Interleukin-1β signaling in osteoarthritis – chondrocytes in focus

Osteoarthritis (OA) can be regarded as a chronic, painful and degenerative disease that affects all tissues of a joint and one of the major endpoints being loss of articular cartilage. In most cases, OA is associated with a variable degree of synovial inflammation. A variety of different cell types including chondrocytes, synovial fibroblasts, adipocytes, osteoblasts and osteoclasts as well as stem and immune cells are involved in catabolic and inflammatory processes but also in attempts to counteract the cartilage loss. At the molecular level, these changes are regulated by a complex network of proteolytic enzymes, chemokines and cytokines (for review: [1]). Here, interleukin-1 signaling (IL-1) plays a central role and its effects on the different cell types involved in OA are discussed in this review with a special focus on the chondrocyte.     

Design,synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).     

Remifentanil preconditioning alleviating brain damage of cerebral ischemia reperfusion rats by regulating the JNK signal pathway and TNF-α/TNFR1 signal pathway

Tumor necrosis factor (TNF) and the TNF receptor (TNFR) superfamily play very important roles for cell death as well as normal immune regulation. Previous studies have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in ischemic brain injury. The purpose of this investigation was to examine the protective effect of remifentanil preconditioning in cerebral ischemia/reperfusion injury (CIR) and its possible molecular mechanism. Results showed that Remifentanil pretreatment significantly decreased the CD4⁺ and increased the CD8⁺ in cerebral tissues. Additionally, CD4⁺/CD8⁺ in CIR + Remifentanil group was markedly lower than that in CIR group. TNF-α and TNFR1 in CIR + Remifentanil group rats was found to be significant lower than that in CIR group rats. The expression levels of Cyt-c, caspase-3, caspase-9 and pJNK proteins in brain of CIR + Remifentanil group rats were found to significantly decreased compared to CIR group rats. In addition, decreased ROS level indirectly inhibit JNK activation and cell death in CIR rat receiving Remifentanil preconditioning. From current experiment results, at least two signal pathways involve into the process of Remifentanil preconditioning inhibiting cerebral damage induced by ischemia reperfusion. The inhibitory effects of Remifentanil preconditioning on the brain damage are achieved probably through blocking the activation of TNF-α/TNFR1, JNK signal transduction pathways, which implies that Remifentanil preconditioning may be a potential and effective way for prevention of the ischemic/reperfusion injury through the suppression extrinsic apoptotic signal pathway induced by TNF-α/TNFR1, JNK signal pathways. Taken together, this study indicated that regulation of the TNF-α/TNFR1 and JNK signal pathways may provide a new therapy for cerebral damage induced by ischemia and reperfusion.     

芽孢杆菌dhs-330-021菌粉的制备及稳定性研究

目的:利用喷雾干燥工艺制备芽孢杆菌dhs-330-021菌粉,并研究菌粉的活性及稳定性。方法:以脱脂乳、海藻糖、β-环糊精和谷氨酸钠为保护剂,采用喷雾干燥(条件为:进口温度100℃,出口温度50～60℃,进样速度2～4mL/min)制备芽孢杆菌菌粉,以喷干存活率和菌粉活菌数为指标,选择最佳制备条件。结果:获得喷干保护剂配方为脱脂乳10.0%、海藻糖6.0%、β-环糊精13.0%、谷氨酸钠15.0%,喷干存活率为65.9%,菌粉活菌数为1.38×109CFU/g,存放180 d后菌粉活菌数为1.03×10~9CFU/g。结论:喷雾干燥工艺可以用于芽孢杆菌dhs-330-021菌粉的制备,获得的菌粉稳定性较好。     

Integrated Bioinformatics Analysis of DNA Methylation Biomarkers in Thyroid Cancer Based on TCGA Database

Biochemical Genetics - Previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes in thyroid cancer (TC), but these...     

Intramyocardial injection of hypoxia-preconditioned adipose-derived stromal cells treats acute myocardial infarction: an in vivo study in swine

Hypoxic preconditioning is a promising method for improving the anti-apoptotic and paracrine signaling capabilities of adipose-derived stromal cells (ADSCs). The purpose of this study was to analyze the influence of different hypoxic conditions on ADSCs and the therapeutic effects of hypoxia-preconditioned ADSCs (HPADSCs) on an animal model of myocardial infarction (MI). For the in vitro studies, ADSCs were divided into five groups and cultured in different oxygen concentrations (1, 3, 5, 10, and 21 %). After 24 h, RT-PCR and western blots showed that 3 % oxygen preconditioning could improve the viability and cytokine secretion of the ADSCs. A Matrigel assay indicated that the HPADSC-conditioned medium could stimulate endothelial cells to form capillary-like tubes. For the in vivo studies, MI was induced by coronary occlusion in 24 mature Chinese minipigs. The animals were divided into three groups and treated by intramyocardial injection with vehicle alone (saline group), with 1?×?10⁸ ADSCs cultured in normoxic conditions (ADSCs group) or with 1?×?10⁸ ADSCs precultured in 3 % oxygen (HPADSCs group). SPECT and echocardiography demonstrated that cardiac function was improved significantly in the HPADSC transplant group compared with the vehicle control group (P?P?相似文献   

微RNA抑制物:竞争性内源RNA和人工miRNA吸附物

microRNA(miRNA)是一类细胞内源性的小片段非编码RNA家族,通过与靶基因3′非翻译区(3′untranslated region,3′UTR)结合,对基因表达进行转录后水平的负性调控,参与多种生理和病理学过程。对细胞内成熟体miRNA的功能抑制机制之一是抑制物与miRNA互补结合,从而阻止其与靶基因的结合。这类抑制物主要包括细胞内天然存在的竞争性内源RNA(competing endogenous RNA,ce RNA),以及人工合成或载体表达的外源性miRNA吸附物。本文分别对这两种机制的作用方式进行综述,并对二者的相似点和不同点进行总结。     

The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth

Background

As a serine/threonine protein kinase, p70S6K plays an important role in tumor cells. Evidence has revealed overexpression of p70S6K and phosphorylated p70S6K (p-p70S6K) in various tumor tissues, with these proteins identified as independent prognostic markers in non-small cell lung cancer (NSCLC). In this study, we explored the role of the p70S6K specific inhibitor PF-4708671 in NSCLC.

Methods

Three NSCLC cell lines (A549, SK-MES-1, and NCI-H460) were treated with PF-4708671 at five different concentrations, including 0.1μM, 0.3μM, 1μM, 3μM and 10μM, and protein levels were determined by Western-blot. Then, PF-4708671’s effects were assessed both in vitro (cell proliferation, apoptosis, cell cycle distribution, and invasion) and in vivo.

Results

The expression levels of p-p70S6K and the downstream effector S6 were significantly reduced by PF-4708671. Diametrically opposite, the downstream protein levels of BAD, Caspase3 and ERK had increased after treatment with PF-4708671. In addition, PF-4708671 drastically inhibited cell proliferation and invasion ability in A549, SK-MES-1 and NCI-H460 cells in vitro, causing cell cycle arrest in G0-G1 phase. Limited effects of PF-4708671 were observed on apoptosis in the three NSCLC cell lines assessed. Importantly, PF-4708671 could inhibit tumorigenesis in nude mice in vivo.

Conclusion

These findings demonstrated that the p70S6K specific inhibitor PF-4708671 has inhibitory effects on NSCLC tumorigenesis in vitro and in vivo. Therefore, P70S6K should be considered a new potential therapeutic target, and PF-470867 may be used as targeted drug for cancer treatment.