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sinomenine increases osteogenesis in mice with ovariectomyinduced bone loss by modulating autophagy

World Journal of Stem Cells 2024年第5期16卷 486-498页

作者： Hai-Xiang Xiao Lei Yu Yu Xia Kai Chen Wen-Ming Li Gao-Ran Ge Wei Zhang Qing Zhang Hong-Tao Zhang De-Chun Geng Department of Orthopedics The Fourth Affiliated Hospital of Soochow UniversitySuzhou Dushu Lake HospitalMedical Centre of Soochow UniversitySuzhou 215006Jiangsu ProvinceChina Department of Orthopedics Jingjiang People’s Hospital Affiliated to Yangzhou UniversityJingjiang 214500Jiangsu ProvinceChina Department of Orthopedics The First Affiliated Hospital of Soochow UniversitySuzhou 215006Jiangsu ProvinceChina Department of Orthopedics Hai’an People’s HospitalHai’an 226600Jiangsu ProvinceChina Department of Orthopedics The Affiliated Huai’an Hospital of Xuzhou Medical UniversityHuai’an Second People’s HospitalXuzhou 223002Jiangsu ProvinceChina Department of Orthopaedics The First Affiliated Hospital of Soochow UniversitySuzhou 215006Jiangsu ProvinceChina

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.

关键词： sinomenine Osteogenesis Autophagy Ovariectomy Osteoporosis

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sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance

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World Journal of Stem Cells 2022年第8期14卷 599-615页

作者： Xiao-Yan Huang Zhan-Kui Jin Meng Dou Bing-Xuan Zheng Xiang-Rong Zhao Qing Feng Yang-Meng Feng Xiang-Long Duan Pu-Xun Tian Cui-Xiang Xu Shaanxi Provincial Key Laboratory of Infection and Immune Diseases Shaanxi Provincial People’s HospitalXi'an 710068Shaanxi ProvinceChina Department of Orthopedics Shaanxi Provincial People’s HospitalXi'an 710068Shaanxi ProvinceChina Department of Kidney Transplantation The First Affiliated Hospital of Xi’an Jiaotong UniversityXi'an 710061Shaanxi ProvinceChina Second Department of General Surgery Shaanxi Provincial People's HospitalXi'an 710068Shaanxi ProvinceChina

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

关键词： Immature dendritic cells Induced pluripotent stem cells sinomenine Immune tolerance Organ transplantation

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Changes in rheumatoid arthritis under ultrasound before and after sinomenine injection

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World Journal of Clinical Cases 2022年第1期10卷 35-42页

作者： Yi-Min Huang Yu Zhuang Zhi-Ming Tan Department of Rheumatology and Immunology Huizhou Central People’s HospitalHuizhou 516001Guangdong ProvinceChina

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%)(P0.05).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)

关键词： Rheumatoid arthritis Articular injection sinomenine Ultrasonic changes Inflammatory factors Zhengqing Fengtongning

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Efficient and selective extraction of sinomenine by deep eutectic solvents

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Chinese Journal of Chemical Engineering 2023年第5期57卷 109-117页

作者： Yunchang Fan Chunyan Zhu Sheli Zhang Lei Zhang Qiang Wang Feng Wang College of Chemistry and Chemical Engineering Henan Polytechnic UniversityJiaozuo 454003China College of Science and Technology Jiaozuo Teachers CollegeJiaozuo 454000China

sinomenine is the main bio-active ingredient of Sinomenii Caulis and usually produced by solventextraction techniques. However, the extraction of sinomenine suffers from the lack of highly efficient and environmentally-benign solvents. In this work, deep eutectic solvents(DESs) based on fragrances were synthesized, hydrogen-bond donors(HBDs) and hydrogen-bond acceptors(HBAs) components of DESs were identified and their extraction ability for sinomenine was evaluated and the extraction conditions were optimized by single-factor and orthogonal design experiments. It was found that the hydrogen-bonding interaction between sinomenine and DESs was the main extraction driving force and there was no explicit relationship between the extraction ability and the hydrophobicity of the DESs. The DESs could be recycled and sinomenine could be recovered quantitatively via backextraction. High-purity sinomenine((95.0 ± 2.3)%) could be produced. These findings suggest that DESs are highly-effective solvents for the isolation of sinomenine and exhibit great potential for the extraction of other bio-active compounds.

关键词： sinomenine Solvent extraction Deep eutectic solvent(DES) Hydrogen-bonding interaction Regeneration Purification

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The Correlation Between Decreased Ornithine Level and Alleviation of Rheumatoid Arthritis Patients Assessed by a Randomized,Placebo-Controlled,Double-Blind Clinical Trial of sinomenine

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Engineering 2022年第9期16卷 93-99页

作者： Ying Shi Hu-Dan Pan Jian-Lin Wu Qing-Hua Zou Xin-Yi Xie Hong-Gang Li Hua Zhou Xi-Qing Bian Wen-Fei Leng Can-Jian Wang Ya-Feng Wang Yong-Fei Fang Liang Liu Department of Rheumatology The Southwest Hospital of Army Military Medical UniversityChongqing 400038China State Key Laboratory of Dampness Syndrome Chinese Medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510000China State Key Laboratory of Quality Research in Chinese Medicine&Macao Institute for Applied Research in Medicine and Health Macao University of Science and TechnologyMacao 999078China People’s Hospital of Changshou Chongqing Chongqing 401220China Traditional Chinese Medicine Hospital Dianjiang Chongqing Chongqing 408300China Medical Management Center World Federation of Chinese Medicine SocietiesBeijing 100101China

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 w

关键词： Rheumatoid arthritis sinomenine Efficacy Safety Inflammatory biomarker

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Effects of plant-derived analgesic compounds sinomenine and salvinorin A in infant rats

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Journal of Integrative Medicine 2020年第2期18卷 174-180页

作者： Conrad J.Mascarenhas Renyu Liu Gordon A.Barr Department of Anesthesiology and Critical Care Children’s Hospital of PhiladelphiaPhiladelphiaPA 19104USA Department of Anesthesiology and Critical Care Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA 19104USA Department of Psychology University of PennsylvaniaPhiladelphiaPA 19104USA

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).

关键词： Thermal pain Formalin test Fos Ontogeny sinomenine Salvinorin A

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sinomenine reduces iNOS expressionvia inhibiting the T-bet IFN-γ pathway in experimental autoimmune encephalomyelitis in rats

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The Journal of Biomedical Research 2012年第6期26卷 448-455页

作者： Bingjie Gu Yanying Zeng Cheng Yin Huijiuan Wang Xiaofan Yang Song Wang Xiaohui Ji Department of Immunology Nanjing Medical University Nanjing Jiangsu 210029 China Department of Neurology the First Affiliated Hospital Nanjing Medical University Nanjing Jiangsu 210029 China

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.

关键词： sinomenine experimental autoimmune encephalomyelitis iNOS T-bet interferon-γ(IFN-γ)

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Effects and safety of sinomenine in treatment of rheumatoid arthritis contrast to methotrexate: a systematic review and Meta-analysis

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Journal of Traditional Chinese Medicine 2016年第5期36卷 564-577页

作者： Liu Weiwei Qian Xian Ji Wei Lu Yan Wei Gang Wang Yue Internal Medicine of Traditional Chinese Medicine Nanjing University of Traditional Chinese Medicine Department of Rheumatism the First Affiliated Hospital of Nanjing University of Traditional Chinese Medicine

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.

关键词： sinomenine Randomized controlled trials Arthritis rheumatoid Methotrexate Meta-analysis

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Influence of sinomenine on protein profiles of peripheral blood mononuclear cells from ankylosing spondylitis patients： a pharmacoproteomics study

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Chinese Medical Journal 2013年第19期126卷 3645-3650页

作者： HUANG Zhi-xiang TAN Jin-hui LI Tian-wang DENG Wei-ming QIU Ke-wei LIAO Ze-tao ZENG Zhao-qiu Department of Rheumatology and Immunology Guangdong No. 2Provincial People's Hospital Guangzhou Guangdong 510317 China Department of Rheumatology Third Affiliated Hospital of Sun Yat-sen University Guangzhou Guangdong 510630 China

Background Ankylosing spondylitis （AS） is a common inflammatory rheumatic disease which lacks satisfactory treatment so far.sinomenine （SIN） is an alkaloid and has recently been utilized in treating multiple rheumatic diseases including AS in China,but its exact mechanism remains to be explored.This study investigated the alteration of proteome in peripheral blood mononuclear cells （PBMCs） from AS patients.Methods Thirty AS patients were enrolled in this study.PBMCs from each AS patient were cultured in medium with or without SIN respectively.Then PBMCs proteins from both groups were separated by two-dimensional electrophoresis （2-DE） and analyzed by mass spectrometry （MS）.Two differentially expressed proteins were then chosen to be verified using Western blotting.Results Seven proteins,including α-synuclein （SNCA）,calmodulin （CALM）,acidic leucine-rich nuclear phosphoprotein 32 family member A （ANP32A）,chloride intracellular channel protein 1 （CLIC1）,guanine nucleotide-binding protein G（I）/G（S）/ G（T） subunit beta-1 （GNB1）,gelsolin （GSN） and histone H2B type 1-M （HISTH2BM）were over-expressed,while coronin1A （CORO1A） was under-expressed in the SIN-treated PBMCs.Further bioinformatics search indicated that the changes of SNCA,ANP32A and CLIC1 pertained to apoptosis,while changes of GSN and CORO1A were associated with both apoptosis and inhibition of immunological function.Subsequently GSN and CORO1A were selected to validate by Western blotting and the results were consistent with those of 2-DE.Conclusion There were 8 differentially expressed proteins in the SIN-treated PBMCs,which might shed some light on the mechanism of SIN in the treatment of AS.

关键词： ankylosing spondylitis sinomenine peripheral blood mononuclear cells pharmacoproteomics

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Mechanism Underlying Antitumor Effects of sinomenine

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Chinese Journal of Integrative Medicine 2019年第11期25卷 873-878页

作者： GAO Le-nyu ZHONG Bing WANG Yong Department of Traditional Chinese Medicine Southwest Hospital the Third Military Medical University (Army Military Medical University)

sinomenine(SIN) is a bioactive alkaloid compound extracted from a Chinese medicinal plant Sinomenium acutum. It is a multitarget antitumor natural substance. Various mechanisms have been proposed for the antitumor effects of SIN, such as direct cytotoxicity, induction of apoptosis, sensitization attenuating radiotherapy and chemotherapy, reversal of drug resistance, resistance to distant metastasis, and antiangiogenesis. SIN can be used as a tumor cell killer and an adjuvant to radiotherapy and chemotherapy. However, recent studies are mostly limited to the basic experimental stage; no systematic clinical studies have yet been reported. Therefore, this paper aimed to review the mechanism underlying the antitumor effects of SIN by consulting relevant domestic and foreign studies and to provide a relevant reference for further development, use, and exploration of SIN.

关键词： antitumor mechanism pharmacology sinomenine Chinese medicine

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