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Meysam Gachpazan, Hoda Kashani, Majid Khazaei, Seyed Mahdi Hassanian, Majid Rezayi, Fereshteh Asgharzadeh Yazdi, Majid Ghayour-Mobarhan, Gordon A Ferns, Amir Avan
Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that may play an important role in the evolution of cancers, due to their effects on cancer cell metabolism. Statins effect several potential pathways, including: cell proliferation, angiogenesis, apoptosis and metastasis. The number of trials assessing the putative clinical benefits of statins in cancer is increasing. Currently, there are several trials listed on the global trial identifier website Given the compelling evidence from these trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant gastrointestinal cancer setting...
December 11, 2018: Current Drug Targets
Shana Claeys, Geertrui Denecker, Kaat Durinck, Bieke Decaesteker, Liselot M Mus, Siebe Loontiens, Suzanne Vanhauwaert, Kristina Althoff, Caroline Wigerup, Daniel Bexell, Emmy Dolman, Kai-Oliver Henrich, Lea Wehrmann, Ellen M Westerhout, Jean-Baptiste Demoulin, Candy Kumps, Tom Van Maerken, Genevieve Laureys, Christophe Van Neste, Bram De Wilde, Olivier De Wever, Frank Westermann, Rogier Versteeg, Jan J Molenaar, Sven Påhlman, Johannes H Schulte, Katleen De Preter, Frank Speleman
ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the 'HMG-box transcription factor 1' (HBP1) through the PI3 K-AKT-FOXO3a signaling axis...
December 11, 2018: Oncogene
Daniel T Thwaites, Clive Carter, Dylan Lawless, Sinisa Savic, Joan M Boyes
The Recombination Activating Genes, RAG1 and RAG2, are essential for V(D)J recombination and adaptive immunity. Mutations in these genes often cause immunodeficiency, the severity of which reflects the importance of the altered residue(s) during recombination. Here, we describe a novel RAG1 mutation that causes immunodeficiency in an unexpected way: The mutated protein severely disrupts binding of the accessory protein, HMGB1. Although HMGB1 enhances RAG cutting in vitro, its role in vivo was controversial...
December 11, 2018: Blood
Anjana Bhardwaj, Harpreet Singh, Celestine Marie Trinidad, Constance T Albarracin, Kelly K Hunt, Isabelle Bedrosian
BACKGROUND: Prevention of triple-negative breast cancer (TNBC) is hampered by lack of knowledge about the drivers of tumorigenesis. METHODS: To identify molecular markers and their downstream networks that can potentially be targeted for TNBC prevention, we analyzed small RNA and RNA sequencing of a cell line model that represent early stages of TNBC development. We have identified direct gene targets of isomiRNA-140-3p and by using cell-based and in vivo model systems we have demonstrated the utility of targeting downstream pathways for prevention of TNBC...
December 11, 2018: Breast Cancer Research: BCR
Mary E Rinella, James F Trotter, Manal F Abdelmalek, Angelo H Paredes, Margery A Connelly, Mark J Jaros, Lei Ling, Stephen J Rossi, Alex M DePaoli, Stephen A Harrison
BACKGROUND: NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with nonalcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol to bile acids. Here, we investigate whether administration of a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor can manage the cholesterol increase seen in NASH patients treated with NGM282...
December 7, 2018: Journal of Hepatology
Won Ho Kim, Chi-Ho Lee, Jung-Hwa Han, Sujin Kim, Seong Yong Kim, Jae Hyang Lim, Kwon Moo Park, Duk Seop Shin, Chang-Hoon Woo
It has been well established that HMG-CoA reductase inhibitors (statins) cause adverse side effects in skeletal muscle ranging from mild to fatal myotoxicity upon dose, drug interaction, and exercise. However, the underlying mechanisms by which statins induce myotoxicity have not been fully addressed. Recent reports showed that statins induce endoplasmic reticulum (ER) stress and cell death in immune cells and myoblasts in vitro. Therefore, the goal of study is to investigate the molecular mechanism by which statins induce skeletal muscle cell death and myopathy via the regulation of ER stress...
December 7, 2018: Biochemical and Biophysical Research Communications
Haosheng Ni, Tingting Ni, Jia Feng, Tingting Bian, Yifei Liu, Jianguo Zhang
Spondin-2, belongs to the SOX (SRY-related HMG box) gene family, plays a vital role in the development of malignancy, however, the role of Spondin-2 in laryngeal squamous cell carcinoma (LSCC) remains unknown. The aim of this study is to investigate the prognostic significance of and probable mechanism of Spondin-2 in LSCC. qRT-PCR, western blotting assays and IHC analysis demonstrated that Spondin-2 was significantly increased in LSCC tissues compared with adjacent non-tumorous tissues. In addition, high levels of Spondin-2 was associated with clinical stage, lymph node metastasis and pathology grade of LSCC patients (P <0...
November 29, 2018: Pathology, Research and Practice
Chuntai Wu, Li Lan, Yu Li, Zhiyi Nie, Rizhong Zeng
BACKGROUND: Expression patterns of many laticifer-specific gens are closely correlative with rubber yield of Hevea brasiliensis (para rubber tree). To unveil the mechanisms underlying the rubber yield, transcript levels of nine major latex metabolism-related genes, i.e., HMG-CoA synthase (HMGS), HMG-CoA reductase (HMGR), diphosphomevalonate decarboxylase (PMD), farnesyl diphosphate synthase (FPS), cis-prenyltransferase (CPT), rubber elongation factor (REF), small rubber particle protein (SRPP), dihydroxyacid dehydratase (DHAD) and actin depolymerizing factor (ADF), were dertermined, and the relationship between rubber yield with their expression levels was analysed...
December 10, 2018: BMC Genomics
Gila Pirzad Jahromi, Alireza P Shabanzadeh, Mina Mokhtari Hashtjini, Seyed Shahabeddin Sadr, Javad Rasouli Vani, Javad Raouf Sarshoori, Jason Charish
Objectives: The beneficial outcomes of bone marrow-derived mesenchymal stem cell (BMSC) treatment on functional recovery following stroke has been well established. Furthermore, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have also been shown to increase neuronal survival and promote the movement of BMSCs towards the sites of inflammation. However, the precise mechanisms mediating the improved neurological functional recovery in stoke models following a combination treatment of Simvastatin and BMSCs still remained poorly understood...
October 2018: Iranian Journal of Basic Medical Sciences
Yingying Wang, Shizhang Wei, Tian Gao, Yuxue Yang, Xiaohua Lu, Xuelin Zhou, Haotian Li, Tao Wang, Liqi Qian, Yanling Zhao, Wenjun Zou
Li-Ru-Kang (LRK), a formula of eight traditional Chinese medicines (TCM), has been used to treat hyperplasia of mammary gland (HMG) in TCM clinics. However, how LRK works in HMG patients is unclear. To explore the possible mechanisms of LRK against HMG, the network pharmacology was used to screen the potential targets and possible pathways that involved in LRK treated HMG. Rat HMG model induced by estrogen and progesterone was used to further verify the effects of the key molecules of LRK selected from the enriched pathways on HMG...
2018: Frontiers in Pharmacology
Zhi Liu, Yang Zhong, Yu Jian Chen, Hui Chen
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality. Identifying key molecules involved in the regulation of HCC development is of great clinical significance. SOX11 is a transcription factor belonging to group C of Sry-related HMG box family whose abnormal expression is frequently seen in many kinds of human cancers. Here, we reported that the expression of SOX11 was decreased in human HCC tumors than that in matched normal tissues. Overexpression of SOX11 promoted growth inhibition and apoptosis in HCC cell line HuH-7...
December 5, 2018: Biotechnology and Applied Biochemistry
Linan Zhang, Jinku Li, Hao Wu, Yingxia Li
Saccharina japonica undergoes an alternating life cycle during which the diploid sporophyte generation alternates with the monoploid gametophyte generation. Saccharina japonica uses the UV sex determination system to determine the sex of its haploid gametophytes. However, the sex-determining genes and the sex-determining mechanisms of kelp gametophytes have not been thoroughly elucidated to date. In this study, a kelp HMG-box-containing gene (SjHMG), which is located within the sex determination region (SDR) of S...
December 5, 2018: Journal of Phycology
Shi-You Jiang, Hui Li, Jing-Jie Tang, Jie Wang, Jie Luo, Bing Liu, Jin-Kai Wang, Xiong-Jie Shi, Hai-Wei Cui, Jie Tang, Fan Yang, Wei Qi, Wen-Wei Qiu, Bao-Liang Song
Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure-activity relationship analysis of sterol analogs...
December 3, 2018: Nature Communications
Qian Chen, Chaoliang Xiong, Kunyun Jia, Jing Jin, Ziyang Li, Yazhou Huang, Yewen Liu, Lingling Wang, Haitao Luo, Haiyan Li, Qing H Meng, Wei Li
To elucidate the transcriptomic changes of long noncoding RNAs (lncRNAs) in high-fat diet (HFD)-fed mice, we defined their hepatic transcriptome by RNA sequencing. Aberrant expression of 37 representative lncRNAs and 254 protein-coding RNAs were observed in the livers of HFD-fed mice with insulin resistance compared with that from control mice. Of these, 24 lncRNAs and 179 protein-coding RNAs were upregulated, whereas 13 lncRNAs and 75 protein-coding RNAs were downregulated. Functional analyses showed that the aberrantly expressed protein-coding RNAs were enriched in various lipid metabolic processes and in the insulin signaling pathway...
November 30, 2018: Journal of Lipid Research
Qinghao Song, Zhen Li, Rouke Chen, Xiaopan Ma, Xiang Xiao, Jun Xu
The discovery of hyperthermophiles has dramatically changed our understanding of the habitats in which life can thrive. However, the extreme high temperatures in which these organisms live have severely restricted the development of genetic tools. The archaeon Pyrococcus yayanosii A1 is a strictly anaerobic and piezophilic hyperthermophile that is an ideal model for studies of extreme environmental adaptation. In the present study, we identified a high hydrostatic pressure (HHP)-inducible promoter (P hhp ) that controls target gene expression under HHP...
November 30, 2018: Applied and Environmental Microbiology
Denghui Zhu, Rong Huang, Liangming Chen, Peipei Fu, Lifei Luo, Libo He, Yongming Li, Lanjie Liao, Zuoyan Zhu, Yaping Wang
T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) proteins from the High Mobility Group (HMG) box family act as the main downstream effectors of the Wnt signaling pathway. HMGB proteins play multifaceted roles in the immune system of mammals. To clarify the immunological characteristics of LEF/TCF genes in grass carp (Ctenopharyngodon idella), five LEF/TCF genes (TCF7, LEF1, TCF7L1A, TCF7L1B, and TCF7L2) were identified and characterized. All five LEF/TCF proteins contained two characteristic domains: a HMG-BOX domain and a CTNNB1_binding region...
November 27, 2018: Fish & Shellfish Immunology
Jian Hou, Yan Long, Bo Hu, Shaojie Huang, Guangtao Xu, Tesheng Gao, Fenfang Wu, Yinxiong Li, Zhong-Kai Wu
BACKGROUND/AIMS: Hepatocyte-like cells derived from human pluripotent stem cells could be an important cell source for hepatocyte transplantation. The present study investigated the effect of retaining mTeSR1 medium during hepatic differentiation on hepatocyte-like cells in vitro. METHODS: Human embryonic stem cell line H1 were treated with activin A and bone morphogenetic protein 4 (BMP4) for definitive endoderm (DE) cell induction and subsequently treated with BMP2 and fibroblast growth factor 4 (FGF4) for early hepatic cell induction...
November 29, 2018: Cellular Physiology and Biochemistry
Stephanie A Heeney, Shelby L Tjugum, Morgan E Corkish, Ian B Hollis
BACKGROUND: Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins, however little data exists using high intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus...
November 28, 2018: Clinical Transplantation
Feijun Ye, Wenli Cao, Jing Lin, Yan Du, Likun Lan, Ying Dong, Jun Zhu, Qi Zhou, Xinyao Pan, Youhui Lu, Fang Zeng, Bangshi Xia, Ling Wang
To compare the clinical outcomes of intrauterine insemination (IUI) with or without ovulation induction (OI), IUI cycles from January 2008 to December 2017 in Zhoushan Maternity and Child Healthcare Hospital were included, consisting of 455 natural cycles and 536 OI cycles. The overall clinical pregnancy rate did not differ between the two groups (P > 0.05). Stratified by OI medications such as clomiphene (CC), human menopausal gonadotropin (HMG) and follicle stimulating hormone (FSH), the pregnancy rates in HMG, CC, CC+HMG, and FSH/FSH+HMG groups were 11...
2018: Bioscience Trends
Clauber Henrique Souza da Costa, Amanda Ruslana Santana Oliveira, Alberto M Dos Santos, Kauê Santana da Costa, Anderson Henrique Lima E Lima, Cláudio N Alves, Jerônimo Lameira
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is mainly involved in the regulation of cholesterol biosynthesis. HMGR catalyses the reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate at the expense of two NADPH molecules in a two-step reversible reaction. In the present study, we constructed a model of human HMGR (hHMGR) to explore the conformational changes of HMGR in complex with HMG-CoA and NADPH. In addition, we analysed the complete sequence of the Flap domain using molecular dynamics (MD) simulations and principal component analysis (PCA)...
November 23, 2018: Journal of Biomolecular Structure & Dynamics
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