Niacin ameliorates ulcerative colitis via prostaglandin D2 ‐mediated D prostanoid receptor 1 activation
Abstract
Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced col...
Source: EMBO Molecular Medicine - March 1, 2017 Category: Molecular Biology Authors: Juanjuan Li, Deping Kong, Qi Wang, Wei Wu, Yanping Tang, Tingting Bai, Liang Guo, Lumin Wei, Qianqian Zhang, Yu Yu, Yuting Qian, Shengkai Zuo, Guizhu Liu, Qian Liu, Sheng Wu, Yi Zang, Qian Zhu, Daile Jia, Yuanyang Wang, Weiyan Yao, Yong Ji, Huiyong Yin, M Tags: Research Article Source Type: research
NRAS destines tumor cells to the lungs
In conclusion, NRAS promotes the colonization of the lungs by various tumor types in mouse models. IL‐8‐related chemokines, NRAS signaling partners in this process, may constitute an important therapeutic target against pulmonary involvement by cancers of other organs.
Mutations in the NRAS oncogene are shown to promote lung metastasis by regulating chemokine expression in tumor cells and hence their affinity for the pulmonary vasculature and their ability to form metastatic niches. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - March 1, 2017 Category: Molecular Biology Authors: Anastasios D Giannou, Antonia Marazioti, Nikolaos I Kanellakis, Ioanna Giopanou, Ioannis Lilis, Dimitra E Zazara, Giannoula Ntaliarda, Danai Kati, Vasileios Armenis, Georgia A Giotopoulou, Anthi C Krontira, Marina Lianou, Theodora Agalioti, Malamati Vreka Tags: Research Article Source Type: research
Moving molecular medicine
Incoming Chief Editor Philippe Sansonetti shares his vision of the role of the journal in the burgeoning areas of molecular medicine.
Incoming Chief Editor Philippe Sansonetti shares his vision of the role of the journal in the burgeoning areas of molecular medicine. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Philippe J Sansonetti Tags: Editorial Source Type: research
Pre ‐clinical validation of a selective anti‐cancer stem cell therapy for Numb‐deficient human breast cancers
Abstract
The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb‐knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb‐deficient human BCs could represent a novel anti‐CSC therapy. Here, using patient‐derived xenografts, we show that expansion of the CSC pool...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Daniela Tosoni, Sarah Pambianco, Blanche Ekalle Soppo, Silvia Zecchini, Giovanni Bertalot, Giancarlo Pruneri, Giuseppe Viale, Pier Paolo Di Fiore, Salvatore Pece Tags: Research Article Source Type: research
Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti ‐tumor immunity with superior safety in bladder cancer models
Abstract
Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high‐grade disease, Bacillus Calmette–Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell‐cycle‐regulated small subunit of ribonucleotide reductase (RRM2). The F4L‐deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor‐selective ...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Kyle G Potts, Chad R Irwin, Nicole A Favis, Desmond B Pink, Krista M Vincent, John D Lewis, Ronald B Moore, Mary M Hitt, David H Evans Tags: Research Article Source Type: research
TFE3 regulates whole ‐body energy metabolism in cooperation with TFEB
Abstract
TFE3 and TFEB are members of the MiT family of HLH–leucine zipper transcription factors. Recent studies demonstrated that they bind overlapping sets of promoters and are post‐transcriptionally regulated through a similar mechanism. However, while Tcfeb knockout (KO) mice die during early embryonic development, no apparent phenotype was reported in Tfe3 KO mice. Thus raising the need to characterize the physiological role of TFE3 and elucidate its relationship with TFEB. TFE3 deficiency resulted in altered mitochondrial morphology and function both in vitro and in vivo due to compromised mitochondrial dynamic...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Nunzia Pastore, Anna Vainshtein, Tiemo J Klisch, Andrea Armani, Tuong Huynh, Niculin J Herz, Elena V Polishchuk, Marco Sandri, Andrea Ballabio Tags: Research Article Source Type: research
Ethics of stem cell ‐derived gametes made in a dish: fertility for everyone?
A timely and thoughtful discussion of the ethical challenges and societal impacts presented by the recent reports demonstrating the successful in vitro generation of functional gametes from somatic and pluripotent stem cells. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Annelien L Bredenoord, Insoo Hyun Tags: Opinion Source Type: research
Supraphysiological levels of GDF11 induce striated muscle atrophy
Abstract
Growth and differentiation factor (GDF) 11 is a member of the transforming growth factor β superfamily recently identified as a potential therapeutic for age‐related cardiac and skeletal muscle decrements, despite high homology to myostatin (Mstn), a potent negative regulator of muscle mass. Though several reports have refuted these data, the in vivo effects of GDF11 on skeletal muscle mass have not been addressed. Using in vitro myoblast culture assays, we first demonstrate that GDF11 and Mstn have similar activities/potencies on activating p‐SMAD2/3 and induce comparable levels of differentiated myotube a...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: David W Hammers, Melissa Merscham ‐Banda, Jennifer Ying Hsiao, Stefan Engst, James J Hartman, H Lee Sweeney Tags: Research Article Source Type: research
STAT3 promotes IFN γ/TNFα‐induced muscle wasting in an NF‐κB‐dependent and IL‐6‐independent manner
Abstract
Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While the multifactorial nature of this syndrome and the implication of cytokines such as IL‐6, IFNγ, and TNFα is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFNγ/TNFα promotes the phosphorylation of STAT3 on Y705 residue in the cytoplasm of muscle fibers by activating JAK kinases. Unexpectedly, this effect occurs both in vitro and in vivo independently of IL‐6, which is considered a...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Jennifer F Ma, Brenda J Sanchez, Derek T Hall, Anne ‐Marie K Tremblay, Sergio Di Marco, Imed‐Eddine Gallouzi Tags: Research Article Source Type: research
Sodium leak through K2P potassium channels and cardiac arrhythmia, an emerging theme
In this issue of EMBO Molecular Medicine, Decher et al () identify a point mutation in the K2P2 (TREK‐1) potassium (K+) channel that changes function in just those ways expected to predispose to right ventricular outflow tract (RVOT) ventricular tachycardia (VT) in the patient they study. Whereas wild‐type channels are selective for K+ and inhibited by β‐adrenergic stimulation, mutant I267T channels pass sodium (Na+) into the cells, even during β‐adrenergic stimulation, and are more active in response to membrane stretch, changes predicted to enhance cardiac myocyte excitability. The report contributes to accumu...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Steve AN Goldstein Tags: News & Views Source Type: research
Gene signature driving invasive mucinous adenocarcinoma of the lung
Abstract
Though invasive mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung Tumor Signature of 143 genes, which was unexpectedly enriched in mucin‐producing gastrointestinal, pancreatic, and breast cancers. The signature genes included transcription factors FOXA3, SPDEF, HNF4A, mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1/B7‐H4 (but not PD‐L1/B7‐H1). Important...
Source: EMBO Molecular Medicine - February 28, 2017 Category: Molecular Biology Authors: Minzhe Guo, Koichi Tomoshige, Michael Meister, Thomas Muley, Takuya Fukazawa, Tomoshi Tsuchiya, Rebekah Karns, Arne Warth, Iris M Fink ‐Baldauf, Takeshi Nagayasu, Yoshio Naomoto, Yan Xu, Marcus A Mall, Yutaka Maeda Tags: Research Article Source Type: research
Faecal microbiota transplantation protects against radiation ‐induced toxicity
Abstract
Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation‐induced toxicity. High‐throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improve...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Ming Cui, Huiwen Xiao, Yuan Li, Lixin Zhou, Shuyi Zhao, Dan Luo, Qisheng Zheng, Jiali Dong, Yu Zhao, Xin Zhang, Junling Zhang, Lu Lu, Haichao Wang, Saijun Fan Tags: Research Article Source Type: research
SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress‐provoked ventricular arrhythmia, which also manifests sinoatrial node (SAN) dysfunction. We recently showed that SK4 calcium‐activated potassium channels are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here SK4 channels were identified in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) from healthy and CPVT2 patients bearing a mutation in calsequestrin 2 (CASQ2‐D307H) and in SAN cells from WT and CASQ2‐D307H knock‐in (KI) mice. TRAM‐34, a selective blocker of SK4...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Shiraz Haron ‐Khun, David Weisbrod, Hanna Bueno, Dor Yadin, Joachim Behar, Asher Peretz, Ofer Binah, Edith Hochhauser, Michael Eldar, Yael Yaniv, Michael Arad, Bernard Attali Tags: Research Article Source Type: research
A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence
Abstract
Klebsiella pneumoniae is an important cause of multidrug‐resistant infections worldwide. Recent studies highlight the emergence of multidrug‐resistant K. pneumoniae strains which show resistance to colistin, a last‐line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB‐associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K. pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inf...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Timothy J Kidd, Grant Mills, Joana S á‐Pessoa, Amy Dumigan, Christian G Frank, José L Insua, Rebecca Ingram, Laura Hobley, José A Bengoechea Tags: Research Article Source Type: research
VEGFA activates an epigenetic pathway upregulating ovarian cancer ‐initiating cells
Abstract
The angiogenic factor, VEGFA, is a therapeutic target in ovarian cancer (OVCA). VEGFA can also stimulate stem‐like cells in certain cancers, but mechanisms thereof are poorly understood. Here, we show that VEGFA mediates stem cell actions in primary human OVCA culture and OVCA lines via VEGFR2‐dependent Src activation to upregulate Bmi1, tumor spheres, and ALDH1 activity. The VEGFA‐mediated increase in spheres was abrogated by Src inhibition or SRC knockdown. VEGFA stimulated sphere formation only in the ALDH1+ subpopulation and increased OVCA‐initiating cells and tumor formation in vivo through Bmi1. In ...
Source: EMBO Molecular Medicine - January 31, 2017 Category: Molecular Biology Authors: Kibeom Jang, Minsoon Kim, Candace A Gilbert, Fiona Simpkins, Tan A Ince, Joyce M Slingerland Tags: Research Article Source Type: research
