中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 周伟, 高奇, 李玉琴
, ZHOU Wei, GAO Qi, LI Yuqin,
硫酸软骨素是一种糖胺聚糖,以动物组织为原料,或者微生物细胞发酵法而制得,在临床上主要用于治疗和预防骨关节炎、心脑血管疾病及眼科疾病。近年来研究表明,硫酸软骨素及其衍生物具有多种潜在的生物活性,如抗炎、抗肿瘤、抗凝、抗血栓等,在多种生理和病理过程中发挥至关重要的作用,具有新药开发的前景。该文从硫酸软骨素及其衍生物现有的药理活性、临床研究方面进行综述,以期为后续研究提供参考。
Chondroitin sulfate is a glycosaminoglycan produced with animal tissues or microbial cell fermentation,and has been mainly used in clinical treatment and prevention of osteoarthritis,cardiovascular and cerebrovascular diseases,and ophthalmic diseases. In recent years,studies have shown that chondroitin sulfate and its derivatives show a variety of potential biological activities,such as anti-inflammatory,antitumor,anticoagulant,antithrombotic and so on,play a vital role in various physiological and pathological processes,and have the potential to be developed as a new drug in the future. In this paper,the pharmacological activities and clinical studies of chondroitin sulfate and its derivatives were reviewed in order to provide a reference for subsequent studies.
开放科学(资源服务)标识码(OSID)
硫酸软骨素(chondroitin sulfate,CS)是一类高分子量酸性黏多糖,主要分布于哺乳动物的软骨、骨骼等部位。CS多使用动物组织作为原料,或者利用微生物细胞发酵法而制得。CS及其衍生物具有抗炎、抗肿瘤、心脑血管保护等多种药理学活性,目前临床上主要用于骨关节炎、心脑血管疾病及眼科疾病的预防和治疗。CS及其衍生物因具有良好的组织相容性,可用于药物修饰和药物载体的构建,具有作为新药开发的前景。本文综述硫酸软骨素及其衍生物研究进展,并阐述了近年来其在各领域的研究现状,为其进一步研究与开发奠定基础。
大量临床试验研究表明,CS可改善患者关节运动功能[1]、修复关节软骨、减轻疼痛[2]和肿胀以及防止间隙狭窄,且长期服用所引起的胃肠道不良反应比非甾体抗炎药小。CS为大分子,不能穿透软骨细胞,因此它通过与膜受体结合而分解为寡糖或二糖发挥其作用[3]。研究发现[4],CS通过减少细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK1/2)、p38丝裂原活化蛋白激酶(p38 MAPK)和c-Jun氨基末端蛋白激酶(c-Jun N-terminal protein kainse,JNK)活化,减少核因子κB(nuclear factor kappa-B,NF-κB)的激活和核转位,增加软骨细胞和滑膜中促炎细胞因子、蛋白水解酶和具有促炎活性的酶来发挥抗炎作用。
SADYKOV等[5]对70例原发性和(或)创伤后单(双)侧膝关节和(或)髋关节骨关节炎(osteoarthritis,OA)患者进行为期2个月的分组治疗,治疗组40例患者接受CS肠外治疗(其中9例使用了非甾体抗炎药),对照组30例患者关节内注射透明质酸。结果发现,使用CS可减轻局部疼痛综合征以及使肌肉骨骼系统功能正常化,非甾体抗炎药使用减少,无痛期延长。值得注意的是,在为期6个月的多中心、随机、双盲、安慰药对照临床试验中,CS和氨基葡萄糖硫酸盐联合治疗在减轻膝关节OA患者的关节疼痛和功能障碍方面未显示优于安慰药[6]。
硫酸锶软骨素(strontium chondroitin sulfate,SrCS)对软骨细胞和成骨细胞均具有良好的生物相容性,能显著提高软骨细胞中胶原蛋白Ⅱ型和聚集蛋白聚糖的表达,降低软骨细胞中基质金属蛋白酶(MMP)1和MMP13的表达,降低软骨细胞和成骨细胞中白细胞介素(IL)-6和IL-1β的表达,因此,SrCS在治疗OA方面具有临床潜力[7]。
姜黄素的抗炎效果引起了国内外学者的广泛关注,为了尽量减少溃疡性结肠炎的症状,口服靶向递送抗炎药物至巨噬细胞成为一种有效途径。ZHANG等[8]将姜黄素封装到聚合物纳米颗粒(polymeric nanoparticles,NPs)中,并将CS结合到它们的表面,得到带负电荷的CS-NPs,口服包埋CS-NPs的壳聚糖/藻酸盐水凝胶对溃疡性结肠炎的治疗效果更好,CS-NPs表现出更强的抑制脂多糖刺激巨噬细胞分泌主要促炎细胞因子的能力,因此有希望被开发用于治疗溃疡性结肠炎。
CS及其衍生物除了具有上述治疗骨关节炎和抗溃疡性结肠炎作用外,还可以通过调节炎症细胞因子水平从而发挥抗动脉粥样硬化、改善认知功能障碍及糖尿病骨质疏松症等作用。
阿尔茨海默病(Alzheimer's disease,AD)发病机制复杂,主要有β淀粉样蛋白级联反应、Tau蛋白过度磷酸化、氧化应激、神经炎症假说等,目前尚未完全弄清。但抑制β-分泌酶和γ-分泌酶以减少Aβ的生成,阻止Tau蛋白聚集及磷酸化酶等控制Tau蛋白的磷酸化情况,抗氧化等都是防治AD的有效思路。
ZHANG等[13]在Aβ1-40肽诱导痴呆的小鼠模型中研究发现,低分子量硫酸软骨素(low molecular weight chondroitin sulfate,LMWCS)可改善Aβ1-40诱导的认知障碍,增加小鼠大脑中的胆碱乙酰转移酶、超氧化物歧化酶和谷胱甘肽过氧化物酶的水平,降低丙二醛和乙酰胆碱酯酶。此外,LMWCS还可以降低小鼠海马CA1区锥体细胞的密度,抑制Bax/Bcl-2、Caspase-3和Caspase-9的蛋白表达。研究发现[14,15,16],LMWCS通过增加超氧化物歧化酶、谷胱甘肽过氧化物酶和Na+/K+/-ATP酶的活性并降低丙二醛含量,抑制Bcl-2和Bax的失衡,降低Caspase-3和Caspase-9的表达,抑制促炎细胞因子[IL-1β、肿瘤坏死因子(TNF)-α和IL-6]的分泌,减少大脑中活性氧(reactive oxygen species,ROS)的产生和磷酸化Tau(Ser404)的水平,抑制Aβ诱导的氧化应激和线粒体功能异常紊乱,来改善AD症状。
通过
酸性黏多糖类药物具有抗凝血作用,肝素是应用最广而且在体内体外都有抗凝血作用的物质。CS的化学结构与肝素相似,也具有一定的抗凝血作用,但CS的抗凝活性是通过纤维蛋白原系统来发挥的。在体外CS具有一定的抗凝血作用,但作用效果远低于肝素[24]。研究发现,与肝素衍生物相比,岩藻糖基CS及其解聚碎片具有不同的抗凝机制,降低了不良反应和出血的风险,然而,由于缺乏结构明确的寡糖,进一步开发受到了阻碍[25]。
从六糖到十八糖的高度纯化的岩藻糖基化CS在体内具有抗血栓作用。经注射后可强烈的表现出抑制静脉血栓形成,这归因于岩藻糖基化CS 9-18寡聚体与各种凝血因子的相互作用,特别是FIXa,最终抑制了静脉血栓形成的产生,而且岩藻糖基化CS 9~18寡聚体可以通过肾脏排泄,在血液循环过程中也不会导致出血、低血压或血小板聚集风险[26]。
CS及其衍生物是重要的生化药物,在抗炎、抗AD、保护心脑血管等方面表现出良好的潜力,未来的研究还应充分考虑其给药途径,否则将难以达到预期疗效。未来众多的研究应在加强生产工艺、分析技术和活性研究的基础上开发新的CS及其衍生物资源,扩展其在食品、保健品等领域的应用。
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DOI:10.1002/art.v69.1
URL
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Osteoarthritis (OA) is the most prevalent musculoskeletal disorder and the leading cause of joint disability in elderly patients. In this study, we fabricated strontium chondroitin sulfate (SrCS), a new polysaccharide-metal ion complex that is the combination of chondroitin sulfate and strontium, which are two widely adopted chemicals in OA clinical management. The structural, chemical compositions and morphology of as-fabricated SrCS were systematically investigated. Cell proliferation test, RT-PCR and preliminary animal studies were conducted to evaluate the clinical potential of SrCS on OA treatment. The materials characterization results verified that the Sr was successfully integrated into CS by replacing sodium in the original structure and formed a new polysaccharide-metal ion complex. The cell proliferation results indicated that the SrCS has excellent biocompatibility for both chondrocyte and osteoblast. The RT-PCR results showed that the SrCS can significantly increase the expression of COLII and ACAN, decrease MMP1 and MMP13 in chondrocyte and decrease the IL-6 and IL-1β in both chondrocyte and osteoblast. Preliminary animal studies demonstrated that SrCS can effectively simulate the articular cartilage formation in SD-rats after modified Hulth's OA modeling surgery. We therefore believed that the SrCS should be a rather effective chemical for OA clinical management as well as a beneficial component for various biomaterials in cartilage tissue engineering. Copyright © 2017 Elsevier Ltd. All rights reserved.
DOI:S0144-8617(17)30466-6
PMID:28521989
[本文引用:1]
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Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer’s disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed with encouraging results in animal models and clinical trials, showcasing their potential for development as therapeutics. In this review, the role GAGs play in both the development and inhibition of cancer and inflammation is presented. Further, advancements in the development of GAGs and their mimetics as anti-cancer and anti-inflammatory agents are discussed.
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The neurotoxicity of aggregated amyloid β (Aβ) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease. In a previous work, we have shown that low-molecular-weight chondroitin sulfate (LMWCS), a derivative of chondroitin sulfate, protected the SH-SY5Y neuroblastoma cells from Aβ25-35-induced neurotoxicity, decreased intracellular reactive oxygen species level and inhibited the cell apoptosis. However, the underlying mechanism of the antioxidative effect of LMWCS in the SH-SY5Y cells has not been well explored. In the present study, the SH-SY5Y cells were cultured and exposed to 30 μM Aβ25-35 in the absence or presence of LMWCS (50, 100 and 200 μg/ml). Results indicate that incubation of cells with LMWCS before Aβ25-35 exposure increased superoxide dismutase, glutathione peroxidase and Na/K-ATPase activities and decreased the malondialdehyde content. In addition, LMWCS inhibited the imbalance of Bcl-2 and Bax and decreased caspase-3 and caspase-9 expressions. LMWCS antagonizes Aβ25-35-induced neurotoxicity by attenuating oxidative stress, and our results suggest that LMWCS might be used as a potential compound for Alzheimer's disease prevention.
DOI:10.1097/WNR.0000000000001092
PMID:29985831
[本文引用:1]
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In this study, the effect of chondroitin sulphate nano-selenium (CS@Se) on Alzheimer's disease (AD) in mice was investigated. CS@Se alleviated anxiety and improved the spatial learning and memory impairment in AD mice. CS@Se significantly reduced cell oedema and pyknosis, protected the mitochondria, and improved abnormal changes in the ultrastructure of hippocampal neuron synapses of AD mice. Moreover, CS@Se significantly increased the levels of superoxide dismutase(SOD), glutathione peroxidase (GSH-Px), Na/K-ATPase assay (Na/K-ATPase) and acetyltransferase (ChAT), and decreased the levels of malondialdehyde (MDA) and acetylcholinesterase (ChAE) in AD mice. Western blot results showed that CS@Se can attenuate excessive phosphorylation of tau (Ser396/Ser404) by regulating the expression of glycogen synthase kinase-3 beta (GSK-3β). In addition, CS@Se can activate the extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) signalling pathways to inhibit nuclear transcription factor kappa B (NF-κB) nuclear translocation, thereby regulating the expression of pro-inflammatory cytokines. In summary, CS@Se can reduce oxidative stress damage, inhibit excessive tau phosphorylation, reduce inflammation to delay AD development, and increase the learning and memory capacities of AD mice. Copyright © 2020 Elsevier B.V. All rights reserved.
DOI:S0141-8130(20)30966-1
PMID:32171837
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The purpose of this study was to ascertain the effect of selenium-chondroitin sulfate nanoparticles (CS@Se) on multi-target-directed therapy for the treatment of Alzheimer's disease (AD). CS@Se nanoparticles were successfully synthesized, and their therapeutic effects were studied in in vitro AD models. CS@Se effectively inhibited amyloid-β (Aβ) aggregation and protected SH-SY5Y cells from Aβ-induced cytotoxicity. Moreover, CS@Se significantly decreased okadaic acid-induced actin cytoskeleton instability in SH-SY5Y cells. In addition, CS@Se decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the levels of glutathione peroxidase (GSH-Px). The Western blot results indicated that CS@Se attenuated the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of GSK-3β. In summary, this study demonstrated that CS@Se could inhibit the aggregation of Aβ, reduce damage to the cytoskeleton, mitigate oxidative stress and attenuate the hyperphosphorylation of tau protein. CS@Se might be a potent multi-functional agent for the treatment of AD and thus warrants further research and evaluation. Copyright © 2019 Elsevier B.V. All rights reserved.
DOI:S0141-8130(19)32376-1
PMID:31593732
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Cigarette smoking is an established risk factor for atherosclerosis. Nicotine, the major constituent of cigarettes, mediates the phenotype switching of vascular smooth muscle cells (VSMCs) and contributes to atherogenesis. Recent studies show that autophagy regulates atherogenesis via several pathways. The aim of this study is to determine whether nicotine regulates autophagy and subsequently mediates the phenotypic transition of VSMCs. Oil Red O and HE staining of aortic sections of ApoE mice showed that nicotine promoted atherosclerosis, and in situ expression of α-SMA indicated the involvement of VSMCs. Western blotting documented that nicotine induced the aorta autophagy. Cultured VSMCs treated with nicotine resulted in the increase of LC3 II-to-LC3 I ratio and the decrease of P62, along with GFP-LC3 puncta assay and transmission electron microscopy, further reflecting nicotine-induced autophagy. In addition, Western blotting and quantitative real-time PCR showed that VSMCs exposed to nicotine underwent changes in the expression of differentiation markers (α-SMA, SM22α and osteopontin), confirming the role of nicotine in VSMC differentiation. Transwell migration and scratch assays demonstrated that nicotine increased the migratory capacity of VSMCs. Finally, nicotine also increased the levels of reactive oxygen species (ROS), as measured by DCFH-DA staining. After respectively inhibiting autophagy (3-MA), oxidative stress (NAC), NF-κB activity (BAY 11-7082, si-p65) and nicotinic acetylcholine receptors (nAChRs, hexamethonium), nicotine-induced autophagy and VSMC phenotype switching were reversed. Nicotine-induced autophagy promotes the phenotype switching of VSMCs and accelerates atherosclerosis, which is partly mediated by the nAChRs/ROS/NF-κB signaling pathway. Copyright © 2019 Elsevier B.V. All rights reserved.
DOI:S0021-9150(19)30086-3
PMID:30856513
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Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.
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Chondroitin sulfate (CS) has antioxidative, anti-inflammatory, anti-osteoarthritic and hypoglycemic effects. However, whether it has antidiabetic osteoporosis effects has not been reported. Therefore, in this study, we established a STZ-induced diabetic rat model; CS (500 mg kg−1 d−1) was orally administrated for eight weeks to study its preventive effects on diabetic osteoporosis. The results showed that eight weeks of CS treatment improved the symptoms of diabetes; the CS-treated group has increased body weight, decreased water or food intake, decreased blood glucose, increased bone-mineral density, repaired bone morphology and decreased femoral osteoclasts and tibia adipocytes numbers. After CS treatment, bone histomorphometric parameters returned to normal, the levels of serum inflammatory cytokines (IL-1β, IL-6 and TNF-α) decreased significantly, serum SOD, GPX and CAT activities increased and MDA level increased. In the CS-treated group, the levels of serum ALP, CTX-1, TRACP 5b, osteocalcin and RANKL decreased and the serum RUNX 2 and OPG levels increased. Bone immunohistochemistry results showed that CS can effectively increase the expression of OPG and RUNX2 and reduce the expression of RANKL in diabetic rats. All of these indicate that CS could prevent STZ induced diabetic osteoporosis—mainly through decreasing blood glucose, antioxidative stress, anti-inflammation and regulation of OPG/RANKL expression. CS can therefore effectively prevent bone loss caused by diabetes.
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