxysophocarpine, allomatrine, sophoramine, anagyrine, cytisine and N-methylcytisine. And 71 related targets were provided of alkaloids for the treatment of eczema from S. flavescens. Furthermore, matrine dose-dependently (50 or 10 mg/kg, 22 days, apply to dorsal skin) remarkable decreased the serum levels of TNF-α and IL-4, and significantly alleviated the skin lesions. The effects of 50 mg/kg of matrine were almost identical to those of 200 mg/kg of the positive drug dexamethasone (DXM). The further RT-qPCR analyses could reveal that matrine down-regulate TNF-α, STAT3 and TP53 at transcriptional level in dorsal skin tissues. CONCLUSION: Pharmacological network analysis can utilize to illuminate the pharmacodynamic substances and the potential molecular mechanism of S. flavescens for treating eczema. Matrine, as the crucial alkaloid from S. flavescens, could be a promising drug candidate for the treatment of eczema ailment.

Identification of the Mechanism of Matrine Combined with Glycyrrhizin for Hepatocellular Carcinoma Treatment through Network Pharmacology and Bioinformatics Analysis.

Matrine and glycyrrhizin are representative active ingredients of traditional Chinese medicine (TCM) used in clinical practice. Studies have demonstrated that matrine has antitumor pharmacological effects and that glycyrrhizin protects liver function. However, the potential bioactive compounds and mechanisms remain unknown, as well as whether they have synergistic effects in killing cancer cells and protecting liver cells. To investigate the synergistic effects and mechanism of matrine combined with glycyrrhizin in hepatocellular carcinoma (HCC) treatment, we used both network pharmacology and bioinformatics analyses. First, the chemical gene interaction information of matrine and glycyrrhizin was obtained from the PubChem database. The pathogenic genes of HCC were accessed from five public databases. The RNA sequencing data and clinical information of HCC patients were downloaded from The Cancer Genome Atlas (TCGA). Next, the overlapping genes among the potential targets of matrine and glycyrrhizin and HCC-related targets were determined using bioinformatics analysis. We constructed the drug-target interaction network. Prognosis-associated genes were acquired through the univariate Cox regression model and Lasso-Cox regression model. The results were verified by the International Cancer Genome Consortium (ICGC) database. Finally, we predicted the immune function of the samples. The drug-target interaction network consisted of 10 matrine and glycyrrhizin targets. We selected a Lasso-Cox regression model consisting of 3 differentially expressed genes (DEGs) to predict the efficacy of the combination in HCC. Subsequently, we successfully predicted the overall survival of HCC patients using the constructed prognostic model and investigated the correlation of the immune response. Matrine and glycyrrhizin have synergistic effects on HCC. The model we obtained consisted of three drug-target genes by Lasso-Cox regression analysis. The model independently predicted the combined effect of matrine and glycyrrhizin in HCC treatment and OS, which will be helpful for guiding clinical treatment. The prognostic model was correlated with the immune cells and immune checkpoints of patients, which had an adjuvant effect on HCC immunotherapy. Matrine and glycyrrhizin can have therapeutic effects on HCC by promoting the production or enhancing the core gene activity in the drug network and improving the immune system function of patients.

A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids.

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant Sophora flavescens, the roots of which are used in traditional Chinese medicine. Biosynthetically, these alkaloids are proposed to derive from three molecules of (-)-lysine via the intermediacy of the unstable cyclic imine Δ1-piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Δ1-piperidine. In this key transformation, two molecules of pyridine are joined with a molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. Using this dearomative annulation, isomatrine is synthesized in four steps from inexpensive commercially available chemicals. Isomatrine then serves as the precursor to additional lupin alkaloids, including matrine, allomatrine, isosophoridine, and sophoridine.

Matrine induces autophagy in human neuroblastoma cells via blocking the AKT-mTOR pathway.

Neuroblastoma (NB) is one of the most common malignant solid tumors in children. Despite significant advances in the treatment strategy, the long-term survival rate of NB patients is only 50%. Developing new agents for NB patients deserves attention. Recent research indicates that matrine, a natural quinolizidine alkaloid component extracted from the traditional Chinese medicine Sophora root, is widely used for various diseases, including antitumor effects against a variety of cancers. However, the effect of matrine on NB is unknown. Herein, we found that matrine exerted antiproliferative activity in human NB cells in dose- and time-dependent manner. Matrine triggered autophagy in NB cells by blocking the AKT-mTOR signaling pathway and suppressing the phosphorylation of AKT and mTOR. 3-Methyladenine (3-MA), a PI3K inhibitor, protected against matrine-induced inhibition of cell proliferation, further supporting that the antitumor activity of matrine was at least partly autophagy-dependent. In vivo, matrine reduced tumor growth of SK-N-DZ cells in a dose-dependent manner. Matrine treatment significantly declined the phosphorylation of AKT and mTOR and enhanced the LC3 II/GAPDH ratio in NB xenografts. Altogether, our work uncovered the molecular mechanism underlying matrine-induced autophagy in NB and provided implications for matrine as a potential therapeutic agent against NB.

Discovery and evaluation of cytisine N-isoflavones as novel EGFR/HER2 dual inhibitors.

Aberrant signaling of EGFR (ErbB) family members, in particular epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2), is associated with the occurrence and development of many types of human malignancies (e.g., breast, lung, and gastric cancers), and dual targeting of EGFR/HER2 by small-molecular inhibitors has proven to be an effective therapeutic approach for treating these cancers. Herein we extracted and isolated from the medicinal plant Sophora alopecuroides L. a new natural product, dubbed Cytisine N-methylene-(4',7-dihydroxy-3'-methoxy)-isoflavone (CNI1) that features a unique molecular framework. Our biochemical kinase assay suggested that one of its derivative CNI3 exhibited the best, micromolar (µM) inhibition activities against the EGFR (IC50 of 1.1 µM; Ki of 0.6 µM) and HER2 (IC50 of 3.5 µM; Ki of 1.8 µM) kinases. By contrast, another derivative CNI4 was most potent in inhibiting the EGFR-overexpressing A431 cancer cell line (IC50 of 45.5 µM) and the HER2-overexpressing BT-474 cancer cell line (IC50 of 32.9 µM), while the respective cellular activities of Lapatinib (a marketed drug) were 24.9 and 20.3 µM under the same assay condition. Moreover, both CNI3 and CNI4 showed desirable anti-metastatic efficacy in another two breast cancer models (viz., MDA-MB-231 and 4T1). In addition, we explored the inhibitory mechanisms of the CNIs against EGFR and HER2 by molecular dynamics simulation and revealed a novel mode of action that engages the cytisine and chromone moieties in CNIs. By combining structure- and ligand-based analysis, we further rationally engineered a new CNI compound that exhibits considerably improved cytotoxicity against both types of A431 and BT-474 cancer cells. Our study demonstrates the CNI compounds as a new class of EGFR/HER2 dual inhibitors and paves a way for their further development.

Carboxymethyl Chitosan Modified Oxymatrine Liposomes for the Alleviation of Emphysema in Mice via Pulmonary Administration.

Pulmonary emphysema is a fatal lung disease caused by the progressive thinning, enlargement and destruction of alveoli that is closely related to inflammation and oxidative stress. Oxymatrine (OMT), as a bioactive constituent of traditional Chinese herbal Sophora flavescens, has great potential to alleviate pulmonary emphysema via its anti-inflammatory and antioxidative activities. Pulmonary administration is the most preferable way for the treatment of lung diseases. To improve the in vivo stability and pulmonary retention of OMT, OMT-loaded liposome with carboxymethyl chitosan (CMCS) modification was developed. The CMCS was modified on the surface of OMT liposomes via electrostatic attraction and covalent conjugation to obtain Lipo/OMT@CMCS and CMCS-Lipo/OMT, respectively. A porcine pancreatic elastase (PPE)-induced emphysema mice model was established to evaluate the alleviation effects of OMT on alveolar expansion and destruction. CMCS-modified liposomal OMT exhibited superior ameliorative effects on emphysema regardless of the preparation methods, and higher sedimentation and longer retention in the lung were observed in the CMCS-Lipo group. The mechanisms of OMT on emphysema were related to the downregulation of inflammatory cytokines and the rebalancing of antioxidant/oxidation via the Nrf2/HO-1 and NF-κB/IκB-α signaling pathways, leading to reduced cell apoptosis. Moreover, the OMT liposomal preparations further enhanced its anti-inflammatory and antioxidative effects. In conclusion, pulmonary administration of OMT is a potential strategy for the treatment of emphysema and the therapeutic effects can be further improved by CMCS-modified liposomes.

Matrine Exerts Pharmacological Effects Through Multiple Signaling Pathways: A Comprehensive Review.

As The main effective monomer of the traditional Chinese medicine Sophora flavescens Ait, matrine has a broad scope of pharmacological activities such as anti-tumor, anti-inflammatory, analgesic, anti-fibrotic, anti-viral, anti-arrhythmia, and improving immune function. These actions explain its therapeutic effects in various types of tumors, cardiopathy, encephalomyelitis, allergic asthma, rheumatoid arthritis (RA), osteoporosis, and central nervous system (CNS) inflammation. Evidence has shown that the mechanism responsible for the pharmacological actions of matrine may be via the activation or inhibition of certain key molecules in several cellular signaling pathways including the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), transforming growth factor-ß/mothers against decapentaplegic homolog (TGF-ß/Smad), nuclear factor kappa B (NF-κB), Wnt (wingless/ integration 1)/ß-catenin, mitogen-activated protein kinases (MAPKs), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. This review comprehensively summarizes recent studies on the pharmacological mechanisms of matrine to provide a theoretical basis for molecular targeted therapies and further development and utilization of matrine.

Effects and Mechanism of Oxymatrine Combined with Compound Yinchen Granules on the Apoptosis of Hepatocytes through the Akt/FoxO3a/Bim Pathway.

The aim of the present study was to investigate the effects and mechanism of oxymatrine (OMT) combined with compound yinchen granules (CYG) on the apoptosis of hepatocytes through the Akt/FoxO3a/Bim pathway in rats with acute liver failure. The rat model of acute liver failure was established using lipopolysaccharide/D-galactosamine (LPS/D-GalN). The expression of proteins in rat liver tissues was detected by western blot analysis. The mRNA expression of FoxO3a, Bim, Bax, Bcl-2, and caspase-3 in rat liver tissues was detected by RT-qPCR. The apoptosis rate of rat hepatocytes was determined by flow cytometry. Western blots showed that when compared with the normal group, the expression of p-Akt and p-FoxO3a in the model group was decreased (P < 0.05), while the expression of Bim was increased (P < 0.01). Compared with the model group, the expression of p-Akt and p-FoxO3a in the OMT group and the OMT combined with CYG groups was increased (P < 0.05 or P < 0.01), while the expression of Bim was decreased (P < 0.05). The Bax/Bcl-2 ratio and caspase-3 protein expression in the model group were significantly higher than those in the normal group (P < 0.01). The Bax/Bcl-2 ratio and the expression of caspase-3 protein in the OMT group and the OMT combined with CYG groups were significantly lower than those in the model group (P < 0.01). The results of RT-qPCR were consistent with those of western blot. The results of flow cytometry showed that the apoptosis rate of hepatocytes in the OMT group and the OMT combined with CYG groups was significantly lower than that in the model group (P < 0.05 or P < 0.01). We concluded that LPS/D-GalN can induce apoptosis of hepatocytes in rats with acute liver failure through the Akt/FoxO3a/Bim pathway. OMT combined with CYG inhibits apoptosis of hepatocytes in rats with acute liver failure via the Akt/FoxO3a/Bim pathway.

Novel protein kinase C phosphorylated kinase inhibitor-matrine suppresses replication of hepatitis B virus via modulating the mitogen-activated protein kinase signal.

HBV (hepatitis B virus) infection still threatens human health. Therefore, it is essential to find new effective anti-HBV compounds. Here, we identified matrine as a novel inhibitor of PKC (protein kinase C) phosphorylated kinase by screening a natural compound library. After HepG2.215 cells were treated with matrine, we carried out a phosphorylated proteomics sequence study and analyzed the prediction of related kinase expression level. In the case of HBV infection, it was found that PKC kinase mediates the activation of mitogen-activated protein kinase (MAPK) signaling pathway known as son of sevenless (SOS) activation. It was also found that PKC kinase inhibits the expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) by inhibiting the activity of activating transcription factor 2/ cAMP response element binding protein (ATF2/CREB), and this effect is independent of its activated MAPK signaling pathway. Finally, Western blot was used to detect the expression of MAPK, ATF2, CREB3 phosphorylation and nonphosphorylation in matrine-treated cells and PKC-treated cells. PKC phosphorylated kinase inhibitor-matrine suppresses the replication of HBV via modulating the MAPK/ATF2 signal. Matrine is a good clinical drug to enhance the autoimmunity in the adjuvant treatment of chronic HBV infection.

Thermosensitive molecularly imprinted polymer coupled with HPLC for selective enrichment and determination of matrine in traditional Chinese medicine.

In this study, a temperature-sensitive molecularly imprinted polymer was prepared by using the bifunctional monomer with the critical phase transition characteristics. Infrared spectrometry, scanning electron microscopy, and specific surface area testing were used to characterize the polymers. Then, the recognizing properties of the polymers were studied. Based on the prepared smart polymers, an SPE-HPLC analytical method for the determination of quinolizidine alkaloids in the extracts of Sophora flavescens was established and verified. Finally, the smart polymers were applied to the enrichment of quinolizidine alkaloids in plant extracts. By changing the temperature and solvents of the solid phase extraction conditions, the extraction process can increase the concentration of quinolizidine alkaloids by 4.3 to 5.2 folds. The extraction process has mild conditions and less time consumption, avoiding the use of a large number of toxic reagents, which indicate that the extraction process are more efficient and environmentally friendly.

Research progress of matrine's anticancer activity and its molecular mechanism.

BACKGROUND: and ethnopharmacological relevance: Matrine (MT), a type of alkaloid extracted from the Sophora family of traditional Chinese medicine, has been documented to exert a variety of pharmacological effects, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrosis, and cardiovascular protection. Sophora flavescens Aiton is a traditional Chinese medicine that is bitter and cold. Additionally, it also exhibits the effects of clearing heat, eliminating dampness, expelling insects, and promoting urination. Malignant tumors are the most important medical issue and are also the second leading cause of death worldwide. Numerous natural substances have recently been revealed to have potent anticancer properties, and several have been used in clinical trials. AIMS OF THE STUDY: To summarize the antitumor effects and associated mechanisms of MT, we compiled this review by combining a huge body of relevant literature and our previous research. MATERIALS AND METHODS: As demonstrated, we grouped the pharmacological effects of MT via a PubMed search. Further, we described the mechanism and current pharmacological research on MT's antitumor activity. RESULTS: Additionally, extensive research has demonstrated that MT possesses superior antitumor properties, including accelerating cell apoptosis, inhibiting tumor cell growth and proliferation, inducing cell cycle arrest, inhibiting cancer metastasis and invasion, inhibiting angiogenesis, inducing autophagy, reversing multidrug resistance and inhibiting cell differentiation, thus indicating its significant potential for cancer treatment and prognosis. CONCLUSION: This article summarizes current advances in research on the anticancer properties of MT and its molecular mechanism, to provide references for future research.