Xiao et al reported on the natural product sinomenine(SIN),which is a traditional Chinese medicine for treating osteoporosis via its modulation of autophagy;however,SIN was dissolved in dimethyl sulfoxide prior to adm...Xiao et al reported on the natural product sinomenine(SIN),which is a traditional Chinese medicine for treating osteoporosis via its modulation of autophagy;however,SIN was dissolved in dimethyl sulfoxide prior to administration,which is not conducive to the development of clinical injectables.By comparing solubilization techniques,including amorphisation,emulsification,micellisation,nanocrystallisation and host-vip inclusion,we found that the solubilization of SIN by host-vip inclusion can enhance solubility and improve stability and has an increased release rate and enhanced bioavailability.Therefore,we conclude that host-vip inclusion holds promise for SIN solubilization.To solubilise SIN,we selectedβ-cyclodextrin as the host agent considering its excellent biocompatibility,efficient encapsulation ability,mature preparation process and adequate drug stability.If the prerequisites of SIN-β-cyclodextrin complexes in terms of safety,efficacy,stability and the relevant laws and regulations are met,its clinical application for the treatment of osteoporosis may be achieved.展开更多
Objective:To evaluate the cardioprotective effects of sinomenine using the ischemia/reperfusion(I/R)rat model.Methods:Wistar rats were randomly divided into 6 groups:group Ⅰ with reperfusion,group Ⅱ perfused with si...Objective:To evaluate the cardioprotective effects of sinomenine using the ischemia/reperfusion(I/R)rat model.Methods:Wistar rats were randomly divided into 6 groups:group Ⅰ with reperfusion,group Ⅱ perfused with sinomenine,group Ⅲ perfused with 5-hydroxydecanoate(5-HD),group Ⅳ perfused with 5-HD+sinomenine,group Ⅴ perfused with L-nitro arginine methyl ester(L-NAME),group Ⅵ perfused with L-NAME+sinomenine.Myocardial ischemia was induced by interrupting the aortic blood supply for 30 min,followed by reperfusion(55 min).Cardiac,hepatic,antioxidant,and inflammatory parameters were assessed.Additionally,endothelin,tissue factor,platelet-activating factor,plasminogen activator inhibitor,plasma fibrinogen,and thromboxane B2 were also analyzed.Results:Administration of 5-HD or L-NAME,used as the selective antagonist of mitoKATP and NO system,respectively,resulted in significantly increased levels of premature ventricular complexes,lactate dehydrogenase,ventricular fibrillation,ventricular tachycardia,and arrhythmia intensity(P<0.05).In contrast,sinomenine significantly reduced the level of troponin Ⅰ,lactate dehydrogenase,creatine kinase,and creatine kinase MB compared to the 5-HD group and the L-NAME group(P<0.05).Additionally,sinomenine significantly reduced malondialdehyde level and enhanced the levels of superoxide dismutase,glutathione peroxidase,catalase,and glutathione/glutathione disulfide ratio(P<0.05).It also significantly suppressed the levels of endothelin-1,platelet-activating factor,tissue factor,plasminogen activator inhibitor 1,thromboxane B2,and plasma fibrinogen(P<0.05).Conclusions:These results suggest that sinomenine exhibits significant cardioprotection effects against I/R-induced cardiac injury in rats.展开更多
The sinomenine hydrochloride （SH） patch, a topical drug delivery system, was prepared and characterized. The in vitro release was studied according to the paddle-over-disk method in the appendix of Chinese Pharmacop...The sinomenine hydrochloride （SH） patch, a topical drug delivery system, was prepared and characterized. The in vitro release was studied according to the paddle-over-disk method in the appendix of Chinese Pharmacopeia （appendix XD, 2005）. Stability of SH patch was evaluated at accelerated testing conditions （40 ℃, 75% RH）. Pharmacological and pharmacokinetics study were also performed. It was found that the release of SH from patches depended on pH value of the release medium. There were no significant differences between SH patches stored for 6 mon and those stored for 0 mon in the drug content, initial adhesion, lasting stickiness, peeling strength and in vitro release. SH patches exhibited better anti-inflammatory activity as well as analgesic efficacy. More importantly, primary pharmacokinetic parameters of SH patch, such as Cmax and AUC, were much lower than those of SH solution dosed orally. In conclusion, the patch might be a promising delivery system for SH, which bypassed the gastrointestinal tract and was a convenient, efficacious, safe and non-invasive delivery method.展开更多
We prepared and characterized the spray formulation of sinomenine for topical administration. The permeation enhancer was selected based on in vitro skin permeation studies. The antioxidant was optimized through stabi...We prepared and characterized the spray formulation of sinomenine for topical administration. The permeation enhancer was selected based on in vitro skin permeation studies. The antioxidant was optimized through stability studies. Pharmacokinetic and pharmacological properties were determined in order to evaluate its side effect and pharmacodynamic action. It was found that azone was the most effective permeation enhancer, and sulfocarbamide was the optimal antioxidant. Alcohol was used as the additive of the sinomenine spray. Sinomenine spray decreased arthritis index of rats induced by Fretmd＇s complete adjuvant. The pharmacokinetic parameters of Cmax and AUCo 24 for spray were 1.17 μg/mL and 3.35 μg/h/mL, respectively, which were lower than those by oral administration. The relative bioavailability was 18.0%. Sinomenine spray was a promising topical delivery system with comparable anti-inflammatory efficacy, but possibly lower side effect.展开更多
OBJECTIVE: To systematically evaluate the curative clinical efficacy and safety of sinomenine(SIN) in treatment of rheumatoid arthritis(RA) in comparison to methotrexate(MTX).METHODS: We searched the China National Kn...OBJECTIVE: To systematically evaluate the curative clinical efficacy and safety of sinomenine(SIN) in treatment of rheumatoid arthritis(RA) in comparison to methotrexate(MTX).METHODS: We searched the China National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, China Science and Technology Journal Database, Wanfang Database, Pubmed and Cochrane Library electronically up to August 31,2015, without language limitation. Only randomized controlled trials(RCTs) were included. Software Review Manager 5.3 was used for Meta-analysis.RESULTS: A total of 16 eligible studies within 1500RA patients were included. The meta-analysis indicated that on basis of MTX, SIN was more effective in total effective rate(P < 0.000 01). Besides, SIN alone versus MTX also showed advantages in RA therapy(P = 0.04) Taken together, adverse events occurred less frequently in combination of SIN and MTX than MTX alone(P < 0.0001), especially in digestive system(P < 0.000 01),while occurred more in dermato mucosal system with SIN treatment versus MTX(P = 0.02), and were similar for both remedies in nervous system(P = 0.12) and hematological system(P = 0.25).CONCLUTION: Compared to MTX, SIN had better clinical efficacy and relatively fewer adverse events in treatment of RA, especially when it was used together with MTX. Due to the poor methodological quality, well-designed, multiple-center RCTs are still required to further confirm the findings.展开更多
Sinomenine(SN)has been used in the clinical treatment of systemic lupus erythematosus and rheumatoid arthritis for many years.Studies showed that SN held protective effects such as anti-inflammation,scavenging free ra...Sinomenine(SN)has been used in the clinical treatment of systemic lupus erythematosus and rheumatoid arthritis for many years.Studies showed that SN held protective effects such as anti-inflammation,scavenging free radicals and suppressing immune response in many autoimmune diseases.The purpose of the present study is to explore the mechanism of anti-inflammation of SN on lipopolysaccharide(LPS)-induced macrophages activation and investigate whether the TLR4/NF-κB signaling pathway participated in.Macrophages isolated from mouse peritoneal cavity were stimulated by 1 pg/mL LPS for 24 h.And then the cells were treated with various concentrations of SN,TLR4 inhibitor respectively for additional 48 h.Drug toxicity was detected by MTT assay and Transwell experiment was used to assess chemotaxis.Furthermore,TLR4 and MyD88 mRNA levels were detected by real-time PCR.Western blotting was used to examine TLR4,MyD88 and phosphorylated IκB protein expression in macrophages.Immunofluorescence assay was applied to observe p65 NF-κB protein expression in macrophage nucleus.We extracted macrophages with high purity and activity from the abdominal cavity of mice.SN remarkably inhibited the chemotaxis and secretion function of LPS-stimulated macrophages.It also down-regulated both the protein levels of inflammatory cytokines(TNF-α,IL-β and IL-6)and the RNA and protein levels of the key factors(TLR4,MyD88,p-IkB)in TLR4 pathway.The expression of p65 NF-κB protein in nuclei was down-regulated,which was correlated with a similar decrease in p-IκB protein level.In conclusion,SN can inhibit the LPS induced immune responses in macrophages by blocking the activated TLR4/NF-κB signaling pathway.These results may provide a therapeutic approach to regulate inflammatory responses.展开更多
AIM:To investigate the inhibitory effects of sinomenine(SIN)combined with 5-fluorouracil(5-FU)on esophageal carcinoma in vitro and in vivo.METHODS:Esophageal carcinoma(Eca-109)cells were cultured in DMEM.The single or...AIM:To investigate the inhibitory effects of sinomenine(SIN)combined with 5-fluorouracil(5-FU)on esophageal carcinoma in vitro and in vivo.METHODS:Esophageal carcinoma(Eca-109)cells were cultured in DMEM.The single or combined growth inhibition effects of SIN and 5-FU on the Eca-109 cells were examined by measuring the absorbance of CCK-8dye in living cells.Hoechst 33258 staining and an Annexin V/PI apoptosis kit were used to detect the percentage of cells undergoing apoptosis.Western blotting was used to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis.SIN at 25mg/kg and 5-FU at 12 mg/kg every 3 d,either combined or alone,was injected into nude mice and tumor growth inhibition and side effects of the drug treatment were observed.RESULTS:SIN and 5-FU,both in combination and individually,significantly inhibited the proliferation of Eca-109 cells and induced obvious apoptosis.Furthermore,the combined effects were greater than those of the individual agents(P<0.05).Annexin V/PI staining and Hoechst 33258 staining both indicated that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone were significantly different from the control(P<0.05).The up-regulation of Bax and downregulation of Bcl-2 showed that the essential mechanism of apoptosis induced by SIN and 5-FU occurs via the mitochondrial pathway.SIN and 5-FU alone significantly inhibited the growth of tumor xenografts in vivo,and the combined inhibition rate was even higher(P<0.05).During the course of chemotherapy,no obvious side effects were observed in the liver or kidneys.CONCLUSION:The combined effects of SIN and 5-FU on esophageal carcinoma were superior to those of the individual compounds,and the drug combination did not increase the side effects of chemotherapy.展开更多
Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we...Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis （EAE） in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase （anti-iNOS） effect, which is related to the reductions of Thl cytokine interferon-y （IFN-7） and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat in- terleukin 12 reduced the expression of T-bet and IFN-y in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibito- ry effect on iNOS produced by astrocytes cultured with IFN-y and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet/IFN-y pathway.展开更多
Sinomenine hydrochloride is generally produced from Caulis Sinomenii. At present, the purification process in industrial production suffers from large amount of solid waste, high solvent toxicity, and low sinomenine h...Sinomenine hydrochloride is generally produced from Caulis Sinomenii. At present, the purification process in industrial production suffers from large amount of solid waste, high solvent toxicity, and low sinomenine hydrochloride yield. In this study, a new purification process for sinomenine hydrochloride was proposed by using the extract obtained from acid extraction of Caulis Sinomenii as the starting material.The process included the following steps: alkalization, extraction, water washing, acid–water stripping,drying, and crystallization. 1-Heptanol was used as the extractant. The distribution coefficients of sinomenine and sinomenine hydrochloride in 1-heptanol–water system were 27.4 and 0.0167, respectively.The dissociation constants of sinomenine hydrochloride were 8.27 and 11.24, respectively. Process parameters of the new purification process were optimized with experimental design. The extractant1-heptanol and sinomenine hydrochloride in the crystallization mother solution can be recycled in the new process. The purity of the obtained sinomenine hydrochloride crystals exceeded 85%, and the yield was about 70%. Compared with current industrial processes, safer extractant, less solid waste, and higher sinomenine hydrochloride yield can be achieved using the new purification process of sinomenine hydrochloride provided in this study.展开更多
Sinomenine is a clinically available drug for the treatment of rheumatoid arthritis（RA）.In a continuous research aiming at discovery of sinomenine derivates with better bioactivity,a cross-coupling reaction of sinom...Sinomenine is a clinically available drug for the treatment of rheumatoid arthritis（RA）.In a continuous research aiming at discovery of sinomenine derivates with better bioactivity,a cross-coupling reaction of sinomenine and 1,2-dihydroxybenzene catalyzed by a fungus Coriolus unicolor afforded an unique C-C cross-coupled compound 2,together with（S）-disinomenine and （R）-disinomenine.The structure of 2 was elucidated by MS and NMR spectroscopy.Compound 2 was further assayed for the inhibitory activity on IL-6 overproduction in SW982 cells and exhibited a much more potent activity on IL-6（96%inhibition） compared with those of（S）-disinomenine and sinomenine（17%and 12%inhibition,respectively）.展开更多
Sinomenine(SIN)is commonly used as part of rheumatoid arthritis(RA)therapy in China,but there is still no published evidence of the efficacy of SIN monotherapy.This work investigates the efficacy and safety of SIN in ...Sinomenine(SIN)is commonly used as part of rheumatoid arthritis(RA)therapy in China,but there is still no published evidence of the efficacy of SIN monotherapy.This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients.In this 24 week,randomized,placebo-controlled,double-blind clinical trial,people with mild to moderate RA were randomly assigned(1:1:1,stratified by hospital)to receive SIN(120 mg,twice daily),methotrexate(MTX)(10 mg per week),or SIN+MTX therapy.The primary outcome was the proportion of patients who achieved a 50%improvement in the American College of Rheumatology(ACR50)criteria at week 24 and who showed improvement according to the clinical disease activity index(CDAI).In this prospective subgroup analysis,we also assessed whether the 24-week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine.Of the 135 enrolled participants,38,39,and 36 patients were treated with SIN,MTX,and SIN+MTX,respectively.In the SIN-treated group,52.63%of patients achieved ACR50 after 24-weeks of treatment,which was comparable to the results in the MTX-treated and SIN+MTX-treated groups.Hepatic and gastrointestinal disorders were the main adverse events;however,the ratio of patients suffering from hepatic disorder in the SIN group(1/38)was much lower than that in the MTX(10/39)and SIN+MTX(8/36)groups.A total of 221 serum samples were collected at the four follow-up time points in the three treatments,and the levels of ornithine,citrulline,and arginine were obtained through ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF/MS).The serum ornithine level decreased after the 24-week treatment along with a decrease in disease activity,and may reflect therapeutic responses with a sensitivity value of 80%.In conclusion,SIN revealed a comparable efficacy to MTX for treating RA patients,but with fewer side effects.In addition,the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA,which shows the value of this measure as an assessment indicator of drugs in treating RA.展开更多
AIM： To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride （SM·HCl） on its pharmacokinetics in beagle dogs. METHODS： The in vitro release behavior of two ...AIM： To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride （SM·HCl） on its pharmacokinetics in beagle dogs. METHODS： The in vitro release behavior of two SM·HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM.HCI pharmacokinetics was investigated and compared. RESULTS： The optimal SM·HCl sustained-release formulation was achieved by mixing slow- and rapidrelease pellets （9：1, w/w）. The SM·HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs68.7%. From a pharmacokinetic standpoint, the 24-h SM.HCI sustainedrelease pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67±0.52 h vs 9.83±0.98 h and the Cmax being 1334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM·HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM·HCl percentage absorption in vivoand the cumulative percentage release in vitro. CONCLUSION： The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves.展开更多
BACKGROUND Rheumatoid arthritis(RA)is a prevalent clinical autoimmune disease that is commonly treated with diclofenac and methotrexate.In recent years,the application of traditional Chinese medicine in RA has receive...BACKGROUND Rheumatoid arthritis(RA)is a prevalent clinical autoimmune disease that is commonly treated with diclofenac and methotrexate.In recent years,the application of traditional Chinese medicine in RA has received widespread attention;it promotes blood circulation,strengthens the immune system,and eliminates evil.The sinomenine preparation of Zhingqeng Fengtongning is studied as a possible treatment for patients with RA.AIM To explore the value of sinomenine injection into the articular cavity for the treatment of RA.METHODS A total of 94 patients with RA treated from January 2019 to January 2021 were selected and divided into the study and control groups with 47 patients each using a simple random number table method.Both groups received conventional treatment with diclofenac sodium and methotrexate tablets.The control group received diproxone and lidocaine by intra-articular administration while the study group received an intra-articular administration of the sinomenine preparation of Zhengqing Fengning and lidocaine.χ^(2) test was used to evaluate the therapeutic effect and synovial thickness,degree of pain through the visual analog scale(VAS),blood flow grade,arthroinflammatory indexes[rheumatoid factor(RF),C-reactive protein(CRP),and erythrocyte sedimentation rate(ESR)]before and after treatment in the two groups.RESULTS The total effective rate of the study group(93.62%)was higher than that of the control group(78.72%)(P<0.05).Before treatment,there were no significant differences between the two groups in terms of synovial thickness,VAS score,blood flow grading,levels of RF,and ESR(P>0.05).After treatment,the synovial thickness and VAS score were significantly lower(P<0.05)in the study group than in the control group(2.05±0.59 mm vs 2.87±0.64 mm and 2.11±0.62 vs 2.90±0.79 scores,respectively).The rate of blood flow at grade 0 in the study group(76.60%)was higher than that in the control group(57.45%),and the rate of blood flow at grade I(10.64%)was lower than that in the control group(31.91%)(P<0.05).Furthermore,the levels of RF(55.61±6.13 U/mL),CRP(11.43±3.59 mg/L),and ESR(29.60±5.56 mm/h)in the study group were lower than those in the control group(73.04±9.23 U/mL,15.07±4.06 mg/L,36.64±6.10 mm/h,respectively)(P<0.05).CONCLUSION Sinomenine administration of Zhengqing Fengtongning in the articular cavity with conventional treatment of RA can improve ultrasonographic blood flow and synovial thickness,reduce pain,regulate inflammation,and enhance therapeutic effect.展开更多
The effect of Sinomenine on IL-8, IL-6, IL-2 and mIL-2R produced by peripheral blood mononuclear cells was investigated by using cell culture, radioimmunoassay and flow cytometry. It was showed that production of IL-...The effect of Sinomenine on IL-8, IL-6, IL-2 and mIL-2R produced by peripheral blood mononuclear cells was investigated by using cell culture, radioimmunoassay and flow cytometry. It was showed that production of IL-8 and mIL-2R was inhibited, but the levels of IL-6 were enhanced by Sinomenine. Our results also demonstrated that Sinomenine did not have any effect on the production of IL-2. The study demonstrated that Sinomenine was able to regulate the production of cytokines. This may be one of the mechanisms by which Sinomenine works on rheumatoid arthritis.展开更多
The current methods used to industrially produce sinomenine hydrochloride involve several issues,including high solvent toxicity,long process flow,and low atomic utilization efficiency,and the greenness scores of the ...The current methods used to industrially produce sinomenine hydrochloride involve several issues,including high solvent toxicity,long process flow,and low atomic utilization efficiency,and the greenness scores of the processes are below 65 points.To solve these problems,a new process using anisole as the extractant was proposed.Anisole exhibits high selectivity for sinomenine and can be connected to the subsequent water-washing steps.After alkalization of the medicinal material,heating extraction,water washing,and acidification crystallization were carried out.The process was modeled and optimized.The design space was constructed.The recommended operating ranges for the critical process parameters were 3.0–4.0 h for alkalization time,60.0–80.0℃ for extraction temperature,2.0–3.0(volume ratio)for washing solution amount,and 2.0–2.4 mol·L^(-1) for hydrochloric acid concentration.The new process shows good robustness because different batches of medicinal materials did not greatly impact crystal purity or sinomenine transfer rate.The sinomenine transfer rate was about 20%higher than that of industrial processes.The greenness score increased to 90 points since the novel process proposed in this research solves the problems of long process flow,high solvent toxicity,and poor atomic economy,better aligning with the concept of green chemistry.展开更多
Objective: Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects,tolerance,...Objective: Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects,tolerance, and potential dependence necessitate research into alternative pain-relieving medications.Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein-coupled receptor member X2 opioid receptor;and salvinorin A, which is a j opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants.Methods: We used the formalin and thermal plantar tests in rats 7 and 21 days of age(PN7 and PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus.Results: Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age.Conclusion: The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period(sinomenine) or after weaning(salvinorin A).展开更多
BACKGROUND A decreased autophagic capacity of bone marrow mesenchymal stromal cells(BMSCs)has been suggested to be an important cause of decreased osteogenic differentiation.A pharmacological increase in autophagy of ...BACKGROUND A decreased autophagic capacity of bone marrow mesenchymal stromal cells(BMSCs)has been suggested to be an important cause of decreased osteogenic differentiation.A pharmacological increase in autophagy of BMSCs is a potential therapeutic option to increase osteoblast viability and ameliorate osteoporosis.AIM To explore the effects of sinomenine(SIN)on the osteogenic differentiation of BMSCs and the underlying mechanisms.METHODS For in vitro experiments,BMSCs were extracted from sham-treated mice and ovariectomized mice,and the levels of autophagy markers and osteogenic differentiation were examined after treatment with the appropriate concen-trations of SIN and the autophagy inhibitor 3-methyladenine.In vivo,the therapeutic effect of SIN was verified by establishing an ovariectomy-induced mouse model and by morphological and histological assays of the mouse femur.RESULTS SIN reduced the levels of AKT and mammalian target of the rapamycin(mTOR)phosphorylation in the phosphatidylinositol 3-kinase(PI3K)/AKT/mTOR signaling pathway,inhibited mTOR activity,and increased autophagy ability of BMSCs,thereby promoting the osteogenic differentiation of BMSCs and effectively alleviating bone loss in ovariectomized mice in vivo.CONCLUSION The Chinese medicine SIN has potential for the treatment of various types of osteoporosis,bone homeostasis disorders,and autophagy-related diseases.展开更多
BACKGROUND Immature dendritic cells(imDCs)play an important role in the induction of donor-specific transplant immunotolerance.However,these cells have limitations,such as rapid maturation and a short lifespan in vivo...BACKGROUND Immature dendritic cells(imDCs)play an important role in the induction of donor-specific transplant immunotolerance.However,these cells have limitations,such as rapid maturation and a short lifespan in vivo.In previous studies,induced pluripotent stem cells(iPSCs)differentiated into imDCs,and sinomenine(SN)was used to inhibit the maturation of imDCs.AIM To study the capacity of SN to maintain iPSC-derived imDCs(SN-iPSCs-imDCs)in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance.METHODS In this study,mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN(iPSCs-imDCs and SN-iPSCs-imDCs).The imDCrelated surface markers,endocytotic capacity of fluorescein isothiocyanate Dextran and apoptosis were analyzed by flow cytometry.The effects of iPSCs-imDCs and SNiPSCs-imDCs on T-cell stimulatory function,and regulatory T(Treg)cell proliferative function in vitro were analyzed by mixed lymphocyte reaction.Cytokine expression was detected by ELISA.The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting.The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice.Statistical evaluation of graft survival was performed using Kaplan–Meier curves.RESULTS Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained,and their biological characteristics and ability to induce immunotolerance were compared.SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs.Reduced major histocompatibility complex II expression,worse T-cell stimulatory function,higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs(P<0.05).The levels of interleukin(IL)-2,IL-12,interferon-γin SN-iPSCs-imDCs were lower than those in iPSCs-imDCs,whereas IL-10 and transforming growth factor-βlevels were higher(P<0.05).The apoptosis rate of these cells was significantly higher(P<0.05),and the expression levels of cleaved caspase3,Bax and cleaved poly(ADP-ribose)polymerase were higher after treatment with lipopolysaccharides,but Bcl-2 was reduced.In Balb/c mice recipients immunized with iPSCsimDCs or SN-iPSCs-imDCs 7 d before skin grafting,the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+T-cell proliferation(P<0.05)and a higher capacity to induce CD4+CD25+FoxP3+Treg cell proliferation in the spleen(P<0.05).The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern.CONCLUSION This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.展开更多
Objective:To investigate the protective effect of sinomenine stellate ganglion block(SGB)on chronic myocardial ischemia and its related mechanism.Methods:SD male and female rats(180~200g)were randomly divided into fou...Objective:To investigate the protective effect of sinomenine stellate ganglion block(SGB)on chronic myocardial ischemia and its related mechanism.Methods:SD male and female rats(180~200g)were randomly divided into four groups:blank group,model group,lidocaine group,lidocaine+sinomenine group.The rats in blank group were fed with normal standard diet without modeling,and the other rats were fed with high-fat diet.After 8 weeks of feeding,the rats in high-fat diet group were significantly different from those in blank control group.Then they were randomly divided into 3 groups,10 rats in model group were injected with 0.9%NaCl into right stellate ganglion(RSG)After 2 weeks of continuous injection,pituitrin injection was continuously injected into sublingual vein of rats for 3 days,once every 24 hours;lidocaine group rats were injected with 0.24 mL 1%lidocaine injection in RSG,the rest was the same as model group;lidocaine+sinomenine group rats were injected with 0.24 mL 1%lidocaine injection+0.095 mL sinomenine hydrochloride+2.9 mL 0.8 mL 0.8 mL in RSG,the rest was the same as model group.At the end of the eighth week of the experiment,the rats in the high-fat diet feeding group and the standard ordinary diet feeding group were given the medicine after there was significant difference in blood lipid;before the third injection of pituitrin,the ECG changes of the rats in each group were observed;the general situation of the rats before and after the administration was observed;after the experiment,the blood of the rats in each group was taken from the abdominal aorta,and the serum oxidative stress indexes,such as total superoxide dismutase(SOD)and malondialdehyde,were detected(MDA,IL-6 and cTnI were measured.Results:compared with the blank group,the ECG of the model group changed significantly(P<0.01),the cTnI value increased significantly(P<0.01),indicating that the rat myocardial ischemia model was successfully established;compared with the model group,the SOD level of lidocaine group and lidocaine+sinomenine group increased significantly(P<0.05,P<0.01),the MDA level decreased significantly(P<0.05,P<0.01),IL-6 decreased significantly(P<0.05,P<0.01)05,P<0.01).Conclusion:sinomenine SGB has protective effect on rats with chronic myocardial ischemia,which is related to anti oxidative stress and inhibition of inflammatory reaction.展开更多
基金Supported by Guangdong Basic and Applied Basic Research Foundation,No.2024A1515011236General Program of Administration of Traditional Chinese Medicine of Guangdong Province,No.20241071.
文摘Xiao et al reported on the natural product sinomenine(SIN),which is a traditional Chinese medicine for treating osteoporosis via its modulation of autophagy;however,SIN was dissolved in dimethyl sulfoxide prior to administration,which is not conducive to the development of clinical injectables.By comparing solubilization techniques,including amorphisation,emulsification,micellisation,nanocrystallisation and host-vip inclusion,we found that the solubilization of SIN by host-vip inclusion can enhance solubility and improve stability and has an increased release rate and enhanced bioavailability.Therefore,we conclude that host-vip inclusion holds promise for SIN solubilization.To solubilise SIN,we selectedβ-cyclodextrin as the host agent considering its excellent biocompatibility,efficient encapsulation ability,mature preparation process and adequate drug stability.If the prerequisites of SIN-β-cyclodextrin complexes in terms of safety,efficacy,stability and the relevant laws and regulations are met,its clinical application for the treatment of osteoporosis may be achieved.
文摘Objective:To evaluate the cardioprotective effects of sinomenine using the ischemia/reperfusion(I/R)rat model.Methods:Wistar rats were randomly divided into 6 groups:group Ⅰ with reperfusion,group Ⅱ perfused with sinomenine,group Ⅲ perfused with 5-hydroxydecanoate(5-HD),group Ⅳ perfused with 5-HD+sinomenine,group Ⅴ perfused with L-nitro arginine methyl ester(L-NAME),group Ⅵ perfused with L-NAME+sinomenine.Myocardial ischemia was induced by interrupting the aortic blood supply for 30 min,followed by reperfusion(55 min).Cardiac,hepatic,antioxidant,and inflammatory parameters were assessed.Additionally,endothelin,tissue factor,platelet-activating factor,plasminogen activator inhibitor,plasma fibrinogen,and thromboxane B2 were also analyzed.Results:Administration of 5-HD or L-NAME,used as the selective antagonist of mitoKATP and NO system,respectively,resulted in significantly increased levels of premature ventricular complexes,lactate dehydrogenase,ventricular fibrillation,ventricular tachycardia,and arrhythmia intensity(P<0.05).In contrast,sinomenine significantly reduced the level of troponin Ⅰ,lactate dehydrogenase,creatine kinase,and creatine kinase MB compared to the 5-HD group and the L-NAME group(P<0.05).Additionally,sinomenine significantly reduced malondialdehyde level and enhanced the levels of superoxide dismutase,glutathione peroxidase,catalase,and glutathione/glutathione disulfide ratio(P<0.05).It also significantly suppressed the levels of endothelin-1,platelet-activating factor,tissue factor,plasminogen activator inhibitor 1,thromboxane B2,and plasma fibrinogen(P<0.05).Conclusions:These results suggest that sinomenine exhibits significant cardioprotection effects against I/R-induced cardiac injury in rats.
文摘The sinomenine hydrochloride （SH） patch, a topical drug delivery system, was prepared and characterized. The in vitro release was studied according to the paddle-over-disk method in the appendix of Chinese Pharmacopeia （appendix XD, 2005）. Stability of SH patch was evaluated at accelerated testing conditions （40 ℃, 75% RH）. Pharmacological and pharmacokinetics study were also performed. It was found that the release of SH from patches depended on pH value of the release medium. There were no significant differences between SH patches stored for 6 mon and those stored for 0 mon in the drug content, initial adhesion, lasting stickiness, peeling strength and in vitro release. SH patches exhibited better anti-inflammatory activity as well as analgesic efficacy. More importantly, primary pharmacokinetic parameters of SH patch, such as Cmax and AUC, were much lower than those of SH solution dosed orally. In conclusion, the patch might be a promising delivery system for SH, which bypassed the gastrointestinal tract and was a convenient, efficacious, safe and non-invasive delivery method.
文摘We prepared and characterized the spray formulation of sinomenine for topical administration. The permeation enhancer was selected based on in vitro skin permeation studies. The antioxidant was optimized through stability studies. Pharmacokinetic and pharmacological properties were determined in order to evaluate its side effect and pharmacodynamic action. It was found that azone was the most effective permeation enhancer, and sulfocarbamide was the optimal antioxidant. Alcohol was used as the additive of the sinomenine spray. Sinomenine spray decreased arthritis index of rats induced by Fretmd＇s complete adjuvant. The pharmacokinetic parameters of Cmax and AUCo 24 for spray were 1.17 μg/mL and 3.35 μg/h/mL, respectively, which were lower than those by oral administration. The relative bioavailability was 18.0%. Sinomenine spray was a promising topical delivery system with comparable anti-inflammatory efficacy, but possibly lower side effect.
基金Supported by National Natural Science Foundation of China(Based on VIP to Investigate the Mechanism of Lung-Intestines Combined Therapeutic Method in Treating Sjogren's Syndrome No.81473607)State Administration of Traditional Chinese Medicine Key Discipline Open Project(Bi-Syndrome of Traditional Chinese Medicine Science,No.BBXK2013101)
文摘OBJECTIVE: To systematically evaluate the curative clinical efficacy and safety of sinomenine(SIN) in treatment of rheumatoid arthritis(RA) in comparison to methotrexate(MTX).METHODS: We searched the China National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, China Science and Technology Journal Database, Wanfang Database, Pubmed and Cochrane Library electronically up to August 31,2015, without language limitation. Only randomized controlled trials(RCTs) were included. Software Review Manager 5.3 was used for Meta-analysis.RESULTS: A total of 16 eligible studies within 1500RA patients were included. The meta-analysis indicated that on basis of MTX, SIN was more effective in total effective rate(P < 0.000 01). Besides, SIN alone versus MTX also showed advantages in RA therapy(P = 0.04) Taken together, adverse events occurred less frequently in combination of SIN and MTX than MTX alone(P < 0.0001), especially in digestive system(P < 0.000 01),while occurred more in dermato mucosal system with SIN treatment versus MTX(P = 0.02), and were similar for both remedies in nervous system(P = 0.12) and hematological system(P = 0.25).CONCLUTION: Compared to MTX, SIN had better clinical efficacy and relatively fewer adverse events in treatment of RA, especially when it was used together with MTX. Due to the poor methodological quality, well-designed, multiple-center RCTs are still required to further confirm the findings.
文摘Sinomenine(SN)has been used in the clinical treatment of systemic lupus erythematosus and rheumatoid arthritis for many years.Studies showed that SN held protective effects such as anti-inflammation,scavenging free radicals and suppressing immune response in many autoimmune diseases.The purpose of the present study is to explore the mechanism of anti-inflammation of SN on lipopolysaccharide(LPS)-induced macrophages activation and investigate whether the TLR4/NF-κB signaling pathway participated in.Macrophages isolated from mouse peritoneal cavity were stimulated by 1 pg/mL LPS for 24 h.And then the cells were treated with various concentrations of SN,TLR4 inhibitor respectively for additional 48 h.Drug toxicity was detected by MTT assay and Transwell experiment was used to assess chemotaxis.Furthermore,TLR4 and MyD88 mRNA levels were detected by real-time PCR.Western blotting was used to examine TLR4,MyD88 and phosphorylated IκB protein expression in macrophages.Immunofluorescence assay was applied to observe p65 NF-κB protein expression in macrophage nucleus.We extracted macrophages with high purity and activity from the abdominal cavity of mice.SN remarkably inhibited the chemotaxis and secretion function of LPS-stimulated macrophages.It also down-regulated both the protein levels of inflammatory cytokines(TNF-α,IL-β and IL-6)and the RNA and protein levels of the key factors(TLR4,MyD88,p-IkB)in TLR4 pathway.The expression of p65 NF-κB protein in nuclei was down-regulated,which was correlated with a similar decrease in p-IκB protein level.In conclusion,SN can inhibit the LPS induced immune responses in macrophages by blocking the activated TLR4/NF-κB signaling pathway.These results may provide a therapeutic approach to regulate inflammatory responses.
文摘AIM:To investigate the inhibitory effects of sinomenine(SIN)combined with 5-fluorouracil(5-FU)on esophageal carcinoma in vitro and in vivo.METHODS:Esophageal carcinoma(Eca-109)cells were cultured in DMEM.The single or combined growth inhibition effects of SIN and 5-FU on the Eca-109 cells were examined by measuring the absorbance of CCK-8dye in living cells.Hoechst 33258 staining and an Annexin V/PI apoptosis kit were used to detect the percentage of cells undergoing apoptosis.Western blotting was used to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis.SIN at 25mg/kg and 5-FU at 12 mg/kg every 3 d,either combined or alone,was injected into nude mice and tumor growth inhibition and side effects of the drug treatment were observed.RESULTS:SIN and 5-FU,both in combination and individually,significantly inhibited the proliferation of Eca-109 cells and induced obvious apoptosis.Furthermore,the combined effects were greater than those of the individual agents(P<0.05).Annexin V/PI staining and Hoechst 33258 staining both indicated that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone were significantly different from the control(P<0.05).The up-regulation of Bax and downregulation of Bcl-2 showed that the essential mechanism of apoptosis induced by SIN and 5-FU occurs via the mitochondrial pathway.SIN and 5-FU alone significantly inhibited the growth of tumor xenografts in vivo,and the combined inhibition rate was even higher(P<0.05).During the course of chemotherapy,no obvious side effects were observed in the liver or kidneys.CONCLUSION:The combined effects of SIN and 5-FU on esophageal carcinoma were superior to those of the individual compounds,and the drug combination did not increase the side effects of chemotherapy.
基金supported by Science Fund of the Health Department of Jiangsu Province (No. H200504)
文摘Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis （EAE） in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase （anti-iNOS） effect, which is related to the reductions of Thl cytokine interferon-y （IFN-7） and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat in- terleukin 12 reduced the expression of T-bet and IFN-y in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibito- ry effect on iNOS produced by astrocytes cultured with IFN-y and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet/IFN-y pathway.
基金supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202002)the National Project for Standardization of Chinese Materia Medica (ZYBZH-C-GD-04)。
文摘Sinomenine hydrochloride is generally produced from Caulis Sinomenii. At present, the purification process in industrial production suffers from large amount of solid waste, high solvent toxicity, and low sinomenine hydrochloride yield. In this study, a new purification process for sinomenine hydrochloride was proposed by using the extract obtained from acid extraction of Caulis Sinomenii as the starting material.The process included the following steps: alkalization, extraction, water washing, acid–water stripping,drying, and crystallization. 1-Heptanol was used as the extractant. The distribution coefficients of sinomenine and sinomenine hydrochloride in 1-heptanol–water system were 27.4 and 0.0167, respectively.The dissociation constants of sinomenine hydrochloride were 8.27 and 11.24, respectively. Process parameters of the new purification process were optimized with experimental design. The extractant1-heptanol and sinomenine hydrochloride in the crystallization mother solution can be recycled in the new process. The purity of the obtained sinomenine hydrochloride crystals exceeded 85%, and the yield was about 70%. Compared with current industrial processes, safer extractant, less solid waste, and higher sinomenine hydrochloride yield can be achieved using the new purification process of sinomenine hydrochloride provided in this study.
基金supported by National Natural Science Foundation of China(Nos20872060,20936002 and 31100080)the Fundamental Research Funds for Central University(No1082020502)
文摘Sinomenine is a clinically available drug for the treatment of rheumatoid arthritis（RA）.In a continuous research aiming at discovery of sinomenine derivates with better bioactivity,a cross-coupling reaction of sinomenine and 1,2-dihydroxybenzene catalyzed by a fungus Coriolus unicolor afforded an unique C-C cross-coupled compound 2,together with（S）-disinomenine and （R）-disinomenine.The structure of 2 was elucidated by MS and NMR spectroscopy.Compound 2 was further assayed for the inhibitory activity on IL-6 overproduction in SW982 cells and exhibited a much more potent activity on IL-6（96%inhibition） compared with those of（S）-disinomenine and sinomenine（17%and 12%inhibition,respectively）.
基金financially supported by grants from the Macao Science and Technology Development Fund(0032/2018/AFJ,0003/2019/AKP,and 0010/2020/A1)the Key Program in Emerging Industry of the Hunan Department of Science&Technology(2014GK1058)funded by Dr.Neher’s Biophysics Laboratory for Innovative Drug Discovery(001/2020/ALC)supported by the Macao Science and Technology Development Fund。
文摘Sinomenine(SIN)is commonly used as part of rheumatoid arthritis(RA)therapy in China,but there is still no published evidence of the efficacy of SIN monotherapy.This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients.In this 24 week,randomized,placebo-controlled,double-blind clinical trial,people with mild to moderate RA were randomly assigned(1:1:1,stratified by hospital)to receive SIN(120 mg,twice daily),methotrexate(MTX)(10 mg per week),or SIN+MTX therapy.The primary outcome was the proportion of patients who achieved a 50%improvement in the American College of Rheumatology(ACR50)criteria at week 24 and who showed improvement according to the clinical disease activity index(CDAI).In this prospective subgroup analysis,we also assessed whether the 24-week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine.Of the 135 enrolled participants,38,39,and 36 patients were treated with SIN,MTX,and SIN+MTX,respectively.In the SIN-treated group,52.63%of patients achieved ACR50 after 24-weeks of treatment,which was comparable to the results in the MTX-treated and SIN+MTX-treated groups.Hepatic and gastrointestinal disorders were the main adverse events;however,the ratio of patients suffering from hepatic disorder in the SIN group(1/38)was much lower than that in the MTX(10/39)and SIN+MTX(8/36)groups.A total of 221 serum samples were collected at the four follow-up time points in the three treatments,and the levels of ornithine,citrulline,and arginine were obtained through ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF/MS).The serum ornithine level decreased after the 24-week treatment along with a decrease in disease activity,and may reflect therapeutic responses with a sensitivity value of 80%.In conclusion,SIN revealed a comparable efficacy to MTX for treating RA patients,but with fewer side effects.In addition,the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA,which shows the value of this measure as an assessment indicator of drugs in treating RA.
文摘AIM： To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride （SM·HCl） on its pharmacokinetics in beagle dogs. METHODS： The in vitro release behavior of two SM·HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM.HCI pharmacokinetics was investigated and compared. RESULTS： The optimal SM·HCl sustained-release formulation was achieved by mixing slow- and rapidrelease pellets （9：1, w/w）. The SM·HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs68.7%. From a pharmacokinetic standpoint, the 24-h SM.HCI sustainedrelease pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67±0.52 h vs 9.83±0.98 h and the Cmax being 1334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM·HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM·HCl percentage absorption in vivoand the cumulative percentage release in vitro. CONCLUSION： The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves.
文摘BACKGROUND Rheumatoid arthritis(RA)is a prevalent clinical autoimmune disease that is commonly treated with diclofenac and methotrexate.In recent years,the application of traditional Chinese medicine in RA has received widespread attention;it promotes blood circulation,strengthens the immune system,and eliminates evil.The sinomenine preparation of Zhingqeng Fengtongning is studied as a possible treatment for patients with RA.AIM To explore the value of sinomenine injection into the articular cavity for the treatment of RA.METHODS A total of 94 patients with RA treated from January 2019 to January 2021 were selected and divided into the study and control groups with 47 patients each using a simple random number table method.Both groups received conventional treatment with diclofenac sodium and methotrexate tablets.The control group received diproxone and lidocaine by intra-articular administration while the study group received an intra-articular administration of the sinomenine preparation of Zhengqing Fengning and lidocaine.χ^(2) test was used to evaluate the therapeutic effect and synovial thickness,degree of pain through the visual analog scale(VAS),blood flow grade,arthroinflammatory indexes[rheumatoid factor(RF),C-reactive protein(CRP),and erythrocyte sedimentation rate(ESR)]before and after treatment in the two groups.RESULTS The total effective rate of the study group(93.62%)was higher than that of the control group(78.72%)(P<0.05).Before treatment,there were no significant differences between the two groups in terms of synovial thickness,VAS score,blood flow grading,levels of RF,and ESR(P>0.05).After treatment,the synovial thickness and VAS score were significantly lower(P<0.05)in the study group than in the control group(2.05±0.59 mm vs 2.87±0.64 mm and 2.11±0.62 vs 2.90±0.79 scores,respectively).The rate of blood flow at grade 0 in the study group(76.60%)was higher than that in the control group(57.45%),and the rate of blood flow at grade I(10.64%)was lower than that in the control group(31.91%)(P<0.05).Furthermore,the levels of RF(55.61±6.13 U/mL),CRP(11.43±3.59 mg/L),and ESR(29.60±5.56 mm/h)in the study group were lower than those in the control group(73.04±9.23 U/mL,15.07±4.06 mg/L,36.64±6.10 mm/h,respectively)(P<0.05).CONCLUSION Sinomenine administration of Zhengqing Fengtongning in the articular cavity with conventional treatment of RA can improve ultrasonographic blood flow and synovial thickness,reduce pain,regulate inflammation,and enhance therapeutic effect.
文摘The effect of Sinomenine on IL-8, IL-6, IL-2 and mIL-2R produced by peripheral blood mononuclear cells was investigated by using cell culture, radioimmunoassay and flow cytometry. It was showed that production of IL-8 and mIL-2R was inhibited, but the levels of IL-6 were enhanced by Sinomenine. Our results also demonstrated that Sinomenine did not have any effect on the production of IL-2. The study demonstrated that Sinomenine was able to regulate the production of cytokines. This may be one of the mechanisms by which Sinomenine works on rheumatoid arthritis.
基金supported by the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202002)the Fundamental Research Funds for the Central Universities(226-2022-00226).
文摘The current methods used to industrially produce sinomenine hydrochloride involve several issues,including high solvent toxicity,long process flow,and low atomic utilization efficiency,and the greenness scores of the processes are below 65 points.To solve these problems,a new process using anisole as the extractant was proposed.Anisole exhibits high selectivity for sinomenine and can be connected to the subsequent water-washing steps.After alkalization of the medicinal material,heating extraction,water washing,and acidification crystallization were carried out.The process was modeled and optimized.The design space was constructed.The recommended operating ranges for the critical process parameters were 3.0–4.0 h for alkalization time,60.0–80.0℃ for extraction temperature,2.0–3.0(volume ratio)for washing solution amount,and 2.0–2.4 mol·L^(-1) for hydrochloric acid concentration.The new process shows good robustness because different batches of medicinal materials did not greatly impact crystal purity or sinomenine transfer rate.The sinomenine transfer rate was about 20%higher than that of industrial processes.The greenness score increased to 90 points since the novel process proposed in this research solves the problems of long process flow,high solvent toxicity,and poor atomic economy,better aligning with the concept of green chemistry.
基金supported in part by the Department of Anesthesiology and Critical Care at the Children’s Hospital of Philadelphia,the James Battaglia Endowed Chair to G.A.Barra Faculty Mentoring Undergraduate Research grant to C.J.Mascarenhas and G.A.Barr+1 种基金supported by National Institutes of Health Grant R01(1R01GM111421)the Department of Anesthesiology and Critical Care at the University of Pennsylvania.
文摘Objective: Premature and ill neonates undergo painful but medically necessary procedures while hospitalized. Although opiate drugs are administered as analgesics, problems associated with their side effects,tolerance, and potential dependence necessitate research into alternative pain-relieving medications.Here we test two plant-derived compounds in infant rats: sinomenine, which targets the Mas-related G-protein-coupled receptor member X2 opioid receptor;and salvinorin A, which is a j opioid receptor agonist. In adult animals both sinomenine and salvinorin A are analgesic, but neither has been tested in infants.Methods: We used the formalin and thermal plantar tests in rats 7 and 21 days of age(PN7 and PN21) for behavioral signs of pain. In addition, brain sections were stained using Fos immunohistochemistry to examine patterns of brain activation in the midbrain periaqueductal gray and the paraventricular nucleus of the hypothalamus.Results: Sinomenine was analgesic in both the formalin and thermal tests on animals 21 days of age. At PN7 only the highest dose elevated response latencies in the thermal test and there were no effects of sinomenine in the formalin test. Analysis of Fos expression in the sinomenine-treated animals showed no drug effect, in contrast to the behavioral results. Salvinorin A was analgesic in the formalin test only at the highest dose at 21 days of age but not in the thermal test at either age.Conclusion: The increased modest effectiveness of sinomenine in older animals and the minimum salvinorin A drug effect suggest that the compounds act on sites that develop during the preweaning period(sinomenine) or after weaning(salvinorin A).
基金Supported by National Natural Science Foundation of China,No.82072425.
文摘BACKGROUND A decreased autophagic capacity of bone marrow mesenchymal stromal cells(BMSCs)has been suggested to be an important cause of decreased osteogenic differentiation.A pharmacological increase in autophagy of BMSCs is a potential therapeutic option to increase osteoblast viability and ameliorate osteoporosis.AIM To explore the effects of sinomenine(SIN)on the osteogenic differentiation of BMSCs and the underlying mechanisms.METHODS For in vitro experiments,BMSCs were extracted from sham-treated mice and ovariectomized mice,and the levels of autophagy markers and osteogenic differentiation were examined after treatment with the appropriate concen-trations of SIN and the autophagy inhibitor 3-methyladenine.In vivo,the therapeutic effect of SIN was verified by establishing an ovariectomy-induced mouse model and by morphological and histological assays of the mouse femur.RESULTS SIN reduced the levels of AKT and mammalian target of the rapamycin(mTOR)phosphorylation in the phosphatidylinositol 3-kinase(PI3K)/AKT/mTOR signaling pathway,inhibited mTOR activity,and increased autophagy ability of BMSCs,thereby promoting the osteogenic differentiation of BMSCs and effectively alleviating bone loss in ovariectomized mice in vivo.CONCLUSION The Chinese medicine SIN has potential for the treatment of various types of osteoporosis,bone homeostasis disorders,and autophagy-related diseases.
基金Supported by National Natural Science Foundation of China,No.81900686Science and Technology Incubation Fund Project of Shaanxi Provincial People’s Hospital,No.2020YXM-08+2 种基金Technology Talent Support Program of Shaanxi Provincial People’s Hospital,No.2021BJ-07Key Projects of Shaanxi Provincial Department of Education,No.21JS038Medical Research Development Fund of Beijing Kangmeng Charity Foundation,No.7B202010.
文摘BACKGROUND Immature dendritic cells(imDCs)play an important role in the induction of donor-specific transplant immunotolerance.However,these cells have limitations,such as rapid maturation and a short lifespan in vivo.In previous studies,induced pluripotent stem cells(iPSCs)differentiated into imDCs,and sinomenine(SN)was used to inhibit the maturation of imDCs.AIM To study the capacity of SN to maintain iPSC-derived imDCs(SN-iPSCs-imDCs)in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance.METHODS In this study,mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN(iPSCs-imDCs and SN-iPSCs-imDCs).The imDCrelated surface markers,endocytotic capacity of fluorescein isothiocyanate Dextran and apoptosis were analyzed by flow cytometry.The effects of iPSCs-imDCs and SNiPSCs-imDCs on T-cell stimulatory function,and regulatory T(Treg)cell proliferative function in vitro were analyzed by mixed lymphocyte reaction.Cytokine expression was detected by ELISA.The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting.The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice.Statistical evaluation of graft survival was performed using Kaplan–Meier curves.RESULTS Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained,and their biological characteristics and ability to induce immunotolerance were compared.SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs.Reduced major histocompatibility complex II expression,worse T-cell stimulatory function,higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs(P<0.05).The levels of interleukin(IL)-2,IL-12,interferon-γin SN-iPSCs-imDCs were lower than those in iPSCs-imDCs,whereas IL-10 and transforming growth factor-βlevels were higher(P<0.05).The apoptosis rate of these cells was significantly higher(P<0.05),and the expression levels of cleaved caspase3,Bax and cleaved poly(ADP-ribose)polymerase were higher after treatment with lipopolysaccharides,but Bcl-2 was reduced.In Balb/c mice recipients immunized with iPSCsimDCs or SN-iPSCs-imDCs 7 d before skin grafting,the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+T-cell proliferation(P<0.05)and a higher capacity to induce CD4+CD25+FoxP3+Treg cell proliferation in the spleen(P<0.05).The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern.CONCLUSION This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.
基金National Administration of traditional Chinese medicine base project(No.jdzx2012144,jdzx2015253)Shaanxi provincial major disease TCM innovation plan:chest obstruction(coronary heart disease)+1 种基金Shaanxi Provincial Administration of traditional Chinese medicine scientific research project(No.15-scjh015,15-lc016,lcpt089,15-scjh016)discipline innovation team of the Second Affiliated Hospital of Shaanxi University of Chinese medicine(No.2020xktd-b03)。
文摘Objective:To investigate the protective effect of sinomenine stellate ganglion block(SGB)on chronic myocardial ischemia and its related mechanism.Methods:SD male and female rats(180~200g)were randomly divided into four groups:blank group,model group,lidocaine group,lidocaine+sinomenine group.The rats in blank group were fed with normal standard diet without modeling,and the other rats were fed with high-fat diet.After 8 weeks of feeding,the rats in high-fat diet group were significantly different from those in blank control group.Then they were randomly divided into 3 groups,10 rats in model group were injected with 0.9%NaCl into right stellate ganglion(RSG)After 2 weeks of continuous injection,pituitrin injection was continuously injected into sublingual vein of rats for 3 days,once every 24 hours;lidocaine group rats were injected with 0.24 mL 1%lidocaine injection in RSG,the rest was the same as model group;lidocaine+sinomenine group rats were injected with 0.24 mL 1%lidocaine injection+0.095 mL sinomenine hydrochloride+2.9 mL 0.8 mL 0.8 mL in RSG,the rest was the same as model group.At the end of the eighth week of the experiment,the rats in the high-fat diet feeding group and the standard ordinary diet feeding group were given the medicine after there was significant difference in blood lipid;before the third injection of pituitrin,the ECG changes of the rats in each group were observed;the general situation of the rats before and after the administration was observed;after the experiment,the blood of the rats in each group was taken from the abdominal aorta,and the serum oxidative stress indexes,such as total superoxide dismutase(SOD)and malondialdehyde,were detected(MDA,IL-6 and cTnI were measured.Results:compared with the blank group,the ECG of the model group changed significantly(P<0.01),the cTnI value increased significantly(P<0.01),indicating that the rat myocardial ischemia model was successfully established;compared with the model group,the SOD level of lidocaine group and lidocaine+sinomenine group increased significantly(P<0.05,P<0.01),the MDA level decreased significantly(P<0.05,P<0.01),IL-6 decreased significantly(P<0.05,P<0.01)05,P<0.01).Conclusion:sinomenine SGB has protective effect on rats with chronic myocardial ischemia,which is related to anti oxidative stress and inhibition of inflammatory reaction.
