Anti-aging effect of DL-β-hydroxybutyrate against hepatic cellular senescence induced by D-galactose or γ-irradiation via autophagic flux stimulation in male rats

The present study aims to shed new light on anti-aging effect of DL-β-hydroxybutyrate (βOHB) against hepatic cellular senescence induced by d-galactose or γ-irradiation. The rats divided into 6 groups. Group 1, control, group 2, exposed to γ-ray (5 GY), group 3, injected by d-galactose (150 mg/kg) daily for consecutive 6 weeks, which regarded to induce the aging, group 4, injected intraperitoneal by β-hydroxybutyrate (βOHB) (72.8 mg/kg) daily for consecutive 14 days, group 5, exposed to γ-ray then treated with βOHB daily for consecutive 14 days, group 6, injected daily with d-galactose for consecutive 6 weeks, then treated with βOHB daily at the last two weeks of d-galactose. Aspartate amino transferase (AST), alanine amino transferase (ALT), Insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were estimated in serum. Moreover, protein expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) ratio, mechanistic target of rapamycin (mTOR), pAMPK, mRNA gene expression of 5′ AMP-activated protein kinase (AMPK), Nucleoporin p62 (p62), cyclin-dependent kinase inhibitor 1(P21^CIP1), cyclin-dependent kinase inhibitor 2A (p16^INK4a) and DNA fragmentation percentage were measured in liver tissue as a biomarker of cellular senescence. The results confirmed that βOHB modulated serum level of AST, ALT, insulin, IL-6 and TNF-α, protein expression of mTOR and LC3-II/LC3-I ratio, pAMPK and p62 in liver aging model induced by d-galactose or γ-irradiation. Histopathological examination results of liver tissue indicated coincidence with those recorded by molecular biochemical inspection. Taken together, these findings suggest that βOHB may be useful in combating hepatic cellular senescence induced by d-galactose or γ-irradiation via autophagy dependent mechanisms.     

结肠癌患者术后认知功能障碍与5－羟色胺受体3B亚基相关性及其对预后的影响

目的探讨结肠癌术后患者认知功能障碍与5－羟色胺受体3B亚基相关性及其对预后的影响。 方法回顾性分析2013年5月至2017年1月86例均在全麻下行腹腔镜结肠癌切除术资料，根据患者术后是否存在认知功能障碍，将患者分为POCD组(认知功能障碍，n＝28)和对照组(无认知功能障碍，n＝58)，采用SPSS22.0完成数据分析，两组患者心理健康状况等采用独立t检验；5－羟色胺受体3B亚基的基因多态性分析采用卡方检验，患者术后POCD的危险因素采用多因素logistics回归分析。P<0.05表示差异有统计学意义。 结果两组患者rs10789970呈多态性分布，POCD组基因型主要表现为CC的野生型比例显著增高(P<0.05)。POCD患者rs10789970为CC、CT和TT的患者智能精神状态评价量表(MMSE)分别为(15.7±3.8)分、(17.8±3.8)分、(20.0±2.8)分(P＝0.000)。多因素logistics回归分析显示rs10789970的野生型CC是结肠癌患者术后POCD发生的独立危险因素[1.21(1.02～1.40), P＝0.002]。术前两组患者焦虑自我评分和抑郁自我评分均无统计学差异(P>0.05)，与对照组比较，POCD组患者术后3 d时焦虑自我评分和抑郁自我评分均显著增高，术后肛门排气时间和住院时间均显著延长，差异均有统计学意义(P<0.05)。 结论结肠癌患者术后认知功能障碍发生与rs10789970多态性分布有关，可恶化患者心理健康状况，影响术后康复。     

蜘蛛香环烯醚萜部位干预CUMS致抑郁小鼠脑组织的1H-NMR代谢组学分析

目的:利用代谢组学技术分析慢性温和不可预知应激(CUMS)抑郁模型小鼠脑组织样本,寻找与抑郁相关的差异代谢物,探讨蜘蛛香环烯醚萜部位(IEFV)可能的抗抑郁作用机制。方法:42只昆明小鼠随机分为6组,包括正常组,模型组,氟西汀组(2.5 mg·kg-1),IEFV低、中、高剂量组(给药剂量分别为5.73,11.47,22.94 mg·kg-1)。采用CUMS对小鼠造模,以IEFV及阳性药(氟西汀)为干预药物,用行为指标和生化指标进行药效学评价。采用核磁共振氢谱(1H-NMR)代谢组学技术分析IEFV对CUMS抑郁模型小鼠脑组织中内源性物质的影响,结合多变量统计分析方法来确认差异代谢物,并对差异代谢物参与的代谢通路进行富集。结果:造模后,小鼠的不动时间大幅度提高、蔗糖偏好率明显下降,兴奋性神经递质5-羟色胺和去甲肾上腺素显著下降,表明造模成功。给予IEFV和氟西汀后,小鼠不动时间、蔗糖偏好率和兴奋性神经递质向正常水平回调,提示给药后抑郁状态得到了一定程度的缓解。脑组织中内源性代谢物主成分分析(PCA)结果显示,模型组可与正常组明显分开,同时IEFV低、中、高剂量组和氟西汀组均显示有偏离模型组向正常组靠拢的趋势,与行为学结果一致。模型组与正常组进行正交偏最小二乘法-判别分析(OPLS-DA)得到了16个变化显著的差异代谢物,包括12个水溶性差异代谢物和4个脂溶性差异代谢物。通过MetPA数据库分析得到7条潜在靶标代谢通路,包括三羧酸循环(TCA),牛磺酸和亚牛磺酸的代谢,丙氨酸、天冬氨酸和谷氨酸代谢等。IEFV高剂量组可显著回调11种差异代谢物。结论:IEFV可能主要通过影响能量代谢,氨基酸代谢和神经递质水平发挥抗抑郁作用,可为IEFV抗抑郁作用机制的深入研究提供参考依据。     

益母草制剂的开发与应用

益母草制剂在临床中应用广泛,主要用于多种妇产科疾病的治疗,且效果显著。其中,益母草注射剂、益母草颗粒、益母草片是临床上最常见的益母草剂型,其有效性和安全性在长期的临床实践中得到认可。本论文结合项目组对益母草制剂的二次开发研究思路,对上述具有代表性的益母草制剂的制剂工艺、质量控制和临床应用进行介绍,以期为益母草制剂的现代研究和临床安全应用提供一定的参考。     

肝癌增强子-miRNA调控作用对的识别与特征分析

目的：探讨肝癌和正常肝组织中增强子与miRNA形成的调控关系及调控miRNA的增强子的特征，筛选出由增强子调控的差异表达miRNA并探讨其与肝癌治疗靶点的相关性。方法：基于TCGA与FANTOM5 数据库，对肝癌和正常肝组织中共417 个样本的增强子与miRNA进行共表达与3D基因组分析得到调控关系。通过ENCODE数据库中肝癌与正常肝组织的组蛋白修饰与转录因子的ChIP-seq 数据分析调控miRNA的增强子上信号值的差异。筛选由增强子调控的差异表达的miRNA，并对患者的生存期与治疗靶点进行相关性分析。结果：在肝癌与正常肝组织中分别识别增强子-miRNA 作用对93 对和40 对。ChIP-seq 数据比对分析发现，肝癌中组蛋白修饰H3K27ac、H3K4me1 和H3K4me3 信号在调控miRNA增强子区域显著高于不调控miRNA的增强子区域（|rho|>0.3，P<0.05）；多种转录因子在肝癌相关增强子中的富集显著低于正常肝组织（|rho|>0.3，P<0.05）。对增强子调控的miRNA进行差异表达分析，识别了6个与肝癌患者生存相关miRNA（hsa-miR-4664、hsa-miR-5003、hsa-miR-1915、hsa-miR-3619、hsa-miR-4745、hsa-miR-6728），发现这些miRNA 与87 个用于靶向治疗的基因以及8 个免疫检查点基因显著相关（|rho|>0.1，FDR<0.05）。结论：成功在肝癌中识别出增强子-miRNA调控作用对与调控miRNA的增强子的特征，并筛选出由增强子调控的与肝癌患者生存和治疗靶点相关的miRNA，为后续深入开展肝癌的基础与临床研究提供了参考依据。     

近端血流阻断加压技术在硬脊膜动静脉畸形血管内治疗中的应用

目的探讨近端血流阻断加压技术在硬脊膜动静脉畸形(SDAVF)血管内治疗中应用的安全性和有效性。方法回顾性分析2017年2月至2018年9月海军军医大学附属长海医院神经外科采用血管内治疗的6例SDAVF患者的临床资料。所有患者术中均应用近端血流阻断加压技术,其中1例因未能完全栓塞,改为显微外科手术治疗。术后即刻行数字减影血管造影(DSA),以判断栓塞情况。对所有患者行门诊或电话随访,随访内容为行Aminoff-Logue评分,判断脊髓功能的恢复情况;门诊随访的患者同时复查脊髓MRI,以判断栓塞情况。结果6例患者的手术均成功。术后即刻DSA显示,5例完全栓塞,1例瘘口残留。所有患者术后均未出现永久性神经系统并发症;其中1例术中造影显示肋间动脉夹层的患者,采用弹簧圈闭塞近端肋间动脉后复查胸椎CT,显示肋间肌内血肿形成,术后持续胸背部疼痛3 d后缓解。6例患者中,5例为门诊随访,1例为电话随访;中位随访时间(范围)为5.5个月(4.0~22.0个月)。术后3个月,6例患者的Aminoff-Logue评分均较术前降低[(2.0±0.7)分、(4.0±1.5)分,P<0.05];脊髓功能得到明显改善。术中因拔管困难而留置体内的1例患者,术后6个月随访时无相关并发症。经显微手术治疗的1例患者出院后10个月行DSA随访,未见瘘口显影。结论初步推测近端血流阻断加压技术在SDAVF血管内治疗中是安全、有效的。     

Anterior segment parameters on optical coherence tomography in healthy South Asian children

PurposeHigh resolution spectral domain optical coherence tomography (SD-OCT) was used to assess the anterior segment structure parameters in healthy South Asian children.Methods108 eyes of 54 healthy children ≤ 16 years were recruited after a thorough eye exam. The anterior segment analysis was be done by Optopol Revo 80 high resolution SD-OCT. Central corneal thickness (CCT), Angle opening distance (AOD), Anterior chamber (AC) angle, Trabecular iris space area (TISA), Trabecular iris angle (TIA), iris thickness at 2 mm, internal AC diameter and lens vault were evaluated.ResultsMean age was 11.38 years. Mean IOP was 13.63 mmHg, mean axial length, 22.82 mm, mean spherical equivalent, -0.14 D, mean CCT, 532.6 µm and mean CDR was 0.31. The mean internal AC diameter was 11609.15 µm. The nasal and temporal AC angles was 53.54° and 50.37°, respectively [P = .033]. The nasal and temporal AOD500 were 0.9 mm and 0.85 mm, respectively [P = .629]. The nasal and temporal AOD750 were 1.21 mm and 1.06 mm, respectively [P = .583]. The nasal TIA was 41.75°; the temporal TIA; 40.24° [P = .325]. The nasal TISA500 was 0.33 mm²; the temporal TISA500, 0.31 mm² [P = .012]. The nasal TISA750 was 0. 59 mm²; the temporal TISA750, 0.56 mm² [P = .746]. The nasal iris thickness at 2 mm was 483.54 µm; the temporal iris thickness, 505.8 µm [P = .273]. The mean lens vault was -519.58 µm.ConclusionsOur study data depicts the normal anterior segment parameters in healthy Pakistani children.     

Targeting autophagy in colorectal cancer: An update on pharmacological small-molecule compounds

Autophagy, an evolutionarily highly conserved cellular degradation process, plays the Janus role (either cytoprotective or death-promoting) in colorectal cancer, so the targeting of several key autophagic pathways with small-molecule compounds may be a new therapeutic strategy. In this review, we discuss autophagy-associated cell death pathways and key cytoprotective autophagy pathways in colorectal cancer. Moreover, we summarize a series of small-molecule compounds that have the potential to modulate autophagy-associated cell death or cytoprotective autophagy for therapeutic purposes. Taken together, these findings demonstrate the Janus role of autophagy in colorectal cancer, and shed new light on the exploitation of a growing number of small-molecule compounds to target autophagy in future cancer drug discovery.