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1. chinaXiv:201605.01740 [pdf]

Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer

Zhang, Bo; Wei, Peng; Hao, Junfeng; Zhao, Lijing; Zhang, Fenglin; Wei, Taotao; Wang, Jing; Huang, Zhen; Wei, Peng; Liu, Ying; Tu, Yaping
Subjects: Biology >> Biophysics >> Oncology

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is abnormally expressed in many cancers. In this study, we showed that TRAP1 is aberrantly upregulated in breast tumors compared to control tissues. TRAP1 knockdown downregulates mitochondrial aerobic respiratory, sensitizes cells to lethal stimuli, and inhibited tumor growth in MDA-MB-231 and MCF-7 breast cancer cells in vivo. TRAP1 overexpression, however, enhances the capacity to cope with stress conditions. These evidences suggested that TRAP1 is required for tumorigenesis. We also found that TRAP1 regulates the mitochondrial morphology. Relatively lower TRAP1 levels are associated with the rod-shaped mitochondrial phenotype in invasive and metastatic MDA-MB-231 breast cancer cells; on the contrary, higher TRAP1 levels are associated with the tubular network-shaped mitochondrial phenotype in non-invasive MCF-7 cells. Interestingly, the expression of TRAP1 in human breast cancer specimens inversely correlates with tumor grade. Overexpression of TRAP1 in MDA-MB-231 cells causes mitochondrial fusion, triggers mitochondria to form tubular networks, and suppresses cell migration and invasion in vitro and in vivo. These data link TRAP1-regulated mitochondrial dynamics and function with tumorigenesis of breast cancer and suggested that TRAP1 may therefore be a potential target for breast cancer drug development.

submitted time 2016-05-15 Hits3573Downloads1313 Comment 0

2. chinaXiv:201605.01518 [pdf]

Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells

Cao, Wei; Zhang, Ran; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Huang, Laiqiang; Cao, Wei; Liu, Ying; Zhang, Ran; Wang, Teng; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Huang, Laiqiang; Cao, Wei; Liu, Ying; Zhang, Ran; Wang, Teng
Subjects: Biology >> Biophysics

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia, on Gefitinib-resistant NSCLC cell lines in vitro and in vivo. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGF beta signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo. Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.

submitted time 2016-05-12 Hits1752Downloads893 Comment 0

3. chinaXiv:201605.01517 [pdf]

Ribosylation triggering Alzheimer's disease-like Tau hyperphosphorylation via activation of CaMKII

Wei, Yan; Han, Chanshuai; Wang, Yujing; Wu, Beibei; Su, Tao; Liu, Ying; He, Rongqiao; Wang, Yujing; Wu, Beibei; Liu, Ying; He, Rongqiao
Subjects: Biology >> Biophysics >> Cell Biology

Type 2 diabetes mellitus (T2DM) is regarded as one of the serious risk factors for age-related cognitive impairment; however, a causal link between these two diseases has so far not been established. It was recently discovered that, apart from high D-glucose levels, T2DM patients also display abnormally high concentrations of uric D-ribose. Here, we show for the first time that the administration of D-ribose, the most active glycator among monosaccharides, produces high levels of advanced glycation end products (AGEs) and, importantly, triggers hyperphosphorylation of Tau in the brain of C57BL/6 mouse and neuroblastoma N2a cells. However, the administration of D-glucose showed no significant changes in Tau phosphorylation under the same experimental conditions. Crucially, suppression of AGE formation using an AGEs inhibitor (aminoguanidine) effectively prevents hyperphosphorylation of Tau protein. Further study shows AGEs resulted from ribosylation activate calcium-/calmodulin-dependent protein kinase type II (CaMKII), a key kinase responsible for Tau hyperphosphorylation. These data suggest that there is indeed a mechanistic link between ribosylation and Tau hyperphosphorylation. Targeting ribosylation by inhibiting AGE formation may be a promising therapeutic strategy to prevent Alzheimer's disease-like Tau hyperphosphorylation and diabetic encephalopathies.

submitted time 2016-05-12 Hits2213Downloads1325 Comment 0

4. chinaXiv:201605.01383 [pdf]

Novelty seeking is related to individual risk preference and brain activation associated with risk prediction during decision making

Wang, Ying; Yang, Lizhuang; Gu, Feng; Li, Xiaoming; Zha, Rujing; Wei, Zhengde; Pei, Yakun; Zhou, Yifeng; Zhang, Xiaochu; Wang, Ying; Yang, Lizhuang; Gu, Feng; Li, Xiaoming; Zha, Rujing; Wei, Zhengde; Pei, Yakun; Zhou, Yifeng; Zhang, Xiaochu; Liu, Ying; Li, Xiaoming
Subjects: Biology >> Biophysics

Novelty seeking (NS) is a personality trait reflecting excitement in response to novel stimuli. High NS is usually a predictor of risky behaviour such as drug abuse. However, the relationships between NS and risk-related cognitive processes, including individual risk preference and the brain activation associated with risk prediction, remain elusive. In this fMRI study, participants completed the Tridimensional Personality Questionnaire to measure NS and performed a probabilistic decision making task. Using a mathematical model, we estimated individual risk preference. Brain regions associated with risk prediction were determined via fMRI. The NS score showed a positive correlation with risk preference and a negative correlation with the activation elicited by risk prediction in the right posterior insula (r-PI), left anterior insula (l-AI), right striatum (r-striatum) and supplementary motor area (SMA). Within these brain regions, only the activation associated with risk prediction in the r-PI showed a correlation with NS after controlling for the effect of risk preference. Resting-state functional connectivity between the r-PI and r-striatum/l-AI was negatively correlated with NS. Our results suggest that high NS may be associated with less aversion to risk and that the r-PI plays an important role in relating risk prediction to NS.

submitted time 2016-05-12 Hits1116Downloads602 Comment 0

5. chinaXiv:201605.01317 [pdf]

Gavage of D-Ribose induces A beta-like deposits, Tau hyperphosphorylation as well as memory loss and anxiety-like behavior in mice

Wu, Beibei; Wei, Yan; Wang, Yujing; Su, Tao; Liu, Ying; He, Rongqiao; He, Rongqiao; He, Rongqiao; Wu, Beibei; Wang, Yujing; Zhou, Lei
Subjects: Biology >> Biophysics >> Oncology

In addition to D-Glucose, D-Ribose is also abnormally elevated in the urine of type 2 diabetic patients, establishing a positive correlation between the concentration of uric D-Ribose and the severity of diabetes. Intraperitoneal injection of D-Ribose causes memory loss and brain inflammation in mice. To simulate a chronic progression of age-related cognitive impairment, we orally administered D-Ribose by gavage at both a low and high dose to 8 week-old male C57BL/6J mice daily for a total of 6 months, followed by behavioral, histological and biochemical analysis. We found that long-term oral administration of D-Ribose impairs spatial learning and memory, accompanied by anxiety-like behavior. Tau was hyperphosphorylated at AT8, S396, S214 and T181 in the brain. A beta-like deposition was also found in the hippocampus for the high dose group. D-Glucose-gavaged mice did not show significant memory loss and anxiety-like behavior under the same experimental conditions. These results demonstrate that a long-term oral administration of D-Ribose not only induces memory loss with anxiety-like behavior, but also elevates A beta-like deposition and Tau hyperphosphorylation, presenting D-Ribose-gavaged mouse as a model for agerelated cognitive impairment and diabetic encephalopathy.

submitted time 2016-05-11 Hits3128Downloads1070 Comment 0

6. chinaXiv:201605.01305 [pdf]

Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer's disease

Tong, Zhiqian; Han, Chanshuai; Qiang, Min; Wu, Beibei; Su, Tao; Liu, Ying; He, Rongqiao; Tong, Zhiqian; Wang, Xiaomin; He, Rongqiao; Han, Chanshuai; Qiang, Min; Wu, Beibei; Su, Tao; Wang, Weishan; Lv, Jihui; Zhang, Shouzi; Luo, Wenhong; Li, Hui; Luo, Hongjun
Subjects: Biology >> Biophysics

Hippocampus-related topographic amnesia is the most common symptom of memory disorders in Alzheimer's disease (AD) patients. Recent studies have revealed that experience-mediated DNA methylation, which is regulated by enzymes with DNA methyltransferase (DNMT) activity, is required for the formation of recent memory as well as the maintenance of remote memory. Notably, overexpression of DNMT3a in the hippocampus can reverse spatial memory deficits in aged mice. However, a decline in global DNA methylation was found in the autopsied hippocampi of patients with AD. Exactly, what endogenous factors that affect DNA methylation still remain to be elucidated. Here, we report a marked increase in endogenous formaldehyde levels is associated with a decline in global DNA methylation in the autopsied hippocampus from AD patients. In vitro and in vivo results show that formaldehyde in excess of normal physiological levels reduced global DNA methylation by interfering DNMTs. Interestingly, intrahippocampal injection of excess formaldehyde before spatial learning in healthy adult rats can mimic the learning difficulty of early stage of AD. Moreover, injection of excess formaldehyde after spatial learning can mimic the loss of remote spatial memory observed in late stage of AD. These findings suggest that aging-associated formaldehyde contributes to topographic amnesia in AD patients. (C) 2015 Elsevier Inc. All rights reserved.

submitted time 2016-05-11 Hits1586Downloads980 Comment 0

7. chinaXiv:201605.01253 [pdf]

Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

Zhai, Yangyang; Zhao, Xiangshuai; Cui, Zhengjie; Wang, Man; Li, Linfeng; Yang, Xi; Zeng, Debin; Liu, Ying; Shang, Luqing; Yin, Zheng; Zhai, Yangyang; Zhao, Xiangshuai; Cui, Zhengjie; Wang, Man; Li, Linfeng; Yang, Xi; Zeng, Debin; Liu, Ying; Shang, Luqing; Yin, Zheng
Subjects: Biology >> Biophysics

Cyanohydrin derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. Compared with the reported inhibitors, cyanohydrins (1S,2S,2'S,5S)-16 and (1R,2S,2'S,5S)-16 exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3C(pro). Cyanohydrin as an anchoring group with high selectivity and excellent inhibitory activity represents a useful choice for cysteine protease inhibitors.

submitted time 2016-05-11 Hits1292Downloads751 Comment 0

8. chinaXiv:201605.01224 [pdf]

Dorsoventral patterning of the Xenopus eye involves differential temporal changes in the response of optic stalk and retinal progenitors to Hh signalling

Wang, Xiumei; He, Rongqiao; Liu, Ying; Lupo, Giuseppe; Harris, William A.; Lupo, Giuseppe; Barsacchi, Giuseppina
Subjects: Biology >> Biophysics >> Developmental Biology

Background: Hedgehog (Hh) signals are instrumental to the dorsoventral patterning of the vertebrate eye, promoting optic stalk and ventral retinal fates and repressing dorsal retinal identity. There has been limited analysis, however, of the critical window during which Hh molecules control eye polarity and of the temporal changes in the responsiveness of eye cells to these signals. Results: In this study, we used pharmacological and molecular tools to perform stage-specific manipulations of Hh signalling in the developing Xenopus eye. In gain-of-function experiments, most of the eye was sensitive to ventralization when the Hh pathway was activated starting from gastrula/neurula stages. During optic vesicle stages, the dorsal eye became resistant to Hh-dependent ventralization, but this pathway could partially upregulate optic stalk markers within the retina. In loss-of-function assays, inhibition of Hh signalling starting from neurula stages caused expansion of the dorsal retina at the expense of the ventral retina and the optic stalk, while the effects of Hh inhibition during optic vesicle stages were limited to the reduction of optic stalk size. Conclusions: Our results suggest the existence of two competence windows during which the Hh pathway differentially controls patterning of the eye region. In the first window, between the neural plate and the optic vesicle stages, Hh signalling exerts a global influence on eye dorsoventral polarity, contributing to the specification of optic stalk, ventral retina and dorsal retinal domains. In the second window, between optic vesicle and optic cup stages, this pathway plays a more limited role in the maintenance of the optic stalk domain. We speculate that this temporal regulation is important to coordinate dorsoventral patterning with morphogenesis and differentiation processes during eye development.

submitted time 2016-05-11 Hits1857Downloads1043 Comment 0

9. chinaXiv:201605.00746 [pdf]

Resting-state functional connectivity between the dorsal anterior cingulate cortex and thalamus is associated with risky decision-making in nicotine addicts

Wei, Zhengde; Yang, Nannan; Yang, Lizhuang; Wang, Ying; Han, Long; Zha, Rujing; Huang, Ruiqi; Zhou, Yifeng; Liu, Ying; Zhang, Peng; Zhang, Xiaochu; Zhang, Xiaochu; Zhang, Xiaochu;
Subjects: Biology >> Biophysics

Nicotine addiction is associated with risky behaviors and abnormalities in local brain areas related to risky decision-making such as the dorsal anterior cingulate cortex (dACC), anterior insula (AI), and thalamus. Although these brain abnormalities are anatomically separated, they may in fact belong to one neural network. However, it is unclear whether circuit-level abnormalities lead to risky decision-making in smokers. In the current study, we used task-based functional magnetic resonance imaging (fMRI) and examined resting-state functional connectivity (RSFC) to study how connectivity between the dACC, insula, and thalamus influence risky decision-making in nicotine addicts. We found that an increase in risky decision-making was associated with stronger nicotine dependence and stronger RSFC of the dACC-rAI (right AI), the dACC-thalamus, the dACC-lAI (left AI), and the rAI-lAI, but that risky decision-making was not associated with risk level-related activation. Furthermore, the severity of nicotine dependence positively correlated with RSFC of the dACC-thalamus but was not associated with risk level-related activation. Importantly, the dACC-thalamus coupling fully mediated the effect of nicotine-dependent severity on risky decision-making. These results suggest that circuit-level connectivity may be a critical neural link between risky decision-making and severity of nicotine dependence in smokers.

submitted time 2016-05-05 Hits1019Downloads529 Comment 0

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