HN1L promotes migration and invasion of breast cancer by up-regulating the expression of HMGB1

Recent reports showed that haematological and neurological expressed 1-like (HN1L) gene participated in tumorigenesis and tumour invasion. However, the expression and role of HN1L in breast cancer remain to be investigated. Here, bioinformatics, western blot and immunohistochemistry were used to detect the expression of HN1L in breast cancer. Wound healing, transwell assay, immunofluorescence assay and mass spectrum were used to explore the role and mechanism of HN1L on the migration and invasion of breast cancer, which was confirmed in vivo using a nude mice model. Results showed that HN1L was significantly over-expressed in breast cancer tissues, which was positively correlated with M metastasis of breast cancer patients. Silencing HN1L significantly inhibited the invasion and metastasis of breast cancer cells in vitro and lung metastasis in nude mice metastasis model of breast cancer. Mechanistically, HN1L interacted with HSPA9 and affected the expression of HMGB1, playing a key role in promoting the invasion and metastasis of breast cancer cell. These results suggested that HN1L was an appealing drug target for breast cancer.     

FAM96A和FAM96B结构与功能的研究进展

96序列相似的家庭成员A和B（family with sequence similarity 96 member A and B,FAM96A和FAM96B）是属于MIP18（MMS19-interacting protein of 18 kD）家族的2个高度保守的同源蛋白,MIP18是与有丝分裂纺锤体相关的MMDX（MMS19-MIP18-XPD）复合体的亚基。研究表明,FAM96A和FAM96B在人胃肠道间质瘤、结肠癌、肝癌、胃癌和乳腺癌等多种肿瘤组织中的表达显著降低,提示其可能是作为潜在的抑癌基因参与肿瘤的发生发展,但目前关于FAM96A和FAM96B在肿瘤发生发展过程中的作用机理并不十分清楚。此外,研究发现FAM96A和FAM96B可通过与其他不同的蛋白质相互作用在体内发挥多种不同的功能。因此,就目前对于FAM96A和FAM96B结构和功能的研究所取得的进展进行了回顾与总结,并对其在肿瘤发生发展中的分子机制和相互作用蛋白鉴定的研究前景进行了展望,以期为临床上将FAM96A和FAM96B作为新的肿瘤诊断标志物和治疗靶点奠定基础,并为揭示二者在体内更多的新功能提供依据。     

Design,synthesis and biological evaluation of novel 1H-1,2,4-triazole,benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Abstract

Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC₅₀ = 15.0?nM) and modest anti-proliferative activity (IC₅₀ = 785.8?nM). Through two rounds of optimisation, the indazole derivative 9?u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC₅₀ = 3.3?nM) and cellular activity (IC₅₀ = 468.2?nM). Moreover, 9?u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.     

Leptin modulates lymphocytes' adherence to hepatic stellate cells is associated with oxidative status alterations

We investigated leptin effects on lymphocyte interactions with hepatic-stellate-cells (HSCs). Leptin showed pro-fibrotic effects on HSCs with oxidative status imbalance.In co-cultures, leptin activates HSCs and consequently adhered HCV-lymphocytes more than healthy ones. Leptin also increased healthy and HCV lymphocyte proliferations; increased their reactive-oxygen-species; decreased antioxidants (reduced-glutathione) levels while inhibited apoptosis only of HCV-lymphocytes. The leptin-treated HCV-lymphocytes activated HSCs, increase interleukin-4 while decreased their apoptosis.Leptin-receptor-deficient (db–db)-HSCs did not adhere lymphocytes. db/db-lymphocytes however showed fewer adherences to HSCs when compared to WT-counterparts.This study presents immune and oxidative modulatory effects of leptin on lymphocytes and their consequent interaction with HSCs.     

Calpain activation mediates microgravity-induced myocardial abnormalities in mice via p38 and ERK1/2 MAPK pathways

The human cardiovascular system has adapted to function optimally in Earth''s 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47^phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47^phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47^phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47^phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.     

Distribution of short neuropeptide F and its receptor in neuronal circuits related to feeding in larval Drosophila

Four forms of short neuropeptide F (sNPF1–4), derived from the gene snpf, have been identified in Drosophila and are known to act on a single G-protein-coupled receptor (sNPFR). Several functions have been suggested for sNPFs in Drosophila, including the regulation of feeding and growth in larvae, the control of insulin signalling and the modulation of neuronal circuits in adult flies. Furthermore, sNPF has been shown to act as a nutritional state-dependent neuromodulator in the olfactory system. The role of sNPF in the larval nervous system is less well known. To analyse sites of action of sNPF in the larva, we mapped the distribution of sNPF- and sNPFR-expressing neurons. In particular, we studied circuits associated with chemosensory inputs and systems involved in the regulation of feeding, including neurosecretory cell systems and the hypocerebral ganglion. We employed a combination of immunocytochemistry and enhancer trap and promoter Gal4 lines to drive green fluorescent protein. We found a good match between the distribution of the receptor and its ligand. However, several differences between the larval and adult systems were observed. Thus, neither sNPF nor its receptor was found in the olfactory (or other sensory) systems in the larva and cells producing insulin-like peptides did not co-express sNPFR, as opposed to results from adults. Moreover, sNPF was expressed in a subpopulation of Hugin cells (second-order gustatory neurons) only in adult flies. We propose that the differences in sNPF signalling between the developmental stages is explained by differences in their feeding behaviour.