Ginseng-Astragalus-oxymatrine injection ameliorates cyclophosphamide-induced immunosuppression in mice and enhances the immune activity of RAW264.7 cells.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Ginseng quinquefolium (L.), Astragalus membranaceus, and Sophora flavescens Aiton are popular folk medicines in many Asian countries and regions. These three traditional Chinese herbs and their extracts have been reported to considerably enhance the immune function. G. quinquefolium (L.) is considered the king of herbs in China. Traditionally, G. quinquefolium (L.) is believed to replenish vitality, which is considered as immune enhancement in modern Chinese pharmacy. One of the main uses of Astragalus is immunity enhancement; S. flavescens and oxymatrine obtained from its extract have been used to treat leukopenia. Considering the pharmacological properties of Ginseng, Astragalus, and oxymatrine, we evaluated the immunopotentiation effects of their combination, Ginseng-Astragalus-oxymatrine (GAO), in the present study. AIM OF THE STUDY: This study aimed to expand the clinical application of GAO and to preliminarily explore its mechanism of action by determining whether GAO injection can enhance immunity in vivo and in vitro. METHODS: Overall, 17 major chemical components in GAO were analysed using HPLC and LC-MS. The immunity-enhancing effect of GAO was studied in the cyclophosphamide (CTX)-induced immunosuppressive mouse model and RAW 264.7 cells. RESULTS: Quantitative analysis showed that the potential active components of GAO include at least ginsenosides, astragaloside IV, and oxymatrine. GAO could significantly improve the nonspecific immunity including the indices of the thymus and spleen, number of peripheral blood leukocytes, levels of TNF-α and IL-6, phagocytic function of macrophages, and cytotoxic activity of natural killer (NK) cells. Additionally, GAO enhanced the humoural immunity, characterised by the antibody production ability of B cells, and cellular immunity, characterised by the activity of T cells, in immunosuppressed mouse. Moreover, GAO could enhance the phagocytic and adhesion functions of RAW 264.7 cells, which may be related to the activation of reactive oxygen species and NF-κB signalling pathway. CONCLUSION: GAO could dramatically ameliorate CTX-induced immunosuppression in mouse and stimulate the immune activity in RAW 264.7 cells possibly by activating the NF-κB signalling pathway.

Characterization of metabolic fate of phellodendrine and its potential pharmacological mechanism against diabetes mellitus by ultra-high-performance liquid chromatography-coupled time-of-flight mass spectrometry and network pharmacology.

RATIONALE: Characterizing the functional mechanism of quality control marker (Q-marker) was of great importance in revealing the primary pharmacological mechanism of herbs or the other complex system, and drug-related metabolites always contribute to the pharmacological functions. Cortex Phellodendri was used as a core herb in the treatment of diabetes mellitus (DM). As a Q-marker of Cortex Phellodendri, the role of phellodendrine in DM was still unclear. Thus, the characterization of phellodendrine-related metabolites in vivo and the subsequent induced functional mechanism exerted great importance in elucidating the anti-DM mechanism of Cortex Phellodendri. METHODS: An ultra-high-performance liquid chromatography-coupled time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method was developed to profile metabolites of phellodendrine in rats. The potential pharmacological mechanism against DM was predicted by network pharmacology. RESULTS: A total of 19 phellodendrine-related metabolites were screened out in rats for the first time. Among them, M4, M5, M9, and M12 were regarded as the primary metabolites. Meanwhile, phase I metabolic reactions of hydroxylation, demethylation, and isomerization and phase II reactions of glucuronidation and sulfation occurred to phellodendrine; glucuronidation and hydroxylation were the two main metabolic reactions. Moreover, the potential targets of phellodendrine and three main metabolites (M4, M5, and M12) were predicted by a network pharmacological method, and they mainly shared 52 targets, including PDE5A, CHRNA3, SIGMAR1, F3, ESR1, DRD1, DRD2, DRD3, and DRD4. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that calcium signaling pathway, cGMP-PKG signaling pathway, and cAMP signaling pathway were regarded as the core mechanism of phellodendrine to treat DM. CONCLUSION: The metabolic feature of phellodendrine in vivo was revealed for the first time, and its anti-DM mechanism information for further pharmacological validations was also supplied. It also gave a direction to further elucidation of pharmacological mechanism of Cortex Phellodendri in treating DM.

Matrine ameliorates cognitive deficits via inhibition of microglia mediated neuroinflammation in an Alzheimer's disease mouse model.

Amyloid ß (Aß) induced microglial activation and attendant neuroinflammation play pivotal roles in Alzheimer's disease (AD) pathogenesis. Matrine is a natural anti-inflammation compound from the Chinese herbal medicine Sophora flavescens Ait. (Kushen). This study aimed to investigate the effects of matrine on memory deficit and neuroinflammation in an oligomeric Aß (oAß)-induced AD mice model. Whether microglial activation and NADPH oxidase were involved in these effects were further studied. Different doses of matrine (10, 20, or 40 mg/kg) were intragastrically administered once a day after intracerebroventricular oAß injection (2.5 µg/µl, 4 µl). 15 days after the oAß injection, behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test were performed. 21 days after the oAß injection, concentration of ROS, TNF-α, IL-1ß and IL-6 as well as expression of NADPH oxidase subunits gp91phox and p47phox in mice hippocampal tissues were assessed, and microglial activation were evaluated by Iba-1 immunohistochemical staining. Results of NOR test and MWM test revealed that oAß injection could remarkably impair learning and memory function in AD mice, and matrine administration could significantly ameliorate the impairment. ROS, TNF-α, IL-1ß and IL-6 levels increased after oAß injection, while matrine could significantly reduce the concentrations of these inflammatory factors. OAß induced protein expression of NADPH oxidase subunits gp91phox and p47phox were also significantly reduced by matrine. Iba-1 immunohistochemistry results showed less activated microglia in matrine-treated mice brain. These results indicate that matrine could ameliorate learning and memory impairment and neuroinflammation induced by oAß injection. These effects were found to be mediated through inhibition of microglial activation and NADPH oxidase expression in hippocampal tissue. The results suggest that matrine may be a valuable natural compound with therapeutic potential against AD.

Matrine inhibits itching by lowering the activity of calcium channel.

Sophorae Flavescentis Radix (SFR) is a medicinal herb with many functions that are involved in anti-inflammation, antinociception, and anticancer. SFR is also used to treat a variety of itching diseases. Matrine (MT) is one of the main constituents in SFR and also has the effect of relieving itching, but the antipruritic mechanism is still unclear. Here, we investigated the effect of MT on anti-pruritus. In acute and chronic itch models, MT significantly inhibited the scratching behavior not only in acute itching induced by histamine (His), chloroquine (CQ) and compound 48/80 with a dose-depended manner, but also in the chronic pruritus models of atopic dermatitis (AD) and acetone-ether-water (AEW) in mice. Furthermore, MT could be detected in the blood after intraperitoneal injection (i.p.) and subcutaneous injection (s.c.). Finally, electrophysiological and calcium imaging results showed that MT inhibited the excitatory synaptic transmission from dorsal root ganglion (DRG) to the dorsal horn of the spinal cord by suppressing the presynaptic N-type calcium channel. Taken together, we believe that MT is a novel drug candidate in treating pruritus diseases, especially for histamine-independent and chronic pruritus, which might be attributed to inhibition of the presynaptic N-type calcium channel.

The synergy of diammonium glycyrrhizinate remarkably reduces the toxicity of oxymatrine in ICR mice.

Most traditional Chinese medicine prescription dosages are imprecise. This study analyzes the toxicities and adverse effects of a combination the active ingredients of licorice and Kushen medicine: oxymatrine (OMT) and diammonium glycyrrhizinate (DG). The median lethal dose (LD50) and mortality were analyzed in single-dose OMT (or DG) intraperitoneally injected mice with or without combination DG (or OMT). Body weight changes as well as levels of serum sodium and potassium, alanine transaminase (ALT), aspartate transaminase (AST), creatinine, and urea were measured in mice treated with a daily dose of OMT and/or DG for 14days. This study showed that the LD50 of OMT for males and females were 347.44 and 429.15mg/kg, respectively. The LD50 of DG were 525.10 and 997.26mg/kg for males and females, respectively. DG significantly decreased the mice LD50-induced mortality of the OMT, however OMT did not succeed in reducing the LD50-induced mortality rate of DG. The combination of OMT and DG obviously attenuated the changes of the body weight, serum sodium, and potassium induced by DG or OMT alone. These results suggested that toxicity and adverse effects of the OMT was significantly attenuated by DG. The OMT neutralized the adverse effects of the DG, but not the toxicity.

Matrine Suppresses the ER-positive MCF Cells by Regulating Energy Metabolism and Endoplasmic Reticulum Stress Signaling Pathway.

Matrine (C15 H24 N2 O), an alkaloid that is one of the main active components from Sophora flavescens. Matrine has been demonstrated to have therapeutic effects on various solid tumors, including breast cancer, but the mechanism still needs further study. Endoplasmic reticulum (ER)-positive Michigan Cancer Foundation cells were cultured, and matrine was added in various amounts to measure the dose-dependent and time-dependent cytotoxicity. Hoechst 33258 staining was used to observed nuclear morphological changes. Apoptosis was measured by AnnexinV/PI double staining assay kit. Intracellular adenosine triphosphate and glycometabolism were detected by assay kit. The protein levels GRP78, p-eIF2α, CHOP, cytochrome c, and HexokinaseII were analyzed. Mechanistic investigations revealed that matrine treatment causes ER dilation and up-regulated the expression of ER stress markers GRP78, eIF2α, and CHOP, increases the levels of apoptotic in Michigan Cancer Foundation cells, subsequently, blocking the ER stress-mediated apoptosis pathway, significantly decreased matrine-induced apoptotic but still has significant difference between control group. In addition, matrine not only promoted the occurrence of ER stress but also inhibited the expression of hexokinase II, down-regulated energy metabolism. In summary, the present study suggests that the induction of ER stress-mediated apoptosis by matrine and down-regulated energy metabolism may account for its cytotoxic effects in human breast cancer cells. Copyright © 2017 John Wiley & Sons, Ltd.

A Novel, Multi-Target Natural Drug Candidate, Matrine, Improves Cognitive Deficits in Alzheimer's Disease Transgenic Mice by Inhibiting Aß Aggregation and Blocking the RAGE/Aß Axis.

The treatment of AD is a topic that has puzzled researchers for many years. Current mainstream theories still consider Aß to be the most important target for the cure of AD. In this study, we attempted to explore multiple targets for AD treatments with the aim of identifying a qualified compound that could both inhibit the aggregation of Aß and block the RAGE/Aß axis. We believed that a compound that targets both Aß and RAGE may be a feasible strategy for AD treatment. A novel and small natural compound, Matrine (Mat), was identified by high-throughput screening of the main components of traditional Chinese herbs used to treat dementia. Various experimental techniques were used to evaluate the effect of Mat on these two targets both in vitro and in AD mouse model. Mat could inhibit Aß42-induced cytotoxicity and suppress the Aß/RAGE signaling pathway in vitro. Additionally, the results of in vivo evaluations of the effects of Mat on the two targets were consistent with the results of our in vitro studies. Furthermore, Mat reduced proinflammatory cytokines and Aß deposition and attenuated the memory deficits of AD transgenic mice. We believe that this novel, multi-target strategy to inhibit both Aß and RAGE, is worthy of further exploration. Therefore, our future studies will focus on identifying even more effective multi-target compounds for the treatment of AD based on the molecular structure of Mat.

Liver, blood microdialysate and plasma pharmacokinetics of matrine following transdermal or intravenous administration.

Matrine is contained in several herbs used in traditional Chinese medicine, named Sophora alopecuroides, Sophora flavescens or Sophora subprostrata. In vitro and in vivo studies have focused on the treatment of chronic hepatitis or liver fibrosis using matrine. However, little is known about its liver pharmacokinetic profile. In this study pharmacokinetics of matrine in rat organs and tissues, such as liver, blood and skin were studied after intravenous (40 mg/kg) or transdermal administration (6 mg/cm2, 5 cm2). Samples were collected at timed intervals for measurement of matrine by a HPLC-UV method. The pharmacokinetic parameters were calculated by non-compartmental analysis using DAS 2.0. The AUC(0-t) values in the liver, blood microdialysates and plasma after intravenous administration were 395.91±74.48, 848.86±146.35 and 1304.07±305.92 min·mg/l, respectively. Following transdermal administration, the AUC(0-t) value in the liver, blood, plasma and skin microdialysates were 695.30±233.79, 1096.07±390.71, 2767.57±518.48 and 42735.77±27938.33 min·mg/l, respectively. Here, we show a promising delivery system for matrine that could replace traditional administration, and a better understanding of the transdermal pharmacokinetics of matrine, which may be helpful for further clinical and laboratory studies.

Oxymatrine synergistically enhances antitumor activity of oxaliplatin in colon carcinoma through PI3K/AKT/mTOR pathway.

Oxymatrine (OMT), one of the main active components of extracts from the dry roots of Sophora flavescens, has been reported to possess many pharmacological properties including cancer-preventive and anti-cancer effects. The aim of the present study is to explore the efficiency of combination therapy with OMT and oxaliplatin (OXA) and identify the in vitro and in vivo cytotoxicity on colon cancer lines (HT29 and SW480) and mice model. Cells were treated with OMT and/or OXA and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay and immunohistochemistry. The results demonstrated that OMT and OXA inhibited the proliferation of colon cancer cells, and combination therapy of OMT and OXA resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with OMT and OXA caused G0/G1 phase arrest by upregulating P21, P27 and downregulating cyclin D, and induced apoptosis through decreasing the expression of p-PI3K, p-AKT, p-mTOR, p-p70S6K. In addition, pretreatment with a specific PI3K/AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of OXA + OMT, demonstrating the important role of PI3K/AKT in this process. Moreover, in nude mice model, co-treatment displayed more efficient inhibition of tumor weight and volume on SW480 xenograft mouse model than single-agent treatment with OXA or OMT. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which consistent with our in vitro results. In conclusion, our findings highlight that the combination therapy with OMT and OXA exerted synergistic antitumor effects in colon cancer cells through PI3K/AKT/mTOR pathway and combination treatment with OMT and OXA would be a promising therapeutic strategy for colon carcinoma treatment.

Matrine induces cell cycle arrest and apoptosis with recovery of the expression of miR-126 in the A549 non-small cell lung cancer cell line.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality in the United States. Chemotherapy prolongs survival rates among patients with advanced disease, however, this is at the cost of clinically significant adverse effects. Matrine is an active component of traditional Chinese medicine and is a promising alternative drug for the treatment of NSCLC. In the present study, the therapeutic effects and the underlying molecular mechanisms of matrine on the A549 NSCLC cell line were investigated. A high concentration of matrine (1.0 mg/ml) significantly (P<0.05) inhibited cell proliferation, by 52.68±3.32%, under which cell shrinkage and disruption were observed. Flow cytometric analysis showed that the proportion of G1/G0 cells was significantly increased, whereas the proportions of S and G2/M cells were significantly decreased (P<0.05) following treatment with matrine for 48 h. These results indicated that cell arrest was induced by matrine. Upregulation of the expression of microRNA (miR)­126, followed by downregulation of the expression of its target gene, vascular endothelial growth factor, were detected following treatment with a low concentration of matrine (0.2 mg/ml) using reverse transcription­quantitative polymerase chain reaction analysis, immunohistochemistry and western blot analysis. In conclusion, matrine induced cell cycle arrest and apoptosis, and recovered the expression of miR­126 in the A549 NSCLC cell line.

MASM, a Matrine Derivative, Offers Radioprotection by Modulating Lethal Total-Body Irradiation-Induced Multiple Signaling Pathways in Wistar Rats.

Matrine is an alkaloid extracted from Sophora flavescens Ait and has many biological activities, such as anti-inflammatory, antitumor, anti-fibrosis, and immunosuppressive properties. In our previous studies, the matrine derivative MASM was synthesized and exhibited potent inhibitory activity against liver fibrosis. In this study, we mainly investigated its protection against lethal total-body irradiation (TBI) in rats. Administration of MASM reduced the radiation sickness characteristics and increased the 30-day survival of rats before or after lethal TBI. Ultrastructural observation illustrated that pretreatment of rats with MASM significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed that pretreatment with MASM had a dramatic effect on gene expression changes caused by TBI. Pretreatment with MASM prevented differential expression of 53% (765 genes) of 1445 differentially expressed genes induced by TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways, such as metabolic pathways, pathways in cancer, and mitogen-activated protein kinase (MAPK) pathways. Our data indicated that pretreatment of rats with MASM modulated these pathways induced by TBI, suggesting that the pretreatment with MASM might provide the protective effects on lethal TBI mainly or partially through the modulation of these pathways, such as multiple MAPK pathways. Therefore, MASM has the potential to be used as an effective therapeutic or radioprotective agent to minimize irradiation damages and in combination with radiotherapy to improve the efficacy of cancer therapy.

Oxymatrine Induces Liver Injury through JNK Signalling Pathway Mediated by TNF-α In Vivo.

Oxymatrine (OMT) is a traditional Chinese medicine monomer and has been used for the treatment of chronic viral hepatitis and many other diseases. We aimed to investigate whether OMT could induce hepatotoxicity in mice and explored the preliminary mechanisms of toxic effects. Twenty-four Institute for Cancer Research male mice were randomly divided into four groups: control group, 40, 160 and 320 mg/kg OMT-treated group. OMT was orally administered once daily for 7 days. The OMT-treated group exhibited an improved liver index and increase in serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase,augmented liver histological injury, elevated levels of malondialdehyde and tumour necrosis factor alpha (TNF-α) accompanied by the activation of caspase-9/-8/-3, up-regulated expressions of tumour necrosis factor receptor l (TNFR1), TNF receptor-associated structure domain (TRADD) and phosphorylation of stress-activated protein kinase/c-jun N-terminal protein kinases (p-SAPK/JNK). Altogether, these results suggest that OMT at a dose of 320 mg/kg leads to liver damage and is related to the activation of JNK signalling pathway mediated by TNF-α in the liver of mice.

Effects of Silymarin, Glycyrrhizin, and Oxymatrine on the Pharmacokinetics of Ribavirin and Its Major Metabolite in Rats.

The herb-derived compounds silymarin, glycyrrhizin, and oxymatrine are widely used to treat chronic hepatitis C virus infections in China. They are often prescribed in combination with ribavirin, which has a narrow therapeutic index. We investigated the influence of these compounds on ribavirin pharmacokinetics following concurrent administration at the human dose in rats. Pharmacokinetic parameters were determined in rats following oral (p.o.) administration of ribavirin (30 mg/kg) with or without silymarin (40 mg/kg, p.o.), glycyrrhizin (15 mg/kg, intraperitoneal [i.p.]), or oxymatrine (60 mg/kg, p.o.). Compared with the animals in ribavirin group, silymarin significantly decreased the area under the plasma concentration-time curve (AUC0-t ) and the peak plasma concentration (Cmax ) of ribavirin and ribavirin base by 31.2-44.5% and 48.9-50.0%, respectively. Glycyrrhizin significantly decreased the Cmax and AUC0-t of both ribavirin and its metabolite by 35.3-37.6% and 38.6-39.8%, respectively. However, silymarin or glycyrrhizin did not change the ribavirin metabolite/parent ratios of the AUC and Cmax . Oxymatrine did not induce significant changes in ribavirin concentration, but it significantly decreased the Cmax (26.6%) and AUC (21.8%) of the metabolite. This study indicates that the therapeutic efficacy of ribavirin may be compromised by the concurrent administration of herbal medicines/dietary supplements containing silymarin, glycyrrhizin, or oxymatrine.

Oral oxymatrine preparation for chronic hepatitis B: A systematic review of randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of oral oxymatrine preparation for the treatment of chronic hepatitis B (CHB). METHODS: Randomized controlled trials (RCTs) on oral oxymatrine preparation in treating patients with CHB were retrieved until October 2013 by searching PubMed, the Cochrane Library, Embase and four Chinese databases, irrespective of language and publication status. Data extraction and data analyses were conducted according to the Cochrane standards. The risk of bias for each included trials and the quality of evidence on pre-specified outcomes were assessed. The RevMan software was used for statistical analyses. RESULTS: Totally 52 RCTs enrolling 5,227 participants were included, of which 51 RCTs were included in meta-analyses. Oral oxymatrine preparation including oxymatrine capsule and oxymatrine tablet were associated with statistically significant effect on the clearance of hepatitis B virus (HBV) DNA, HBV surface antigen and HBV e antigen, and were beneficial to the normalization of serum alanine aminotransferase and aspartate aminotransferase. Nevertheless, the overall methodological quality and the quality of evidence in the included trials were poor. In addition, safety of oral oxymatrine preparation was not confirmed. CONCLUSIONS: Oral oxymatrine preparation showed some potential benefits for patients with CHB. However, the overall quality of evidence was limited and the safety of oral oxymatrine preparation for CHB patients was still unproven. More high quality evidence from rigorously designed RCTs is warranted to support the clinical use of oral oxymatrine preparation for patients with CHB.

[Effects of baicalin, matrine, glycyrrhetinic acid and emodin in three kinds of emulsifier cream system on transdermal absorption in vitro].

To study effects of APG, Span-Tween and A6/25 emulsifier cream system on transdermal absorption in vitro of baicalin, matrine, glycyrrhetinic acid and emodin in emulsifier. Permeations studies were carried out in vitro with excised mice skin by improved Franz diffusion cells. The cumulative penetration amounts and the retention amounts of Chinese herbal medicinal ingredients in three kinds of emulsifier cream systems were determined by HPLC. The effects of different Chinese herbal medicinal ingredients in the same emulsifier system and the same herbal medicinal ingredients in different emulsifier systems on cumulative permeation amount, skin retention amount and permeation rate were investigated. According to the results, the order of different Chinese herbal medicinal ingredients in same kinds of emulsifier system by the cumulative permeation amount and the permeation rate were matrine>baicalin>glycyrrhetinic acid>emodin. With respect to the effect of different emulsifier systems on cumulative permeation amount and permeation rate of the same herbal medicinal ingredients, glycyrrhetinic acid and emodin showed no significant difference, Span-Tween emulsifier cream system had higher cumulative permeation amount and permeation rate. The cumulative permeation amount and the permeation rate of Chinese herbal medicinal ingredients in the three kinds of emulsifier cream systems had an identical regularity. However, the cumulative permeation amount, the skin retension amount and the permeation rate of the same herbal medicinal ingredients in different emulsifier systems had no regularity.

Oxymatrine inhibited cell proliferation by inducing apoptosis in human lung cancer A549 cells.

To investigate the inhibition effect of oxymatrine induces human lung cancer A549 cells apoptosis. The A549 cells were cultured for 24 h, than the various concentration of oxymatrine (2 mmol/L, 4 mmol/L, 8 mmol/L, 15 mmol/L) were added into different experimental group cells, and 5-fluorouracil were added into the positive control group cells for 12 h, 24 h, 36 h, 48 h respectively. The A549 cells inhibition rate, apoptosis, and the expression of Bcl-2 and Bax were examined by MTT method, Annexin V/PI double staining method, real-time quantitative PCR and western blot, respectively. At same time, the morphological changes of A549 cells were observed with an inverted microscope. In the range of 2 mmol/L~15 mmol/L, oxymatrine had obvious inhibition effects on the proliferation of A549 cells. Compared with the negative control group, it has significantly different (P<0.01). There was remarkably the time- and dose-dependent correlation. After A549 cells were treated with 8 mmol/L oxymatrine for 24 h, the morphological change of cell apoptosis was observed and the extent of apoptosis was quantified by flow cytometry. Furthermore, the expression of Bcl-2 was reduced and the expression of Bax was increased remarkably (P<0.05). Oxymatrine has significant inhibition effects on the cells proliferation and the effects showed time-dependent and dose-dependent. Oxymatrine can induce apoptosis of the A549 cells by regulating the expression of Bcl-2 and Bax.

Anti-tumor activities of active ingredients in Compound Kushen Injection.

Kushen (Radix Sophorae Flavescentis) has a long history of use for the treatment of tumors, inflammation and other diseases in traditional Chinese medicine. Compound Kushen Injection (CKI) is a mixture of natural compounds extracted from Kushen and Baituling (Rhizoma Smilacis Glabrae). The main principles of CKI are matrine (MT) and oxymatrine (OMT) that exhibit a variety of pharmacological activities, including anti-inflammatory, anti-allergic, anti-viral, anti-fibrotic and cardiovascular protective effects. Recent evidence shows that these compounds also produce anti-cancer actions, such as inhibiting cancer cell proliferation, inducing cell cycle arrest, accelerating apoptosis, restraining angiogenesis, inducing cell differentiation, inhibiting cancer metastasis and invasion, reversing multidrug resistance, and preventing or reducing chemotherapy- and/or radiotherapy-induced toxicity when combined with chemotherapeutic drugs. In this review, we summarize recent progress in studying the anti-cancer activities of MT, OMT and CKI and their potential molecular targets, which provide clues and references for further study.

[Effect of matrine on NO and ADMA metabolism pathways in serum and tissues of mice with lipopolysaccharide-induced intestine tissue inflammation].

OBJECTIVE: To discuss the effect of matrine on nitric oxide (NO) and asymmetric methylarginine (ADMA) metabolism pathways in serum and tissues of mice with lipopolysaccharide (LPS) -induced intestine tissue inflammation. METHOD: Kunming mice were randomly divided into five groups: the normal control group, the LPS group and matrine (80, 40, 20 mg x kg(-1) x d(-1)) groups. The mice were intragastrically administered with drugs for 3 d (distilled water of the same volume for the normal control group and the LPS group). One hour after the last intragastrical administration, normal saline or LPS (1 mg x kg(-1)) were intraperitoneally injected. Twelve hours later, serum and tissues were collected to determine NO and ADMA levels and observe the pathological changes of intestinal tissues. The Western blot method was adopted to detect the protein expressions of arginine methyltransferases 1 (PRMT1) and dimethylarginine dimethylaminohydrolase 2 (DDAH2) in intestinal tissues. RESULT: Compared with the model group, matrine (80, 40, 20 mg x kg(-1) x d(-1)) groups showed lower NO content in serum and tissues, higher ADMA level in serum and increased PRMT1 expression in intestinal tissues, but without effect on DDAH2 expression. CONCLUSION: Matrine could inhibit LPS-induced intestine tissue inflammation in mice. Its action mechanism is related to the decreased NO content in serum and tissues and increased ADMA level in serum and PRMT1 expression in intestinal tissues.

[Study on preparation of matrine double-sensitive colon-specific pellets and in vitro release].

OBJECTIVE: To prepare matrine double-sensitive colon-specific pellets and study the factors affecting its quality and evaluateing the colon-specific effects of preparation. METHOD: Matrine enzyme-sensitive pellets core were prepared by carboxymethyl konjac glucomannan as the main carrier material, and coated the core by acrylic resin II and III to prepare matrine double-sensitive colon-specific pellets. The prescription and technology of the matrine colon-specific pellets were studied by the single factor investigation, through the in vitro release test and coating rate determination. RESULT: The optimized process conditions: FeCl3 concentration is 4.0 g x L(-1), chitosan concentration is 3.0 g x L(-1), carboxymethyl konjac glucomannan concentration is 20 g x L(-1), mixed gel solution pH value is 3. The release of matrine is less than 30% in the simulation of the upper gastrointestinal medium. The release of matrine is close to 100% in simulated full gastrointestinal medium, the coating weight is 7%. CONCLUSION: The prepared pellets have good colon positioning effect in vitro.

Antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury.

CONTEXT: Sophora alopecuroides L. (Leguminosae) is a commonly used Chinese herbal drug that possesses antipyretic, anti-inflammatory and analgesic effects. Among various alkaloids isolated from S. alopecuroides, matrine has been identified as the major bioactive component contributing to a variety of pharmacological effects, and studies have also shown that matrine has an analgesic effect. OBJECTIVE: To investigate the antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury (CCI) in mice. MATERIALS AND METHODS: The von Frey, plantar, cold-plate, locomotor activity and rota-rod test were performed to assess the degree of mechanical, radiant, thermal, spontaneous locomotor activity and motor coordination changes respectively, at different time intervals, i.e., one day before surgery and 7, 8, 10, 12 and 14 days post surgery. Matrine was administered from the 8th day after the surgery for seven days. RESULTS: Our present study shows that matrine at the dose of 30 mg/kg i.p. increased the paw withdrawal threshold (0.88 ± 0.16), paw withdrawal latency (7.01 ± 0.11) and the counts of paw withdrawal (19.7 ± 1.15) from the day 8 for the nerve injured paw compared to the CCI group (0.18 ± 0.04, 4.62 ± 0.18, 44.3 ± 2.99, respectively). Matrine, in a dose-dependent effect, was also found to produce a protective role in both plantar and cold-plate tests. The analysis of the effect supports the hypothesis that matrine is useful in neuropathic pain therapy. DISCUSSION AND CONCLUSION: The results of this study suggest that matrine could be useful in the treatment of different kinds of neuropathic pains as an adjuvant to conventional medicines.