淫羊藿苷干预大鼠椎间盘源性腰痛的实验研究

目的:探讨淫羊藿苷(icariin,ICA)干预大鼠椎间盘源性腰痛的效果及可能的作用机制。方法:将45只8周龄SPF级雄性SD大鼠随机分为5组,假手术组、生理盐水组、ICA 50 mg·kg^-1组、ICA 100 mg·kg^-1组各10只,塞来昔布组5只。生理盐水组、ICA 50 mg·kg^-1组、ICA 100 mg·kg^-1及塞来昔布组大鼠通过L_4~5和L_5~6椎间盘穿刺建立大鼠腰痛模型;假手术组仅显露椎间盘,不进行穿刺。自造模后第7天开始进行药物干预,至造模后第21天结束。ICA 50 mg·kg^-1组和ICA 100 mg·kg^-1组以ICA溶液进行灌胃(ICA溶于去离子水中),每天剂量分别为50 mg·kg^-1和100 mg·kg^-1;塞来昔布组以塞来昔布胶囊进行灌胃(塞来昔布胶囊粉剂溶于去离子水中),每天100 mg·kg^-1;生理盐水组以生理盐水灌胃,每天100 mg·kg^-1;假手术组常规饲养,不进行干预。从各组随机选取5只大鼠,分别于造模前、造模后第7天、第14天、第21天、第28天、第35天进行足底机械性疼痛阈值检测。造模后第35天,足底疼痛阈值测定结束后处死假手术组、生理盐水组、ICA 50 mg·kg^-1组和ICA 100 mg·kg^-1组的5只大鼠,以qRT-PCR法测定椎间盘组织中P物质(substance P,SP)mRNA和降钙素基因相关肽(calcitonin gene related peptide,CGRP)mRNA的含量。造模后第21天时,处死假手术组、生理盐水组、ICA 50 mg·kg^-1组和ICA 100 mg·kg^-1组其余的5只大鼠,以ELISA法测定大鼠椎间盘组织中细胞因子诱导的中性粒细胞趋化剂-1(cytokine-induced neutrophil chemoattractant-1,CINC-1)含量。结果:①足底机械性疼痛阈值。时间因素和分组因素存在交互效应(F=17.971,P=0.001)。5组大鼠的足底机械性疼痛阈值总体比较,差异有统计学意义,即存在分组效应(F=146.660,P=0.000)。造模前后不同时点间足底机械性疼痛阈值的差异有统计学意义,即存在时间效应(F=118.057,P=0.000)。假手术组足底机械性疼痛阈值随时间未见明显变化,一直处于较高水平[(14.60±0.89)g,(14.79±0.47)g,(15.00±0.00)g,(15.00±0.00)g,(15.00±0.00)g,(15.00±0.00)g,F=0.836,P=0.537]。生理盐水组足底机械性疼痛阈值造模后明显降低,后期一直维持在较低水平[(14.67±0.74)g,(3.44±2.22)g,(3.19±1.37)g,(2.84±0.96)g,(3.92±1.36)g,(3.02±0.98)g,F=58.882,P=0.000]。ICA 50 mg·kg^-1组、ICA 100 mg·kg^-1组和塞来昔布组造模前后的足底机械性疼痛阈值变化趋势基本一致,造模后均先降低,药物干预开始后逐渐回升,药物干预结束后又逐渐降低[(15.00±0.00)g,(2.78±0.81)g,(4.64±1.67)g,(5.59±1.25)g,(8.52±1.63)g,(6.11±1.49)g,F=56.088,P=0.000;(14.66±0.76)g,(2.53±1.37)g,(10.65±2.69)g,(9.67±2.41)g,(10.67±2.04)g,(8.59±2.95)g,F=16.684,P=0.000;(15.00±0.00)g,(2.28±1.03)g,(12.09±1.28)g,(12.37±1.34)g,(6.71±2.89)g,(5.18±1.88)g,F=44.668,P=0.000]。造模后第7天时,ICA 50 mg·kg^-1组、ICA 100 mg·kg^-1组和塞来昔布组的足底机械性疼痛阈值两两比较,组间差异均无统计学意义。造模后第14天时,ICA 100 mg·kg^-1组和塞来昔布组的足底机械性疼痛阈值均高于ICA 50 mg·kg^-1组(P=0.001;P=0.000);ICA 100 mg·kg^-1组和塞来昔布组的足底机械性疼痛阈值比较,差异无统计学意义。造模后第21天时,ICA 100 mg·kg^-1组和塞来昔布组的足底机械性疼痛阈值均高于ICA 50 mg·kg^-1组(P=0.009;P=0.000);ICA 100 mg·kg^-1组和塞来昔布组的足底机械性疼痛阈值比较,差异无统计学意义。造模后第28天时,ICA 100 mg·kg^-1组的足底机械性疼痛阈值高于塞来昔布组(P=0.049);ICA 50 mg·kg^-1组与ICA 100 mg·kg^-1组、塞来昔布组比较,组间差异均无统计学意义。造模后第35天时,ICA 50 mg·kg^-1组、ICA 100 mg·kg^-1组和塞来昔布组的足底机械性疼痛阈值两两比较,组间差异均无统计学意义。②椎间盘组织CINC-1含量。造模后第21天,假手术组、生理盐水组、ICA 50 mg·kg^-1组及ICA 100 mg·kg^-1组大鼠椎间盘组织中CINC-1含量比较,差异有统计学意义[(534.2±142.6)pg·mL^-1,(28 376.0±976.7)pg·mL^-1,(21 866.0±1 536.0)pg·mL^-1,(9 956.0±1 010.0)pg·mL^-1,F=423.000,P=0.000]。生理盐水组的CINC-1含量高于假手术组、ICA 50 mg·kg^-1组和ICA 100 mg·kg^-1组(P=0.000;P=0.003;P=0.000);ICA 50 mg·kg^-1组的CINC-1含量高于ICA 100 mg·kg^-1组(P=0.000)。③椎间盘组织SP mRNA和CGRP mRNA含量。造模后第35天,假手术组、生理盐水组、ICA 50 mg·kg^-1组及ICA 100 mg·kg^-1组大鼠椎间盘组织中SP mRNA和CGRP mRNA含量比较,组间差异均有统计学意义(1.04±0.49,183.50±118.60,55.50±10.26,19.53±8.05,F=9.499,P=0.000;0.74±0.21,6.29±2.06,1.55±0.69,1.19±0.37,F=27.180,P=0.000)。生理盐水组的SP mRNA含量高于假手术组、ICA 50 mg·kg^-1组和ICA 100 mg·kg^-1组(P=0.008;P=0.042;P=0.015);ICA 50 mg·kg^-1组的SP m RNA含量高于ICA 100 mg·kg^-1组(P=0.000)。生理盐水组的CGRP m RNA含量高于假手术组、ICA 50 mg·kg^-1组和ICA 100 mg·kg^-1组(P=0. 000;P=0. 001;P=0. 000);ICA 50mg·kg^-1组和ICA 100 mg·kg^-1组的CGRP m RNA含量比较,差异无统计学意义。结论:ICA可有效缓解大鼠椎间盘源性腰痛,其镇痛效果与剂量有关,与同剂量的塞来昔布相比其镇痛效果持续时间更长,降低大鼠椎间盘组织中CINC-1的水平可能是其镇痛的作用机制之一。     

芒针对脊髓损伤大鼠运动功能和炎症水平的影响

目的探究芒针深刺秩边穴对大鼠脊髓损伤后运动功能的影响及可能作用机制。方法选择健康雄性Wister大鼠81只,随机分为正常组、模型组和芒针组(正常组9只,其余两组各36只),采用改良Allen's造模法制备大鼠脊髓中度损伤模型,模型组不做特殊处理,芒针组采用芒针深刺秩边穴,每日1次,每次30 min。分别于术后1 d、3 d、5 d、7 d行BBB(Basso-Beattie-Bresnahan)运动功能评分;术后1 d、3 d、5 d、7 d取受损段脊髓组织行酶联免疫吸附测定(ELISA)、实时荧光定量PCR(RT-qPCR)和苏木素-伊红染色(HE染色)。结果术后5 d和7 d,芒针组大鼠BBB评分高于模型组,差异有统计学意义(P<0.01);脊髓损伤后,模型组和芒针组大鼠脊髓组织中高迁移率族蛋白B1(HMGB1)、核转录因子kB(NF-kB)、白介素-6(IL-6)含量及HMGB1mRNA、NF-kBmRNA、IL-6mRNA水平显著升高(P<0.05);受损的脊髓组织松散,灰质中有许多空洞形成,伴有炎性细胞浸润。芒针治疗后,芒针组大鼠脊髓组织中HMGB1、NF-kB、IL-6含量及HMGB1mRNA、NF-kBmRNA、IL-6mRNA水平较模型组降低,且在3 d、5 d、7 d差异有统计学意义(P<0.05);受损部位的空洞及炎性细胞逐渐减少。结论脊髓损伤后,炎症因子的大量聚集引起级联性炎症反应,影响大鼠运动功能的恢复。芒针的抗炎机制可能包括抑制HMGB1的表达,降低NF-kB信号通路的传导,下调促炎因子IL-6的分泌。     

急性乙型肝炎患者pDCs上CD86表达变化及意义

目的 探讨外周血浆细胞样树突状细胞(pDCs)在急性乙型肝炎(AHB）患者临床转归中的变化及作用。方法 纳入2015年6月至2017年5月收治的急性乙型肝炎(AHB组)患者40例， 给予退黄、降酶、保肝等药物，并加用恩替卡韦0．5 mg空腹口服，1次/d。另纳入健康体检者26例为健康对照组（ HC组）。HC组于体检当天、AHB组于治疗前及治疗后6周采集外周静脉全血，采用ELISA法检测2组血浆HBV DNA、HBsAg、HbeAg及肝功能指标水平，并应用流式细胞仪检测pDCs的频数及其功能分子CD86的表达水平。结果 治疗6周后，AHB组临床症状显著缓解，血清学指标和乙型肝炎标志物水平显著下降（P<0.01）。治疗6周后，AHB组HBV DNA转阴率为82.5%，HBsAg清除率为72.5%，HBeAg血清学转换率为75.0%，与治疗前比较差异均有统计学意义（P<0.01）, HC组pDCs频数显著高于AHB组治疗前。AHB组治疗后CD86+pDCs显著高于治疗前。HC组CD86ABC显著低于AHB组治疗前。结论 在急性乙型肝炎患者外周血pDCs的数量降低。急性乙型肝炎患者在治疗后CD86+pDCs增多。急性乙型肝炎患者pDCs上CD86表达上调。     

Clinical Benefit-Risk Profile of Lenalidomide in Patients With Lower-risk Myelodysplastic Syndromes Without del(5q): Results of a Phase III Trial

BackgroundIn the phase III MDS-005 study of patients with lower-risk, non-del(5q) myelodysplastic syndromes, lenalidomide was associated with a higher rate of ≥ 8 weeks red blood cell transfusion independence (RBC-TI) compared with placebo, but also with a higher risk of hematologic adverse events (AEs).Patients and MethodsThis analysis evaluated the ratio of clinical benefit-risk in patients treated with lenalidomide or placebo, and assessed the effect of lenalidomide dose reductions on response. Clinical benefit was a composite endpoint defined as RBC-TI, transfusion reduction ≥ 4 units packed red blood cells, hemoglobin increase ≥ 1.5 g/dL, or cytogenetic response.ResultsThe rate of clinical benefit was higher with lenalidomide than with placebo (31.9% vs. 3.8%). The ratio of response (RBC-TI and clinical benefit) to risk (hematologic AEs) favored lenalidomide over placebo. Patients who underwent ≥ 1 lenalidomide dose reduction had a longer duration of treatment, received a higher cumulative dose, and were more likely to experience clinical benefit versus patients without dose reductions.ConclusionDespite the occurrence of hematologic AEs, the overall benefit-risk profile supported lenalidomide treatment. Appropriate management of hematologic AEs by dose reductions may help patients with myelodysplastic syndromes to remain on treatment and achieve clinical benefit.     

头颈区黏膜淋巴瘤的WHO分类更新及诊断方法

2017年1月与9月，《WHO头颈肿瘤分类》（第4版）与《WHO造血淋巴组织肿瘤分类》（修订第4版）两本蓝皮书相继面世，笔者也有幸受邀参与了《WHO头颈肿瘤分类》（第4版）一书中淋巴造血组织肿瘤有关章节的编写工作，分别对这两个新分类中关于头颈区黏膜淋巴组织增生性疾病的内容更新、头颈区黏膜淋巴瘤的诊断方法以及该区域常见淋巴瘤类型的诊断与鉴别诊断要点作一简介。     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

Biogenic silver,gold and copper nanoparticles - A sustainable green chemistry approach for cancer therapy

The advent of nanotechnology has revolutionized the way clinicians are treating cancers. Treatment for cancer includes surgery, radiotherapy, hormonal therapy, chemotherapy, and now nano therapy, which could be a possible alternative. This new treatment regime can be beneficial since it shows minimum side effects as compared to other treatment methods. Metallic nanoparticles synthesized through green chemistry by using biological entities minimizes the side effects and enhances the properties of the metal against cancer cells. These green nanoparticles are widely used in research and have shown promising cytotoxic activity against various cancer cell lines. Mechanistically, these nanoparticles can enter the cancer cell and cause cell death by the activation of various molecular pathways such as apoptosis, necrosis and autophagy. This review focuses on the metal nanoparticles (silver, gold and copper) synthesized by the green chemistry approach that have been utilized to study the cancer cell death and we are also discussing the underlying molecular pathways.