Bioinformatics Based Therapeutic Effects of Sinomenium Acutum / 中国结合医学杂志

OBJECTIVE@#To decipher the possible mechanisms of Sinomenium Acutum (SA) in treating diseases by a bioinformatics method.@*METHODS@#SA ingredients were searched according to Chinese Pharmacopoeia, Chinese Medicine Dictionary and Traditional Chinese Medicines Database (TCMD). Active compounds and target proteins of SA were acquired through the Pubchem platform. Pathway, network and function analyses of SA were performed with ingenuity pathway analysis (IPA), a bioinformatics analysis platform. Disease, biofunction-target networks were established with Cytoscape.@*RESULTS@#Eighteen ingredients from SA were obtained. Seven active ingredients with 31 active target proteins were acquired according to PubChem Bioassay test. By IPA analysis, 277 canonical pathways belonging to 17 function categories were collected, 23 kinds of diseases, 21 categories bio-functions were obtained. Based on P value, calculated by IPA, the top 5 significant pathway of SA targets include phosphatidylinositol 3 kinase/Akt (PI3K/Akt) signaling, prostate cancer signaling, macrophage migration inhibitory factor (MIF) regulation of innate immunity, Guanosine-binding protein coupled receptor (GPCR) signaling, and ataxia telangiectasia mutated protein (ATM) signaling. Disease and bio-function network analysis indicated that mitogen activated protein kinase 1 (MAPK1), MAPK3, p65 nuclear factor κB (RELA), nuclear factor of κB inhibitor alpha (NFκBIA), interleukin 1β(IL-1β), prostaglandin G/H synthase 2 (PTGS2) and tumor protein 53 (TP53) were the critical targets in various diseases treated by SA.@*CONCLUSION@#In the different view of target, pathway, disease and bio-function, inflammation was found to be a central theme in many chronic conditions. SA could be used not only as an anti-inflammatory agent, but also for the treatment of cancers, neurological diseases, psychological disorders and metabolic diseases.

Sinomenine, an Alkaloid Derived from Sinomenium acutum Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep in Rodents

Sinomenium acutum has been long used in the preparations of traditional medicine in Japan, China and Korea for the treatment of various disorders including rheumatism, fever, pulmonary diseases and mood disorders. Recently, it was reported that Sinomenium acutum, has sedative and anxiolytic effects mediated by GABA-ergic systems. These experiments were performed to investigate whether sinomenine (SIN), an alkaloid derived from Sinomenium acutum enhances pentobarbital-induced sleep via γ-aminobutyric acid (GABA)-ergic systems, and modulates sleep architecture in mice. Oral administration of SIN (40 mg/kg) markedly reduced spontaneous locomotor activity, similar to diazepam (a benzodiazepine agonist) in mice. SIN shortened sleep latency, and increased total sleep time in a dose-dependent manner when co-administrated with pentobarbital (42 mg/kg, i.p.). SIN also increased the number of sleeping mice and total sleep time by concomitant administration with the sub-hypnotic dosage of pentobarbital (28 mg/kg, i.p.). SIN reduced the number of sleep-wake cycles, and increased total sleep time and non-rapid eye movement (NREM) sleep. In addition, SIN also increased chloride influx in the primary cultured hypothalamic neuronal cells. Furthermore, protein overexpression of glutamic acid decarboxylase (GAD(65/67)) and GABA(A) receptor subunits by western blot were found, being activated by SIN. In conclusion, SIN augments pentobarbital-induced sleeping behaviors through GABA(A)-ergic systems, and increased NREM sleep. It could be a candidate for the treatment of insomnia.

Computational simulation of multi-target research on the material basis of Caulis sinomenii in treating osteoarthritis / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore the material basis of Caulis sinomenii (CS) in treating osteoarthritis (OA), and to give a pharmacodynamic illustration for the multi-targeting therapeutics of CS.</p><p><b>METHODS</b>The computational methods, consisting of molecular docking and biological network were carried out to search the database targeting twelve important OA related enzymes: ASAMTS4, ASAMTS5, MMP-1, MMP-3, MMP-13, MMP-8, MMP-2, COX-2, COX-1, IL-1beta, TNF-alpha, iNOS, and map the ligand-target interaction networks about molecules from CS and DrugBank. After that, an aggregate analysis was performed to analyze the mechanisms of compositions in CS.</p><p><b>RESULTS</b>Totally 14 had good interaction in all molecules in database with two or more than two of the OA correlated enzymes, and 6 molecules had interaction with four or more enzymes. Moreover, both herb ligand-target interaction network and drug ligand-target interaction network were similar in the interaction profiles and network features, which revealed multi-drugs effects in CS.</p><p><b>CONCLUSIONS</b>There were a lot of multi-target molecules in CS, providing pharmacodynamic illustrations for the multi-target therapeutics of Chinese medicine. Meanwhile, they supplied certain reference and inspiration for finding out new drugs for OA therapy.</p>

Preparation of sustained release microspheres containing extracts from Caulis sinomenii with polylactic acid and their release property in vitro / 中国中药杂志

<p><b>OBJECTIVE</b>To prepare polylactic acid microspheres containing total alkaloid extracts of Caulis sinomenii and study their release characteristics in vitro.</p><p><b>METHOD</b>Polylactic acid microspheres containing total alkaloid extracts of C. sinomenii were prepared by O/W emulsification solvent-evaporation process. The microspheres were characterized in terms of morphology, encapsulation efficiency, and particle size distribution. The effect of different conditions on release property of microspheres was studied.</p><p><b>RESULT</b>The formed microspheres were spherical with smooth surfaces. The encapsulation efficiency and rate of drug loading were (83.4 +/- 5.63)% and (8.7-0.35)%, respectively. The distribution of particle size was uniform and the average size was (21.5 +/- 1.22) microm. In vitro release study revealed that the 32-hour accumulative release percentage reached 80%.</p><p><b>CONCLUSION</b>Polylactic acid microspheres containing total alkaloid extracts of C. sinomenii were prepared successfully. Microspheres with good sustained-release characteristics can be produced by controlling different process parameters.</p>

Preparation of sinomenine microemulsion and its transdermal absorption / 中国中药杂志

<p><b>OBJECTIVE</b>To screen the optimum formulation and prepare O/W sinomenine microemulsion and investigate its in vitro transdermal delivery ability.</p><p><b>METHOD</b>The microemulsions were prepared with the formulation containing oleic acid-tween 80-dehydrated alcohol-water by the pseudo-ternary phase diagram. The permeation flux of sinomenine was determined in vitro by Franz diffusion cell fitted with rat skin. The sinomenine was determined by HPLC. The transdermal characteristics of sinomenine microemulsion were compared with that of sinomenine gels.</p><p><b>RESULT</b>The steady state flux of sinomenine microemulsion was significantly higher than that of sinomenine gels. The average permeation rate of sinomenine microemulsion was 116. 44 microg x cm(-2) x h(-1) in vitro.</p><p><b>CONCLUSION</b>These results indicated that the studied microemulsion system with high permeation rate may be a potential vehicle for the transdermal delivery of sinomenine.</p>

Studies on preparation of sinomenine hydrochloride-loaded bovine serum albumin microspheres / 中国中药杂志

<p><b>OBJECTIVE</b>To prepare Sinomenine hydrochloride-loaded bovine serum albumin microspheres (SM-BSA-MS).</p><p><b>METHOD</b>SM-BSA-MS was prepared by spray drying technique. The morphology, drug-loading and release in vitro of SM-BSA-MS was studied.</p><p><b>RESULT</b>The diameters of SM-BSA-MS were in the range of 1-3 m. The drug loading of microspheres, formulated with different drug/albumin ratios as 1, 2, 1:1, 2:1, were 31.6%, 47.7% and 67.9% , respectively. And the drug entrapment efficiencies of different drug/albumin ratios were higher than 94%. The results of in vitro release experiments showed that the drug loaded microspheres have the properties of sustained-release compared with the Sinomenine hydrochloride injection. Different release characteristics could be obtained by adjusting the prescription composition and the thermal denaturation condition.</p><p><b>CONCLUSION</b>Spray drying technique is a simple and feasible method for preparing SM-BSA-MS. The drug loaded microspheres had high drug-loading and sustained-release effect.</p>

Determination of HPLC fingerprint of Qingfengtong capsule / 中国中药杂志

<p><b>OBJECTIVE</b>To establish a fingerprint analysis method of Qingfengtong capsule by HPLC.</p><p><b>METHOD</b>The samples were extracted with 70% ethanol in an ultrasonic bath. The extracts were analyzed at 35 degrees C on a Diamonsil C18 column (4.6 mm x 250 mm, 5 microm) with 0.1 mol x L(-1) potassium dihydrogen phosphate water-solution as mobile phase A, and methanol as mobile phase B. The analysis followed a linear gradient elution program. Initial condition of the mobile phase was 10% B for 2 minutes; then changed to 90% B in 40 minutes. The flow rate was kept at 1.0 ml x min(-1) and the detector wavelength was 262 nm.</p><p><b>RESULT</b>The main peaks in fingerprint chromatogram of Qingfengtong capsules were separated fairly well. The results of method validation meet the requirements for the fingerprints.</p><p><b>CONCLUSION</b>The established method can be used for the quality control of Qingfengtong capsules.</p>

Effects of Caulis Sinomenii and sinomenine on morphine-induced place preference and brain histamine level in mice / 南方医科大学学报

<p><b>OBJECTIVE</b>To evaluate the effects of Caulis Sinomenii and sinomenine on conditioned place preference (CPP) induced by morphine and brain histamine level in mice.</p><p><b>METHODS</b>Sixty mice were randomized into 6 equal groups and morphine (Mor) was injected subcutaneously (9 mg/kg) for 6 consecutive days to induce CPP using a shuttle box. Since the 4th day of training, the mice in 5 of the groups were treated for 3 consecutive days with Caulis Sinomenii (10 g/kg), sinomenine (60 mg/kg), diphenhydramine (30 mg/kg), CP48/80 (5 mg/kg) and L-histidine (750 mg/kg) in addition to morphine (9 mg/kg) treatment, respectively, leaving the other group with exclusive morphine treatment. Another 10 mice received saline injection to serve as saline control group. The content of histamine (HA) in the mouse brain was measured by fluorospectrophotometry.</p><p><b>RESULTS</b>In morphine group, the mice showed significantly extended stay in morphine-paired compartment whose HA content in the brain was markedly increased (P<0.01). Treatment with Caulis Sinomenii and sinomenine resulted in significantly reduced time of stay in morphine-paired compartment and brain HA level (P<0.01).</p><p><b>CONCLUSION</b>CPP induced by morphine in mice is associated with increased HA level in the brain. Caulis Sinomenii and sinomenine can suppress the acquisition of place preference induced by morphine and modulate HA level in the central nervous system in morphine-dependent mice.</p>

Study on determination of entrapment efficiency of sinomenine liposomes / 中国中药杂志

<p><b>OBJECTIVE</b>To establish an HPLC method for the determination of entrapment efficiency of sinomenine liposomes.</p><p><b>METHOD</b>The liposomes and dissociated drugs were separated by sephadex filtration, mini-column centrifugation and dialysis. The methodology study and the optimization of determining condition were carried out at the same time.</p><p><b>RESULT</b>Sephadex filtration could effectively separate the sinomenine liposomes from dissociated sinomenine. The column recovery was 98.8%, the average entrapment efficiency of three tests was64.9%, RSD 2.67%.</p><p><b>CONCLUSION</b>The method was simple, exact, and had a good reappearance. It can be used to examine the entrapment efficiency of sinomenine liposomes.</p>

Determination in vitro of rat plasma protein binding rate of sinomenine by using microdialysis method / 药学学报

<p><b>AIM</b>To determine in vitro the rat plasma protein binding rate by using microdialysis method.</p><p><b>METHODS</b>The binding rate was determined by using microdialysis probe as sampling tools and zero-net flux method as calibrating method. The regression equation was made by the difference of concentrations between the dialysis sample and the perfusate. The x-intercept of regression equation was the free drug concentration (Cf). The plasma protein binding rate was calculated by using the following equation: f = ( C0 - Cf)/C0.</p><p><b>RESULT</b>The binding rate was kept relatively stable in the studied concentration range.</p><p><b>CONCLUSION</b>It is feasible that the plasma protein binding rate can be determined by using microdialysis method.</p>

Immunopharmacological action of sinomenine, an alkaloid isolated from Sinomenium acutum, and its mechanism of action in treating rheumatoid arthritis / 药学学报

<p><b>AIM</b>To observe the effects of sinomenine on the immune functions and apoptosis of murine lymphocyte as well as on human synovial fibroblast proliferation.</p><p><b>METHODS</b>Both in vivo and in vitro tests were adopted. The lymphocyte proliferation induced by mitogens was assayed by MTT method. Spleen T lymphocyte subtypes were tested with flow cytometry. Spleen lymphocyte apoptosis was analyzed by flow cytometry and DNA ladder methods. In vitro test was adopted to observe the effects of sinomenine on the proliferation of human fibroblast of rheumatoid arthritis.</p><p><b>RESULTS</b>Sinomenine can inhibit the proliferation of mouse lymphocytes induced by ConA, LPS and anti-CD3 mAb but not PMA in vitro, and inhibit the proliferation induced by LPS and PMA in vivo. Sinomenine can reduce up-regulated CD4+/CD8+ ratio of T lymphocyte subtype in adjuvant arthritis rat. At the same concentration increased apoptosis ratio. As to human synovial fibroblast, sinomenine can significantly inhibit proliferation of human fibroblast.</p><p><b>CONCLUSION</b>Sinomenine can inhibit the immunological function and correct imbalance of CD4+/CD8+ ratio of T lymphocyte subtype. It can also increase apoptosis ratio of spleen lymphocyte. This may be the mechanism of its immunological inhibitory effect.</p>

Effect of sinomenine on adjuvant arthritis and its mechanisms / 中国中药杂志

<p><b>OBJECTIVE</b>To discuss the anti-inflammatory mechanism of sinomenine on inflammatory media in joint of adjuvant arthritis rats.</p><p><b>METHOD</b>Rats were randomly divided into the normal group and the model group, the prednisone group, the small, medium, large of sinomenine group (30, 60, 120 mg x kg(-1)). Except for the rats in the normal group, animals were modeled to adjuvant arthritiswith freund's complete adjuvant. The arthritis index (AI) and the swelling degree of paws were recorded, and the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were determined.</p><p><b>RESULT</b>Compared with the normal group, the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were increased significantly in the model group (P < 0.05). Compared with the model group, it was shown to exert a dramatic inhibitory effect on secondary reaction of freund's adjuvant arthritis of rats, and the activity of IL-1, TNF and the levels of NO, PGE2 in joint fluids of secondary arthritis were significantly decreased in the sinomenine group (P < 0.05).</p><p><b>CONCLUSION</b>Sinomenine has a remarkable treatment effect on RA. It is via NO to inhibit the activity of cytokines and decrease the level of inflammation mediators, which may be one of its curing RA mechanism.</p>

New study progress of sinomenine / 中国中药杂志

To further understand sinomenine, this paper has introduced the abstract technology, assaying, pharmaceutical chemistry, pharmacological action, pharmacotoxicology, pharmacokinetics and clinical application of sinomenine based on the important and significant contents of reference which have been consulted in the past ten years. Sinomenine is a kind of non-steroidal anti-inflammatory drugs with very effective and little side effect and expected it as a good new drug withdrawal medicine in the future.

Synthesis and anti-inflammatory analgesic activities of sinomenine derivatives / 药学学报

<p><b>AIM</b>To provide basic data for the synthesis of new sinomenine derivatives.</p><p><b>METHODS</b>The C ring in sinomenine was modified.</p><p><b>RESULTS</b>Seven compounds were prepared and screened for anti-inflammatory and analgesic activities. Compounds 2 and 5 showed better activities.</p><p><b>CONCLUSION</b>Modification of the C ring in sinomenine should be worthy to be studied further.</p>

Inhibitory effect of sinomenine on expression of cyclooxygenase-2 in lipopolysaccharide-induced PC-12 cells / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effects of sinomenine (Sin) on cell proliferation, intracellular expression of cyclooxygenase-2 (COX-2), and production of PGE2 in lipopolysaccharide-induced PC-12 cells, To explore the Sin's mechanism on nerve cell.</p><p><b>METHOD</b>PC-12 cells were cultured with nerve growing factors (NGF), and pretreated with Sin at various concentrations (0, 3 x 10(-6), 30 x 10(-6), 150 x 10(-6) mol x L(-1)) for 2 hours, then with or without stimulation of lipopolysaccharide (LPS). The proliferation activity of PC-12 cells was determined by 3H-TdR incorporation, and the production of PGE2 in culture supernatants of PC-12 cells was detected with competitive ELISA. Expression of COX-2 mRNA in PC-12 cells was analyzed by semi-quantitative RT-PCR, and expression of COX-2 protein was estimated by Western blot method and cellular enzyme immunoassay. Nuclear factor-kappa B (NF-kappaB) activity in whole-cell extract of PC-12 cells was also measured by an ELISA-based method.</p><p><b>RESULT</b>The data showed that Sin down-regulated the expression of COX-2 mRNA and protein, and reduced the production of PGE2 in the LPS-stimulated PC-12 cells which correlated with Sin's concentrations positively. In addition, NF-kappaB activity in LPS-stimulated cells was suppressed significantly by Sin. No inhibition of proliferation of PC-12 cells due to Sin treatment was observed.</p><p><b>CONCLUSION</b>Sin mediates the down-regulation of expression of COX-2 and production of induced PGE2 in PC-12 cells by suppressing the activity of NF-kappaB.</p>

The effect of sinomenine on cyclooxygenase activity and the expression of COX-1 and COX-2 mRNA in human peripheral monocytes / 中国中药杂志

<p><b>OBJECTIVE</b>To observe in vitro the effect of Sinomenine, a pure alkaloid extracted from the chinese medical plant Sinomenium acutum on the activity of cyclooxygenase (COX-1 and COX-2) and the expression of COX-1 and COX-2 mRNA.</p><p><b>METHOD</b>Mononuclear leukocytes were obtained from healthy adults. Isolated mononuclear leucocytes from human peripheral blood (PBMC) were incubated (1 x 10(6).mL-1) with or without sinomenine (or indomethacin), after incubated for 24 hours at 37 degrees C with 5% CO2; the media were assayed for the PGE2 by radioimmunoassay (RIA). LPS was used to stimulate the monocytes at a concentration of 5 micrograms.mL-1. And by RT-PCR, both COX-1 and COX-2 mRNAs were detected in Mononuclear leukocytes after incubation for different hours with drug (sinomenine or indomethacin) or not.</p><p><b>RESULT</b>LPS (stimulated) induced the production of PGE2 in PBMC increasing with high expression of COX-2 mRNA; sinomenine reduced PGE2 production in LPS stimulated human monocytes more than in non-stimulated human monocytes. In comparative experiments, indomethacin, a non selective COX inhibitor, reduced the production of PGE2 equally in both states. Meanwhile, neither sinomenine(0.1-1 mmol.L-1) nor indomethacin(0.5-10 mumol.L-1) inhibited the expression of both COX-1 and COX-2 mRNAs by RT-PCR with beta-actin as reference.</p><p><b>CONCLUSION</b>In contrast with indomethacin, Sinomenine shows a preferential inhibitory effect on COX-2 over COX-1, These results suggest that Sinomenine is a selective COX-2 inhibitor, which may be directly related to suppressing cyclooxygenase activity.</p>

Retrospective study of adverse events in patients with rheumatoid arthritis treated with second-line drugs / 中华流行病学杂志

<p><b>OBJECTIVE</b>To evaluate rates on the adverse side effect and discontinuation of second-line drugs frequently used in the treatment of rheumatoid arthritis (RA).</p><p><b>METHOD</b>Eight hundred and sixty-four RA patients were studied in a retrospective program.</p><p><b>RESULTS</b>Upper abdominal discomfort was most commonly seen when using second-line drugs. Rash was often associated with D-penicillamine (20.6%) and Sinomenium therapy (13.7%). Methotrexate (MTX) was uniquely characterized by substantial upper GI toxicity (32.2%) and Tripterygium wilfordii Hook. f. (TWH) (14.4%) by menstrual abnormality. Sulfasalazine users reported adverse events including upper abdominal trouble (39.0%), nausea (7.3%) and anorexia (7.3%) while the risk of GI malaise was greater. Patients taking hydroxychloroquine complained of blurred vision (19.6%) but no one went blind. Toxic side effects seemed to be the most common reasons for stoppages, and the patients taking MTX had the lowest discontinuation rate. Combination of D-penicillamine and Methotrexate did not increase the incidence of adverse events.</p><p><b>CONCLUSIONS</b>Knowledge on these different patterns of toxicity provided choices in the selection of second line agents for particular RA patients. However, long-term monitor are required when drugs are being used.</p>