CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Non‐melanoma skin cancer frequently results from chronic exposure to ultraviolet (UV) irradiation. UV‐induced DNA damage activates cell cycle arrest checkpoints through degradation of the cyclin‐dependent kinase activators, the cell division cycle 25 (CDC25) phosphatases. We previously reported increased CDC25A in nonmelanoma skin cancer, but CDC25B and CDC25C had not been previously examined. Consequently, we hypothesized that increased expression of CDC25B and CDC25C increases tumor cell proliferation and skin tumor growth. We found that CDC25B and CDC25C were increased in mouse and human skin cancers. CDC25B was primarily cytoplasmic in skin and skin tumors and was significantly increased in the squamous cell carcinoma (SCC), while CDC25C was mostly nuclear in the skin, with an increased cytoplasmic signal in the premalignant and malignant tumors. Surprisingly, forced expression of CDC25B or CDC25C in cultured SCC cells did not affect proliferation, but instead suppressed apoptosis, while CDC25C silencing increased apoptosis without impacting proliferation. Targeting CDC25C to the nucleus via mutation of its nuclear export sequence, however, increased proliferation in SCC cells. Overexpression of CDC25C in the nuclear compartment did not hinder the ability of CDC25C to suppress apoptosis, neither did mutation of sites necessary for its interaction with 14‐3‐3 proteins. Analysis of apoptotic signaling pathways revealed that CDC25C increased activating phosphorylation of Akt on Ser⁴⁷³, increased inhibitory phosphorylation of proapoptotic BAD on Ser¹³⁶, and increased the survival protein Survivin. Silencing of CDC25C significantly reduced Survivin levels. Taken together, these data suggest that increased expression of CDC25B or CDC25C are mechanisms by which skin cancers evade apoptotic cell death.     

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.     

中药抗乙肝病毒活性及作用机制的研究进展

乙肝病毒是一种能导致机体产生急性或慢性乙型肝炎（乙肝）的嗜肝性DNA病毒。乙肝现已成为全球性公共卫生疾病，易恶化发展为肝硬化、肝衰竭，甚至肝癌，严重威胁着人类的健康。中药及其活性成分发挥着重要的抗乙肝病毒活性，对中药抗乙肝病毒活性及其作用机制进行综述，以期为今后抗乙肝病毒研究提供一定的参考。     

葫芦素B固体分散体的制备

目的制备葫芦素B固体分散体。方法溶剂法制备固体分散体后,以溶出度为评价指标筛选药物-载体(PVP K30)比例。扫描电子显微镜(SEM)、傅里叶变换红外光谱(FTIR)、差示扫描量热(DSC)、X射线衍射(XRD)进行表征。结果药载比为1∶11时,60 min内溶出度为62.01%。葫芦素B可能以无定形状态分散于载体中。结论该方法简便可行,葫芦素B制成固体分散体后体外溶出度明显提高。     

下调FAM111B对乳腺癌细胞增殖和凋亡的影响

目的:探讨下调FAM111B对乳腺癌细胞系MDA-MB-231和MCF7细胞增殖和凋亡的影响及其机制。方法:构建siR-FAM111B慢病毒载体,转染乳腺癌MDA-MB-231和MCF7细胞,qRT-PCR检查转染组与对照组FAM111B mRNA表达,Western blotting法检测各组细胞FAM111B蛋白表达。用CCK-8法检测细胞的增殖能力。流式细胞术检测Annexin-V/PI双染各组细胞的凋亡情况。Western blotting法检测凋亡相关蛋白Bax和Bcl-2的表达。结果:siR-FAM111B成功转染MDA-MB-231和MCF7细胞,转染后应用qRT-PCR和Western blotting检测,结果显示,FAM111B mRNA与蛋白水平均下调。siR-FAM111B能抑制两种细胞的增殖。Annexin-V/PI双染结果显示,下调FAM111B诱导两种细胞凋亡。Western blotting结果显示,下调FAM111B可以促进两种细胞Bax的表达,抑制Bcl-2的表达。结论:下调FAM111B能够抑制乳腺癌细胞的增殖,通过调节线粒体凋亡通路诱导细胞凋亡。     

乙肝肝硬化肝胆湿热及肝肾阴虚证物质基础研究＊

目的 运用代谢组学技术分析乙肝肝硬化患者肝肾阴虚及肝胆湿热两种典型证候（同病异证）的血清差异代谢产物及其代谢通路，探寻虚、实两种典型证候的内在物质基础，以期从代谢水平上为中医证候分类提供客观依据。方法 对符合纳入标准的111例不同证候的乙肝肝硬化患者（肝胆湿热证40例，肝肾阴虚证41例，隐证(无证可辨）者30例）中医症状及体征进行描述性分析，发现两种不同证型的临床信息分布规律及证候特征；采用气相色谱-飞行时间质谱联用（GC-TOF/MS）技术对乙肝肝硬化患者，以及与之相匹配的60例健康人的血清样本进行检测，经非监督的主成分分析（Principal Components Analysis，PCA）、有监督的偏最小二乘判别分析（Partial Least Square Discriminant Analysis，PLS-DA）及监督的正交偏最小二乘法（Orthogonal Partial Least SquareDiscriminant Analysis，OPLS-DA）分析，找出与乙肝肝硬化疾病本身及其两种典型证候相关的差异性物质；运用MetaboAnalyst 3.0数据库，寻找并解析肝胆湿热及肝肾阴虚虚实两种证候间差异性物质的相关代谢通路。结果 （1）肝胆湿热证中出现频率较高（50%以上）的症状为小便色黄，口干，口苦，口臭或有异味等。肝肾阴虚证中出现频率较高的症状为口干、腰酸、乏力、腿软等。两证共见症/征为口干、尿黄、易怒、舌红。（2）各组间丙氨酸氨基转移酶（Alanine Aminotransferase,ALT）数值无统计学差异（P > 0.05）；与健康组比较，隐证组中白蛋白（Albumin，ALB），肝胆湿热证中总胆红素（Total Bilirubin，TBil）、直接胆红素（Direct Bilirubin，DBil）、谷草转氨酶（Aspartate Transaminase，AST）、碱性磷酸酶（Alkaline Phosphatase，ALP）、谷氨酰转肽酶（Gamma-Glutamyl Transpeptidase，GGT）、总胆汁酸（Total Biliary Acid，TBA）及ALB，肝肾阴虚证TBil、ALP、GGT、TBA、ALB值差异均有统计学意义（P < 0.05）；与隐证比较，肝胆湿热证TBil、DBil、AST、ALP、TBA、ALB，肝肾阴虚证TBA、ALB差异有统计学意义（P < 0.05）；肝胆湿热证与肝肾阴虚证相比，TBil、DBil差异有统计学意义（P < 0.05）。（3）代谢组学检测及代谢通路分析，发现各组之间代谢谱均有良好的区分，并获得各组间的差异性物质。发现肝胆湿热及肝肾阴虚两典型证的共同物质10个，去除疾病（隐证）的信息，则得到两证共同物质6个，涉及的代谢通路为甘氨酸、丝氨酸及苏氨酸代谢和苯丙氨酸代谢；同时，分别获得两证各自特异性的代谢物质各8个，分别涉及亚油酸代谢和甘氨酸、苏氨酸及丝氨酸代谢。结论 运用代谢组学技术，发现肝胆湿热及肝肾阴虚不同证之间既存在病的共同物质（同病），也存在证的差异物质（异证），从而在代谢层面上为中医证候分类的科学性提供科学依据。     

Inhibition of PI3K/Akt/NF-κB signaling by Aloin for ameliorating the progression of osteoarthritis: In vitro and in vivo studies

Osteoarthritis (OA) is a progressive and degenerative joint disease. Aloin is a bitter and yellow-brown-coloured compound from the Aloe plant and is allowed for use in foods as a “natural flavour”. In our study, we examined the protective effects of Aloin on the inhibition of OA development as well as its underlying mechanism in both in vitro and vivo experiments. In in-vitro experiments, the protective effect of aloin on the anabolism and catabolism of the extracellular matrix (ECM) induced by IL-1 β in chondrocytes by inhibiting the expression of pro-inflammatory factors, including TNF-α (p = 0.016), IL-6 (p = 0.006), iNOS (p = 0.001) and COX-2 (p = 0.006). Mechanistically, Aloin suppressed the IL-1β-induced activation of the PI3K/Akt/NF-κB signalling pathway cascades. Moreover, molecular docking studies demonstrated that Aloin bound strongly to PI3K. In vivo, Aloin ameliorated the OA process in the destabilization of the medial meniscus (DMM) model.In summary, our findings demonstrate that Aloin ameliorates the progression of OA via the PI3K/Akt/NF-κB signalling pathways, which supports Aloin as a promising therapeutic agent for the treatment of OA.     

PELP1 signaling contributes to medulloblastoma progression by regulating the NF-κB pathway

Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown. The objective of this study is to examine the role of PELP1 in the progression of MB. Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in the MB specimens compared to normal brain. Knockdown of PELP1 reduced cell proliferation, cell survival, and cell invasion of MB cell lines. The RNA-sequencing analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation and extracellular matrix. Gene set enrichment analysis confirmed that the PELP1-regulated genes were negatively correlated with nuclear factor-κB (NF-κB), extracellular matrix, and angiogenesis gene sets. Interestingly, PELP1 knockdown reduced the expression of NF-κB target genes, NF-κB reporter activity, and inhibited the nuclear translocation of p65. Importantly, the knockdown of PELP1 significantly reduced in vivo MB progression in orthotopic models and improved the overall mice survival. Collectively, these results suggest that PELP1 could be a novel target for therapeutic intervention in MB.     

B cell and B cell-related pathways for novel cancer treatments

B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, −21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies.     

维生素B12和叶酸干预对绝经后骨质疏松症妇女的骨代谢及同型半胱氨酸水平的影响

目的观察叶酸和维生素B12对绝经后骨质疏松症妇女的骨代谢及同型半胱氨酸水平的影响。方法 80例绝经后骨质疏松症妇女参加研究。所有参与者随机接受叶酸和维生素B12(n=40)或安慰剂(n=40)治疗。在干预前的基线及干预后3个月和6个月,测量两组患者血清同型半胱氨酸、维生素B12和骨代谢标志物的水平。结果治疗前,两组患者血清同型半胱氨酸、维生素B12和骨代谢标志物水平比较差异无统计学意义(P0.05)。治疗后,两组患者同型半胱氨酸均下降,但比较差异无统计学意义(P0.05)。6个月后各组间血清维生素B12、骨钙素、CTX的变化均有显著改变且差异有统计学意义(P0.05)。结论绝经后骨质疏松症妇女补充叶酸和维生素B12可以一定程度改善同型半胱氨酸及骨代谢指标水平。