左旋肉碱经Runx2/COL1A1通路抑制老年鼠肿瘤恶液质的骨骼肌纤维化

目的 探讨左旋肉碱经Runx2/COL1A1通路抑制老年鼠肿瘤恶液质的骨骼肌纤维化。方法 用结肠癌MC38细胞在C57老年鼠右侧腹股沟皮下植瘤构建肿瘤恶液质模型,实验分为非荷瘤组、荷瘤组和左旋肉碱组,并进行相应干预。实验结束后取一侧腓肠肌称重,行苏木精⁃伊红染色（HE染色）和Masson染色后,分别测量腓肠肌横截面积和胶原纤维面积占比;对侧腓肠肌提取总蛋白,蛋白质印迹法检测Runx2和COL1A1蛋白水平。体外实验用转化生长因子-β1（TGF-β1）诱导NIH/3T3细胞,建立体外纤维化模型,经左旋肉碱干预后,分别提取总蛋白和mRNA,蛋白质印迹法检测Runx2和COL1A1蛋白水平,并用qRT⁃PCR检测COL1A1 mRNA水 平,转染cDNA⁃Runx2验证左旋肉碱通过Runx2调控COL1A1。结果 三组进行比较,荷瘤组腓肠肌重量明显低于非荷瘤组（[ 98.12±17.04）mg 比 (122.18±6.91）mg（] P<0.05）;荷瘤组腓肠肌横截面积（207.46±54.55）µm2显著低于非荷瘤组（488.61±46.72）µm2和左旋肉碱组（434.54±113.84）µm（2 P<0.05）;胶原纤维面积占比荷瘤组（9.69±1.55）%明显高于左旋肉碱组（5.48±1.19）%和非荷瘤组（3.88±0.86）% （P<0.05）。蛋白质印迹法结果显示,与其他两组相比,荷瘤组Runx2和COL1A1高表达（P<0.05）。体外研究表明,左旋肉碱可逆转TGF⁃β1诱导的Runx2蛋白和COL1A1 mRNA高表达。过表达Runx2结果证实左旋肉碱通过抑制Runx2蛋白的表达下调COL1A1 mRNA。结论 左旋肉碱通过降低Runx2/COL1A1改善老年鼠肿瘤恶液质的骨骼肌纤维化。     

中药调节肠道菌群改善肿瘤恶液质作用的研究进展

肠道菌群与肿瘤相关性的研究目前仍是临床上一个值得期待的研究热点。肠道菌群失调与肿瘤恶液质的发生发展有着重大的联系。运用中药调节肠道菌群可以作为肿瘤放化疗后的辅助治疗,对机体的免疫调节起着很重要的作用,而肿瘤恶液质的发生与发展一定程度上会受到肠道菌群的影响,在肿瘤恶液质的防治中肠道菌群也起到了重要作用。从另一方面来讲,肿瘤恶液质的发生也会造成机体肠道菌群的失调,对于这种情况,用中药来对肠道菌群失调来进行调节,在一定程度上对肿瘤恶液质起到改善作用,通过中药调节肠道菌群对肿瘤恶液质的影响来探索中药、肠道菌群失调以及肿瘤恶液质三者之间的关系是本文所要阐述的,目的是促进祖国医学在肿瘤治疗方面发挥更大的效用,充分发挥中医的特色优势,尽早攻克肿瘤这个医学难题。     

肿瘤恶液质诱导骨骼肌氧化代谢调节作用的研究进展

改善生存率和生活质量是肿瘤患者成功治疗的主要目标,恶液质治疗也是肿瘤治疗的重要部分之一。肿瘤恶液质是一组症状和体征,常见于晚期转移的肿瘤,恶液质可在50%的肿瘤患者中出现,是肿瘤患者死亡的主要原因之一。虽然恶液质的进展与肿瘤患者的发病率和死亡率直接相关,但是恶液质的发病机制和治疗仍然不清。有证据表明,肿瘤引起的体重减轻与全身内分泌和代谢异常以及许多组织和器官的功能破坏有关,其中肿瘤引起的骨骼肌消耗已成为重要的研究方向。近年来,肿瘤恶液质中骨骼肌氧化代谢调节作用得到越来越多的关注,氧化代谢已经成为肿瘤患者肌肉萎缩的生物学治疗靶点之一。虽然骨骼肌对炎症、激素和收缩等外界刺激的反应需要涉及多种细胞器对细胞信号通路的整合,但是肌肉线粒体参与调节消耗和代谢过程的作用已经得到确认,线粒体含量和功能受到机体许多刺激因素的影响,包括肌肉活动增加和减少,全身炎症和全身性激素信号传导等。随着恶液质进展,炎症细胞因子增加和性类固醇的降低可以破坏肌肉氧化代谢能力,恶液质患者活动力的下降与骨骼肌消耗萎缩密切相关。本篇综述将探讨与肿瘤恶液质相关的骨骼肌氧化代谢调节的作用及进展。     

肿瘤恶液质相关心脏萎缩临床诊治进展

近年来,全球恶性肿瘤患者数量急剧上升,肿瘤恶液质及其相关并发症造成的医疗、经济负担也在剧增。肿瘤恶液质是一种复杂的多因素综合征,它的主要特点是骨骼肌进行性丢失,并与多器官功能障碍相关,靠常规的营养治疗手段不能完全逆转。肿瘤恶液质相关心脏并发症,包括心脏萎缩、重塑、功能障碍,甚至心力衰竭。肿瘤恶液质相关心脏萎缩,主要是由于恶液质介质和泛素蛋白酶体途径之间相互作用的结果。蛋白生成抑制引发心肌萎缩,泛素—蛋白酶体系统(UPS)激活降低心肌蛋白质合成,炎症状态加速心肌萎缩过程,胰岛素抵抗导致储存蛋白消耗,并阻碍组织细胞对营养物质的摄取利用。肿瘤恶液质相关心脏萎缩是肿瘤恶液质患者心血管系统的早期并发症,经常被临床忽视,或将其与心脏原发病混淆。未及时诊治心脏萎缩,不仅会加重肿瘤恶液质,也会降低抗肿瘤治疗疗效,因此,对肿瘤恶液质相关心脏萎缩进行科学诊治,可以帮助提升抗肿瘤治疗疗效,进而提高肿瘤患者生存率。因此,肿瘤恶液质相关心脏萎缩的早期筛查、诊断和治疗,对肿瘤治疗有重要意义。     

肿瘤恶液质的诊治

肿瘤恶液质是以肿瘤患者骨骼、内脏的肌肉消耗为特征,伴或不伴有食欲减退、厌食、饱胀感、体重下降、肌肉萎缩、乏力、贫血、水肿、低蛋白血症等一系列临床并发症。肿瘤恶液质的存在使患者的抗肿瘤治疗难以进行,影响患者生存;同时临床并发症的出现也严重影响了患者的生活质量。临床中,肿瘤患者恶液质的发病率高,死亡率高,而且一旦进入恶液质期难以逆转。因此早期发现、早期干预才能改善体重、防止肌肉丢失、减轻恶液质的相关症状,以达到提高生活质量、延长生存、改善预后的治疗目的。本文以肿瘤恶液质的定义为基础,从三大营养物质的代谢改变出发,总结了目前关于肿瘤恶液质可能的发病机制,进而阐述了肿瘤恶液质的筛查与评定及诊断要点,综述了对应的治疗策略及方法,包括营养干预、运动干预、心理干预及其他药物干预等,并对未来肿瘤恶液质多学科规范化诊疗进行了展望,期望通过多学科诊疗（MDT）的模式,能为肿瘤恶液质患者的早诊早治、延长生存、改善预后提供新的理念,创建新的平台。     

运动治疗:肿瘤恶液质患者的未来?

肿瘤患者恶液质的发病率和死亡率高,一旦进入恶液质期难以逆转,主要以患者骨骼、内脏的肌肉消耗为特征。目前还没有针对恶液质的常规干预措施,因此,建议在肿瘤早期采取积极主动的方法,以维持或减缓功能丧失。运动对健康的益处已经越来越明确,运动可以减少恶性肿瘤的发生风险,降低转移和复发风险,提高肿瘤患者的生活质量,并可能改善其生存结局。但运动对肌肉和/或体重恢复的可行性和有效性的最佳证据大多是在非恶液质患者中发现的。运动在肿瘤恶液质患者中的临床研究较少,其作用尚不能确定。运动、营养补充和非甾体抗炎药的组合目前仍是多模式干预的首选治疗方法,但其阻止或逆转肌肉和/或体重丢失的益处需要更多的临床和基础研究进一步证实。尽管指南推荐肿瘤患者需加强运动,但恶液质患者应在充分考虑安全性的基础上制订个性化的运动处方。本文着重概述了运动在肿瘤恶液质中的应用情况,结合动物模型研究和临床应用研究的最新进展,探讨运动疗法在对抗肿瘤恶液质中的应用与前景。     

肿瘤恶液质认识和处理

恶液质是恶性肿瘤患者的常见并发症,近80%晚期肿瘤患者会出现恶液质。恶液质往往与患者较低的生活质量和较差的预后相关,并引起肿瘤治疗的耐受性降低以及肿瘤治疗的敏感性下降。全文分析肿瘤恶液质综合征人群常见的体重下降和厌食的处理。     

恶液质与肿瘤转移的相关分子机制

恶液质是一种骨骼肌量进行性下降的代谢综合征,伴随或不伴随脂肪量减少,在晚期肿瘤患者中普遍存在。恶 液质降低抗肿瘤治疗疗效,增加肿瘤放化疗不良反应,增加肿瘤患者死亡率,是预后不良的重要因素之一。恶液质促进肿 瘤的侵袭和转移,其机制尚不明确,可能与恶液质患者中存在的炎性反应、乏氧状态、瘦素水平下降、促血管生成因子释 放等有关。肿瘤恶液质的病理生理机制错综复杂,普遍认为肿瘤转移的患者,肿瘤负荷增加,患者发生恶液质的风险增加, 且其治疗效果欠佳,目前仍缺乏标准的治疗方案。进一步明确恶液质的病理生理特点及其促进肿瘤转移的机制,有助于指 导早期营养筛查和营养评估,明确恶液质的诊断,并对恶液质进行分期和分级管理,有效地预防和治疗恶液质,进而减少 肿瘤转移,改善患者生活质量及预后。本文通过探讨恶液质的病理生理特点及其促进肿瘤转移的相关分子机制,综述恶液 质与肿瘤转移的相关分子机制,为恶液质及肿瘤转移的治疗提供重要依据。     

肿瘤恶液质药物治疗进展

肿瘤恶液质主要表现为肌肉质量的逐渐减少与厌食、疲劳、功能状态受损,其中以胃肠道及肺恶性肿瘤最常见,严重影响患者的生活质量及生存时间。药物治疗在综合治疗中占据重要地位,但目前临床较为常用的药物,如食欲刺激剂和一些控制症状的药物,疗效不尽如人意。近年来,许多代谢调节剂、靶向药物及中医中药在肿瘤恶液质的治疗中展现出良好的疗效及耐受性,如促进生长和合成代谢的激素食欲刺激素类似物和抑制分解代谢的单克隆抗体等。治疗恶液质需要临床多学科协作进行全方位的干预,才有可能控制甚至逆转。本文就现今药物治疗方面的进展展开阐述。     

肿瘤恶液质的药物治疗研究进展

当恶性肿瘤发展到晚期的时候,肿瘤恶液质是其中较为常见的一类并发症,临床症状表现为肌肉、骨骼量减少,或存在脂肪含量降低、食欲下降、人体代谢失调,进而导致器官功能缺失。研究发现约五分之一的恶性肿瘤患者因肿瘤恶液质导致死亡,肿瘤恶液质的发生对患者生活造成严重影响,增加治疗时间、提高治疗成本、生活质量下降、减少生存时间。肿瘤恶液质发病机制较为复杂,目前已知的发病机制包括在肿瘤组织的长期刺激下引发的不可逆转性慢性炎症;炎症反应后影响人体代谢平衡;炎性因子抑制中枢神经有益物质的分泌,减少人体食欲信号等。现阶段临床上对于该疾病的发病原理取得一定研究成果,随着研究的不断深入,对其治疗药物具有一定的认识。针对其发病机制治疗肿瘤恶液质需要多种渠道共同作用,给予患者充分的营养以及药物联用等。本文将从目前使用较多的食欲刺激类药物（孕激素、胃饥饿素）、抗炎类（非甾体抗炎药、沙利度胺、ω-3脂肪酸）、蛋白降解抑制类、代谢调节类（雄激素受体调节剂、β-受体阻滞剂）药物治疗的效果展开分析,并针对目前药物联合治疗的研究进展进行讨论。     

Amelioration of muscle wasting by gintonin in cancer cachexia

Cancer cachexia is characterized by systemic inflammation, protein degradation, and loss of skeletal muscle. Despite extensive efforts to develop therapeutics, only few effective treatments are available to protect against cancer cachexia. Here, we found that gintonin (GT), a ginseng-derived lysophosphatidic acid receptor (LPAR) ligand, protected C2C12 myotubes from tumor necrosis factor α (TNFα)/interferon γ (IFNγ)- induced muscle wasting condition. The activity of GT was found to be dependent on LPAR/Gαi2, as the LPAR antagonist Ki16425 and Gαi2 siRNA abolished the anti-atrophic effects of GT on myotubes. GT suppressed TNFα-induced oxidative stress by reducing reactive oxygen species and suppressing inflammation-related genes, such as interleukin 6 (IL-6) and NADPH oxidase 2 (NOX-2). In addition, GT exhibited anti-atrophy effects in primary normal human skeletal myoblasts. Further, GT protected against Lewis lung carcinoma cell line (LLC1)-induced cancer cachexia in a mouse model. Specifically, GT rescued the lower levels of grip strength, hanging, and cross-sectional area caused by LLC1. Collectively, our findings suggest that GT may be a good therapeutic candidate for protecting against cancer cachexia.     

Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

Purpose  To determine the effectiveness of the polyanionic, metal binding agent d-myo-inositol-1,2,6-triphosphate (alpha trinositol, AT), and its hexanoyl ester (HAT), in tissue wasting in cancer cachexia. Methods  The anti-cachexic effect was evaluated in the MAC16 tumour model. Results  Both AT and HAT attenuated the loss of body weight through an increase in the nonfat carcass mass due to an increase in protein synthesis and a decrease in protein degradation in skeletal muscle. The decrease in protein degradation was associated with a decrease in activity of the ubiquitin-proteasome proteolytic pathway and caspase-3 and -8. Protein synthesis was increased due to attenuation of the elevated autophosphorylation of double-stranded RNA-dependent protein kinase, and of eukaryotic initiation factor 2α together with hyperphosphorylation of eIF4E-binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2. In vitro, AT completely attenuated the protein degradation in murine myotubes induced by both proteolysis-inducing factor and angiotensin II. Conclusion  These results show that AT is a novel therapeutic agent with the potential to alleviate muscle wasting in cancer patients.     

Epigallocatechin-3-gallate effectively attenuates skeletal muscle atrophy caused by cancer cachexia

Cachexia, also known as wasting syndrome notably with skeletal muscle atrophy, costs nearly one-third of all cancer deaths in man. (-)-Epigallocatechin-3-gallate (EGCG), the principal polyphenolic component in green tea, is a potent preventive against cachexia as well as cancers. However, how EGCG counteracts cachexia-provoked muscle wasting is unclear. EGCG was demonstrated to be able to retard tumor progression as well as to prevent body weight from loss, because EGCG attenuates skeletal muscle leukocytic infiltration and down-regulates tumor-induced NF-κB and E3-ligases in muscle. In mice, the dosages optimized against cachexia were determined to be 0.2 mg/mouse/day for prevention and to be 0.6 mg/mouse/day for treatment. Anti-cachexia effects were assessed using the LLC tumor model. Mice with the same body weight were divided into groups, including control, tumor bearing, and tumor-bearing but receiving water or EGCG in both prevention and treatment experiments. RT-PCR was used to assess mRNA expressions of NF-κB, MuRF 1, and MAFbx. The intracellular NF-κB, MuRF 1 and MAFbx were determined and quantified by immunofluorescence and Western blotting, respectively. Our results conclude EGCG regulates the expressions of NF-κB as well as downstream mediators, MuRF 1 and MAFbx, so EGCG may be an appropriate agent to be included in ensemble therapeutics of the tumor-induced muscle atrophy.     

恶性肿瘤恶病质骨骼肌萎缩分子机制研究进展

目的：总结国内外对恶性肿瘤恶病质状态下骨骼肌萎缩的分子机制研究进展。方法：应用PubMed和维普期刊资源整合平台,以“恶性肿瘤、恶病质、骨骼肌萎缩、泛素-蛋白酶体途径和自噬信号通路”作为关键词,检索2002—01—01—2013—12—31相关文献。纳入标准：1）恶性肿瘤;2）恶病质;3）骨骼肌萎缩;4）泛素-蛋白酶体途径;5）自噬信号通路。根据纳入标准符合分析的文献33篇。结果：机体在各种刺激下主要通过UPP和ALP降解骨骼肌细胞,ALP在恶病质状态下活性明显升高,UPP可能在恶性肿瘤恶病质中晚期激活。在饥饿和应激等情况下,UPP和ALP可能主要经Akt／PI3K-／mTOR调控;在恶性肿瘤恶病质状态下,FoxO被抑制,骨骼肌萎缩可能主要与NF-κB和p38MAPK有关。NF-gB能调控E3s转录,并且在Beclinl的基因序列上有相应结合位点;p38MAPK抑制剂SB202190能使E3s及LC3表达下调。结论：对恶性肿瘤恶病质状态下骨骼肌萎缩调控机制的研究将有助于靶向药物的研发,以期改善恶性肿瘤恶病质患者的预后。     

糖脂代谢异常对恶性肿瘤影响的研究进展

肿瘤是全球主要的死亡原因之一,其发病率正在逐年上升。糖脂代谢异常可导致多种恶性肿瘤的发病率及死亡率 增加,如乳腺癌、肝癌、胰腺癌、结直肠癌等。糖脂代谢异常导致肿瘤进展的多种机制,包括影响细胞代谢、引起机体炎症与免 疫失调、抑制肿瘤细胞凋亡以及促进肿瘤细胞增殖和转移等,然而尚不清楚导致恶性肿瘤发生、发展的主要原因。此外,糖脂 代谢异常与恶性肿瘤的相互作用限制药物的选择、增加恶性肿瘤化学耐药性、影响手术疗效和患者预后,使恶性肿瘤治疗方案 的制定更具挑战性。二甲双胍与他汀类药物可降低多种肿瘤的风险,但相关的临床前瞻性试验尚无定论。因此,本文对糖脂 代谢紊乱与恶性肿瘤相关的研究进展进行阐述,旨在探讨糖脂代谢异常与恶性肿瘤发生的相关性,以及促进恶性肿瘤生长与 进展的潜在病理生理机制,最后将讨论降糖、降脂策略在治疗恶性肿瘤中的潜在作用。     

肺癌相关异常脂代谢的研究进展

在对肺癌发生、发展及治疗的研究中发现,其脂代谢与上述过程均有密切关系。分析脂代谢与肺癌的关系,可能有助于准确诊断肺癌、预测疗效及评估预后,并开发基于肿瘤脂代谢的治疗药物。对肺癌患者的血脂表现特点、与疗效的关系及可能影响脂代谢的药物进行了综述,以期为临床工作提供参考。     

Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg(-1)) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2alpha phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-kappaB (NF-kappaB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia.