共轭亚油酸异构体对人类癌细胞增殖的抑制作用研究

目的研究不同共轭亚油酸对人类胃癌细胞AGS、肝癌细胞Bel7402和肠癌细胞Lovo细胞增殖的影响。方法采用体外培养的AGS、Bel7402和Lovo细胞为模型,测定不同处理后活细胞数量。结果研究采用的5种共轭亚油酸异构体都对AGS、Bel7402和Lovo细胞增殖表现出了抑制作用,对AGS的抑制作用要普遍高于对Bel7402和Lovo的抑制作用,并且浓度不同,抑制作用也具有差异。结论五种共轭亚油酸异构体都具有抑制癌细胞增殖的作用,并且这种作用受到共轭亚油酸浓度的影响。     

新疆家蚕抗菌肽诱导人胃癌细胞AGS凋亡的研究

目的探讨新疆家蚕抗菌肽(cecropin XJ)是否通过诱导人胃癌细胞AGS凋亡产生抗肿瘤的作用。方法选择0.01~1 000 mg·L-1浓度范围内的cecropin XJ与人胃癌细胞AGS和人正常胃上皮细胞GES-1共培养24 h,采用MTT法检测cecropin XJ对AGS细胞和GES-1细胞增殖的影响;透射电镜观察细胞超微结构变化;Hoechst染色观察细胞凋亡情况;流式细胞术检测细胞内活性氧和线粒体膜电位的变化;实时荧光定量PCR(qRT-PCR)和Western blot检测Bax、Bcl-2、caspase-3以及细胞色素C mRNA和蛋白水平的表达变化。结果 Cecropin XJ在体外能明显抑制胃癌AGS细胞的增殖(P<0.05),并具有浓度依赖性,IC50值为61.19 mg·L-1,但对GES-1细胞无明显的抑制增殖作用。经cecropin XJ处理24 h后,AGS细胞核固缩,呈现典型细胞凋亡特征,同时细胞内活性氧增加,线粒体膜电位下降。qRT-PCR和Western blot结果表明,cecropin XJ能够引起Bcl-2表达下调,Bax表达上调,促进细胞色素C的释放并活化caspase-3。Cecropin XJ促进caspase-3活性呈剂量依赖,经caspase-3和caspase-9特异性抑制剂处理后可降低cecropin XJ介导的AGS细胞死亡率。结论 Cecropin XJ可通过下调Bcl-2表达,上调Bax表达和活化caspase-3诱导AGS细胞凋亡,是其抗肿瘤机制之一。     

Synonymous Mutations in RNASEH2A Create Cryptic Splice Sites Impairing RNase H2 Enzyme Function in Aicardi–Goutières Syndrome

Aicardi–Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full‐length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.     

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.     

Investigational therapies targeting CD37 for the treatment of B-cell lymphoid malignancies

Introduction: While chemotherapy still remains a cornerstone of oncologic therapy, immunotherapy with monoclonal antibodies has steadily improved the treatment strategy for several hematologic malignancies. New treatment options need to be developed for relapsed and refractory non-Hodgkin lymphoma (NHL) patients. Currently, novel agents targeting specific molecules on the surface of lymphoma cells, such as anti-CD37 antibodies, are under considerable investigation. Here we report on anti-CD37 targeting for the treatment of patients with B-cell NHL.

Areas covered: CD37 seems to be the perfect therapeutic target in patients with NHL. The CD37 antigen is abundantly expressed in B-cells, but is absent on normal stem cells and plasma cells. It is hoped that anti-CD37 monoclonal antibodies will increase the efficacy and reduce toxicity in patients with both newly diagnosed and relapsed and refractory disease. Recent clinical trials have shown promising outcomes for these agents, administered both as monotherapy and in combination with standard chemotherapeutics.

Expert opinion: The development of new therapeutic options might help to avoid cytotoxic chemotherapy entirely in some clinical settings. This article presents the latest state of the art on the new treatment strategies in NHL patients. It also discusses recently approved agents and available clinical trial data.